CN107427471A - The nano-carrier delivery system of lyophobic dust - Google Patents
The nano-carrier delivery system of lyophobic dust Download PDFInfo
- Publication number
- CN107427471A CN107427471A CN201680017476.3A CN201680017476A CN107427471A CN 107427471 A CN107427471 A CN 107427471A CN 201680017476 A CN201680017476 A CN 201680017476A CN 107427471 A CN107427471 A CN 107427471A
- Authority
- CN
- China
- Prior art keywords
- nano
- delivery system
- carrier delivery
- tocotrienols
- lipoid plastid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/644—Transferrin, e.g. a lactoferrin or ovotransferrin
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Organic Chemistry (AREA)
- Optics & Photonics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of nano-carrier delivery system of lyophobic dust, includes Nanoparticulate compositions.The nano particle includes surfactant, cholesterol, hydrophilic polymer, the functionalized polymeric containing carboxyl end groups, chemical linking agent and the targeting proteins of ascorbyl palmitate.A kind of method for producing nano particle and the nano particle are used for the purposes for preparing the medicine in the treatment and/or prevention of cancer and cancer related disorders.
Description
Technical field
Present invention relates in general to nano-carrier delivery system.More particularly the invention relate to encapsulate hydrophobicity
The nano particle of material such as tocotrienols, specifically lipoid plastid (niosome, vesicle), produce the nano-carrier
Method and for treating cancer and the medicine obtained of cancer related disorders.
Background technology
Nano particle research is currently the various potential applications due to biomedical, optics and electronic applications and caused strong
The field of scientific interest.Regardless of its size, integral material (bulk material) should have constant physical property, but
It is the size-dependent matter for often observing nanoscale.Therefore, when it is closely sized to nanoscale, the property of material changes
Become.These properties are favourable in many commercial Applications.One of favorable property of nano particle is their ability to be suspended in fluid
In, density variation is overcome because the interaction of particle surface and solvent is powerful enough, otherwise density variation would generally be led
Cause material sedimentation or floating in a liquid.
Nano particle is connectable to the biomolecule for potentially acting as address tag (address tags), so as to which this be received
Rice grain is guided to internal specific site.Liposome (liposome) and lipoid plastid are applied to this purpose.
Liposome is the spherical vesicles (vesicle) for the artificial preparation being made up of lamellar phase double-layer of lipoid, and lipoid is
Spherical vesicles based on nonionic surfactant, mainly it is incorporated to by nonionic surfactant and as the cholesterol of excipient
And formed.Lipoid plastid is structurally similar to double-deck liposome, however, making it for the material for preparing lipoid plastid
It is more stable, therefore lipoid plastid provides more the advantages of being better than liposome.Lipoid plastid can be by protecting molecule from life
Substance environment and improve curative properties and improve the bioavilability of the molecule, cause by by medicine effect be limited to targeting it is thin
Born of the same parents and obtain more preferable availability and controlled medicine delivery.
It is believed that a kind of compound for targeted delivery is γ-tocotrienols.Tocotrienols is vitamin E group
The member of (the body essential nutrients for serving as antioxidant).Tocotrienols is in selection vegetable oil, including rice bran oil and palm fibre
Palmitic acid oil, wheat embryo, barley, saw palmetto (saw palmetto), Arnotto (anatto) and some other kinds of seeds, heavily fortified point
Fruit, cereal, and the native compound by being found in its derivative oil.Compared with remaining, palm oil contains special high concentration
Tocotrienols (in its vitamin E content be up to 70%).Tocotrienols is a kind of effective antioxidant, because
Its unsaturated terminal chain helps to penetrate into brain and the saturated fat layer of liver.This can aid in protection sex resistance apoplexy and nerve moves back
Row disease.Tocotrienols can also reduce tumour formation, DNA damage and cellular damage and reduce cholesterol.
It is its high hydrophobicity to prepare one of major obstacle of pharmaceutical composition of tocotrienols.Low aqueous solubility solubility limits
The effect of having made medicine, limit its clinical practice.Routine techniques for improving solubility utilizes organic solvent, surface-active
Agent, microemulsion etc..However, these methods are not always effective, and need at least 15:1 and up to 1000:1 it is very high
Excipient and drug ratio, this may cause with medicine in itself compared with, adverse side effect is caused due to the high excipient of concentration.
There is the method for several bioavilabilities that lyophobic dust is improved using nano particle.PCT publication WO 2011/
028757A1 discloses a kind of tocotrienols composition, and it includes one group of diameter about 250-1000nm particle, wherein this
Grain is made up of tocotrienols, non-tocotrienols lipid and surfactant.Said composition and statins (statin)
It is used as pharmaceutical composition together.The statins and tocotrienols are encapsulated in the lipid carrier of nanometer construction.With not having
The absorption rate for having the tocotrienols of non-tocotrienols lipid is compared, and the lipid carrier of this nanometer construction adds fertility three
Alkene phenol enters the absorptivity of tissue.However, the particle does not include the targeted molecular for being used for the targeted delivery tocotrienols.This
Outside, the particle diameter of the said composition of the PCT publication is 250-1000nm, and this is significantly greater than the IUPAC definition of nano particle.It is larger
Particle diameter will cause the heterogeneity of particle in itself.Under larger size, particle can also lose nanoparticle suspension in stream
Ability in body, this will cause the particle to be separated with suspension.
Two periodical publications that one of inventor delivers, Fu, et al., 20091And Fu, et al., 20112, disclose
The method that tocotrienols is encapsulated in lipoid plastid, the lipoid plastid are combined with transferrin molecules with targeted delivery to tumour
Cell.Said preparation has used Span 60 as the principal surfactant in lipoid plastid making.In the publication of 2011
In, the particle diameter of the particle of the combination is 341nm according to surveying and determination, is limited far above the nanoparticle size defined by IUPAC, and 2009
Particle diameter in year publication is determined to 137nm.It has been found that the preparation of 2009 and publication in 2011 is unstable;It is high
Particle up to 30% can prematurely discharge the tocotrienols of encapsulating.Also it has been found that said preparation can lump in freeze-drying
(cake) and coalesce and (agglomerate, reunite), so as to generate the problem of said preparation is made into pharmaceutical composition.
Therefore, it is necessary to which a kind of nano-carrier delivery system, lyophobic dust is delivered to the cell of targeting by it, and is steady
It is fixed and nontoxic, it is suitable for producing pharmaceutical composition.Therefore, present invention seek to address that in these problems of prior art one
It is a little or whole.
1Fu, J.Y., Blatchford, D.R., Tetley, L.&Dufes, C., 2009.Tumor regression
after systemic administration of tocotrienol entrapped in tumor-targeted
Niosomes.Journal of Controlled Release, Issue 140, pp.95-99.
2Fu, J.Y.et al., 2011.Novel tocotrienol-entrapping niosomes can
eradicate solid tumors after intravenous administration.Journal of Controlled
Release, Issue 154, pp.20-23.
The content of the invention
According to an aspect of the invention, there is provided a kind of nanometer of lyophobic dust comprising Nanoparticulate compositions carries
Body delivery system.The nano particle includes following components:
Surfactant comprising ascorbyl palmitate;
Cholesterol;
Hydrophilic polymer;
Functionalized polymeric containing carboxyl end groups;
Chemical linking agent;With
Targeting proteins.
The targeting proteins form the targeted nano for strengthening targeted delivery of the lyophobic dust in mammal body
Grain, and the nano particle has improved storage stability, has the degradation rate less than about 5%.The nano particle is a kind of
Lipoid plastid substantially spherical in shape.The particle diameter of the lipoid plastid is less than 150nm.
In one embodiment, ascorbyl palmitate has Nanoparticulate compositions 0.5-1.00 mole
Than.
In another embodiment, cholesterol is 3 beta-hydroxy -5- cholestene, the β -ol of 5- cholestene -3.The nano particle
The mol ratio of cholesterol is 0.5-1.00 in composition.
In another embodiment, hydrophilic polymer is vitamin E TPGS (TPGS).TPGS mol ratio is should
The 0.1-0.2 of Nanoparticulate compositions.
In one embodiment, functionalized polymeric is DSPE-PEG (2000) carboxylic acid.DSPE-PEG (2000) carboxylic acid
Mol ratio be the Nanoparticulate compositions 0.02-0.06.
In another embodiment, chemical linking agent is 1- ethyls -3- [3- dimethylaminopropyls] carbon imidodicarbonic diamide
Hydrochloride (EDC) and/or Sulfo-N-hydroxy succinimide (Sulfo-NHS).The molar concentration of the chemical linking agent is received for this
The 0.09M of rice grain composition.
In another embodiment, targeting proteins are transferrins.The molar concentration of the transferrins is the nanometer
The 60mg/ml of grain composition.
In the second aspect of the present invention, there is provided a kind of method for producing nano-carrier delivery system, wherein this method
Comprise the following steps:
I) lyophobic dust is dissolved in organic solvent to form hydrophobic sol;
Ii) hydrophobic sol is mixed with surfactant, cholesterol and hydrophilic polymer unpurified molten to generate
Liquid;
Iii) excessive organic solvent is removed to form desciccator diaphragm from the unpurified solution;
Iv film hydration will) be dried into suspension;
V) chemical linking agent in cushioning liquid is provided separately to produce buffer suspension;
Vi) unpurified lipoid plastid is mixed into the buffer suspension;
Vii targeting proteins solution) is then added;
Viii obtained mixture) is purified;With
Ix) it is freeze-dried obtained mixture.
In one embodiment, organic solvent is hexane and methanol.The hexane that is added and the organic solvent of methanol
Ratio is 9:1.
In another embodiment, the hydration step in step (iv) used phosphate buffer (PBS,
phosphate buffered saline)。
In another embodiment, the cushioning liquid used in step (v) is 2-ethanesulfonic acid (MES).
In a single embodiment, targeting proteins solution includes transferrins and PBS.
A kind of lyophobic dust that can be encapsulated in the nano-carrier delivery system of the present invention is γ-tocotrienols.
In another aspect of the present invention, nano-carrier delivery system gives mammalian therapeutic cancer and cancer for preparation
The medicine of disease associated conditions.The medicine can be given so that about 5mg/kg to about 500mg/kg body weight effective dose is oral or intravenous
Give, treatment phase is 10-60 days.
It is an object of the invention to provide one kind be used for encapsulate lyophobic dust (but not exclusively for encapsulating γ-fertility triolefin
Phenol) nano-carrier delivery system, for preparing pharmaceutical composition.
The nano-carrier delivery system of the present invention and the medicine obtained are provided and will be expanded on further in lower page
Various advantages.
Brief description of the drawings
Following description is carried out to embodiment by reference to accompanying drawing and illustrates the present invention, but not limited to this, wherein:
Fig. 1, which illustrates, to be remained in DSPE-PEG- lipoid plastids in different time points after 3-5 DEG C of storage and turns iron
The percentage curve of tocotrienols in protein binding lipoid plastid (transferrin-conjugated niosomes)
Figure.Result is the average value ± SD analyzed in triplicate.
Fig. 2 illustrates the tocotrienols extracted from nano particle and PMC chromatogram.
Fig. 3 illustrates the fertility of the lipoid plastids of Span 60 release of the storage at 4 DEG C in 30 days determined in triplicate
The percentage curve figure of trienol.
Embodiment
The present invention relates to a kind of nano particle comprising for encapsulating lyophobic dust such as tocotrienols, particularly lipoid
The nano-carrier delivery system of plastid, the pharmaceutical composition for producing the method for the nano-carrier and obtaining.
Nanoparticulate compositions
The nano particle of the present invention mainly includes surfactant, cholesterol, hydrophilic polymer, the official containing carboxyl end groups
Can fluidized polymer, chemical linking agent, targeting proteins and lyophobic dust.
Any suitable surfactant can be used.It is preferred that ascorbyl palmitate (AP) is used to be used as surface-active
Agent.AP is added in Nanoparticulate compositions with 0.5-1.00 mol ratio.Preferred molar ratio is 1.00.
AP is a kind of vitamin C analog, biodegradable, and can be metabolized completely by human body, so that toxicity is made
With minimum.AP is also biocompatibility, and inflammatory and immune response when giving people with minimum.
Any suitable cholesterol can be used.In the present invention, 3 beta-hydroxy -5- cholestene, 5- cholestene -3 have been used
β -ol is as cholesterol components.The cholesterol components are added in Nanoparticulate compositions with 0.5-1.00 mol ratio.It is excellent
Selection of land, mol ratio 0.5.
Cholesterol is the key component for making the nano particle, because cholesterol and surface active agent composition can align with shape
Into the double-layer of lipoid of lipoid plastid characteristic.Because lipoid plastid is nonionic, the liposome similar to structure is on the contrary, therefore
Lipoid plastid is more stable in chemistry compared with liposome and has longer storage life, and this provides more advantages.
Any suitable hydrophilic polymer can be used.In the present invention, used also referred to as vitamin E TPGS or
Abbreviation TPGS D- alpha-tocopherol cetomacrogol 1000 succinates are as hydrophilic polymer components.TPGS is with 0.1-0.2's
Mol ratio is added in Nanoparticulate compositions.Preferably, mol ratio 0.2.
Any suitable functionalized polymeric can be used.In the present invention, also referred to as DSPE-PEG (2000) has been used
1,2- distearyl acyl group-sn- glyceryl -3- phosphoethanolamines-the N- [carboxyl (polyethylene glycol) -2000] of carboxylic acid are used as functionalization
Polymers compositions.DSPE-PEG (2000) carboxylic acids are added in Nanoparticulate compositions with 0.02-0.06 mol ratio.It is preferred that
Ground, mol ratio 0.04.
Hydrophilic polymer and functionalized polymeric play cosurfactant (co- in the formation of nano particle
Surfactant effect).Surfactant molecule-AP, TPGS and DSPE-PEG (2000), it is intended to by its own with
Under type orients:Outwardly, and hydrophobic side is facing with each other so as to forming bilayer for the water-wet side of the nonionic surfactant.By
All it is nonionic molecule in TPGS and DSPE-PEG (2000), together with AP and cholesterol, they form nonionic lipids plastid.
Lipoid plastid has the compatibility of height with biosystem due to its non-ionic nature and is hypotoxicity.
Chemical linking agent is that covalently bound crosslinking agent is carried out between functionalized polymeric and targeting proteins.Covalent bond ensures
The sufficiently stable property of conjugate.
Any suitable chemical linking agent can be used.In the present invention, 1- ethyls -3- [3- dimethylaminos have been used
Propyl group] carbon imidodicarbonic diamide hydrochloride (EDC) and Sulfo-N-hydroxy succinimide (Sulfo-NHS) be used as chemical linking agent group
Point.The chemical linking agent component is added in Nanoparticulate compositions with 0.09M molar concentration.
Carboxylate on functionalized polymeric is reacted with EDC so as to form unstable ester.It is to improve ester to add NHS
The stability and solubility of intermediate, it will react with the amido on targeting proteins.This will be illustrated in the following paragraphs.
Any suitable targeting proteins can be used.In the present invention, it is used as targeting proteins component using transferrins.Turn
Ferritin is added in Nanoparticulate compositions with molar concentration 60mg/ml.
Transferrins is that one kind transports iron and specific recognition its acceptor i.e. TfR in mammal body
Protein.Because iron is to the high demand of tumour growth, thus TfR is generally overexpressed in cancer cell.Therefore,
Transferrins may be used as by the way that transferrins is combined with by the molecule of delivering active ingredients to cell that active component is special
The opposite sex is delivered to the targeting strategy of cancer cell.
The nano-carrier of the present invention can encapsulate any suitable lyophobic dust.One example is γ-tocotrienols
(tocotrienols).Tocotrienols can be added in Nanoparticulate compositions with 0.24M mol ratio.
Targeting proteins are attached on lipoid plastid, its by serve as by guide the lipoid plastid to body specific cells (such as
Cancer cell) address tag.Because tocotrienols is encapsulated in lipoid plastid, thus tocotrienols is from biotic environment
Influence, while in blood by the way that medicine effect to be limited to internal specific cells and causes to obtain more preferable bioavilability
And targeted delivery.
The nanoparticle formulations of the present invention can be used for encapsulating hydrophilic molecule (replacement hydrophobic molecule).Lipoid plastid
Hydrophobic drug can be embedded in the vesicle bilayer film at lipoid plastid center, also hydrophilic medicament can be encapsulated in lipoids
In the aqueous compartments at body center.
It was surprisingly found that with document Fu, et al., 2009 and Fu, et al., the two kinds of foregoing systems delivered in 2011
Agent is compared, and the nanoparticle formulations are significantly more stable.In the publication of 2009 and 2011, said preparation stores 30 at 4 DEG C
Discharged too early by tocotrienols 30% after it.To the test result such as embodiment 8 of the preparation of publication in 2009 and 2011
Shown in.
It has been found that the preparation of the present invention remains in that stabilization after being stored 2 months at 4 DEG C, degraded is less than 5%.This is as implemented
Shown in example 6.
The method for preparing Nanoparticulate compositions
The preparation method of Nanoparticulate compositions mainly includes the following steps that:
I) lyophobic dust is dissolved in organic solvent to form hydrophobic sol;
Ii) hydrophobic sol is mixed with surfactant, cholesterol and hydrophilic polymer unpurified molten to produce
Liquid;
Iii) excessive organic solvent is removed to form desciccator diaphragm from the unpurified solution;
Iv) by the drying film hydration into suspension;
V) chemical linking agent in cushioning liquid is provided separately to produce buffer suspension;
Vi) unpurified lipoid plastid is mixed into the buffer suspension;
Vii targeting proteins solution) is then added;
Viii obtained mixture) is purified;With
Ix) it is freeze-dried obtained mixture.
Any suitable organic solvent can be used in step (i).Preferably, lived using hexane and methanol as surface
Property agent.The ratio of hexane and methanol is by volume 9:1.Lyophobic dust and organic solvent mixing are hydrophobic to generate until uniformly
Solution.
In step (ii), then surfactant, cholesterol and hydrophilic polymer are added in hydrophobic solvent, and
Mix until uniformly to generate unpurified solution.
Any suitable method for removing excessive solvent from the unpurified solution may be used to step
(iii).It is, for example, possible to use rotary evaporator removes excessive solvent.When removing excessive solvent, in the rotary evaporator
Flask walls on form thin desciccator diaphragm.
In step (iv), any hydration process can be used.In the present invention, phosphate buffer can be used
(PBS) desciccator diaphragm is hydrated into suspension at room temperature, then with 80% probe sonication 4 minutes of maximum output.
In step (v), buffering liquid suspensions are provided separately by mixed chemical bridging agent and cushioning liquid.It can make
With any suitable cushioning liquid.It is, for example, possible to use 2-ethanesulfonic acid (MES) is used as cushioning liquid.Chemical linking agent and buffering
Solution is mixed until uniformly to generate buffer suspension.
Then the lipoid plastid that do not purify by the storage from step (vi) is added in buffer suspension, and at room temperature
Incubate 15 minutes, while be gently mixed until uniform.
Targeting proteins solution is added after this step.Before targeting proteins solution is added, by step (vii) mixture
Adjust to pH 7-8.Any suitable pH adjusting agent can be used.For example, sodium hydroxide is used for the pH value for adjusting the present invention.
Targeting proteins solution includes targeting proteins and solvent.Any suitable targeting proteins can be used.For example, in this hair
It is bright middle to use transferrins as targeting proteins.Targeting proteins are dissolved in phosphate buffer (PBS) and target egg to obtain
White solution.Mixing 3 hours is stirred at room temperature in the solution obtained, until uniformly from combining.
Then by the purifying mixture obtained to remove any uncombined material.Any suitable purifying can be used
Method.For example, using 4 DEG C of operation temperature with 41,000rpm ultracentrifugations 3 hours, for purifying obtained mixture, from
And obtain the transferrins combination lipoid plastid only purified.
After the mixture that purifying obtains, then the mixture is freeze-dried.Any suitable freezing can be used
Drying means.It is, for example, possible to use Freezone Labconco lyophilization systems.By the mixture in -84 DEG C of freeze-dryings
24 hours with generation suitable for storage and the stable powder for being used subsequently to prepare medicine.
The purposes of lyophilized lipoid plastid
The invention provides the new application of the transferrins combination lipoid plastid of the lipoid plastid comprising therapeutically effective amount.Class
Liposome is applied to treatment and/or pre- anti-cancer or cancer related disorders.
In another embodiment, the Nanoparticulate compositions comprising lipoid plastid can be processed as giving mammal
Such as people's treatment and/or the medicine of pre- anti-cancer or cancer related disorders.
The pharmaceutical composition can contain any other suitable additive, for promote the easy consumption of the medicine/to
Medicine and the shelf-life for extending the medicine.
Form can be suitably consumed using any.In one embodiment, can use such as pill, tablet,
The form of capsule, particle or liquid.
The medicine can be easy to be administered to patient with unit dose packaging.Any suitable packaging can be used.For example,
Blister package (blister pack) for tablet and capsule, bottle or use for liquid concentrate or liquid suspension
In the IV bags of intravenous therapy.
The medicine can with fix unit dose to give effectively treatment and/or pre- anti-cancer or cancer related disorders.Can
To use any suitable effective dose.Preferably, the effective dose is about 5 to about 500mg/kg body weight.The management phase can be with
It is any suitable length.Preferably, the management phase is about 10-60 days.
Embodiment
Following examples merely illustrate various aspects, the method and steps of present invention process method.These embodiments are simultaneously
The unrestricted present invention, the scope of the present invention are illustrated in the following claims.
Embodiment 1
Uncombined nano particle is prepared using film hydration method
It is determined that structure nano particle component, including a) surfactant, b) cholesterol, c) hydrophilic polymer, d) contain
The functionalized polymeric of carboxyl end groups, e) chemical linking agent and f) targeting proteins.
The component is prepared based on mol ratio as shown in table 1 below.
Table 1:The composition (mol ratio) of prepared preparation.
γ-tocotrienols is dissolved in the ORGANIC SOLVENT MIXTURES being made up of hexane and methanol first in round-bottomed flask
In.
Afterwards, with different mol ratios by ascorbyl palmitate (AP), cholesterol and hydrophilic polymer (TPGS)
It is added in the solvent.The solvent is removed at 50 DEG C by using rotary evaporator, until forming thin desciccator diaphragm on flask inwall.
Then the film is hydrated in room temperature with 10ml PBS, being then set in its 80% maximum output with the instrument carries out probe sonication
Processing 4 minutes.The purifying of lipoid plastid is carried out using ultracentrifugation (2 circulations, 41,000rpm, 4 hours, 25 DEG C).Each super
After centrifuge cycle, the lipoid plastid pill is set to suspend again with 10ml PBS.
The nano suspending liquid is freeze-dried and is used as pale powder to harvest.Then by the powder storage in preventing illumination
Desiccator (desiccator, drier) in.
Embodiment 2
Transferrins is bound on nano particle
In order to prepare transferrins combination lipoid plastid, using the cross linking procedure described in Ishida et al. and Paola et al..
First, EDC and sulfo-NHS is prepared in MES buffer solutions with 90 μm of ol/mL.Then, by 10mL EDC's and 10mL
Sulfo-NHS solution is added in the unpurified lipoid plastids of 10mL.The mixture incubates 15 minutes in ambient temperature with gentle stirring.
After incubation, the pH of the mixture is adjusted to pH 7-8 with 1.0M NaOH.Then, 2mL is added into the mixture
Transferrin solution (is prepared) using the 120mg transferrins in 2.0mL PBS.The mixture is incubated 3 hours again, together
When stirred in ambient temperature with gentle to combine.
Use and uncombined material is removed with 41,000rpm and 4 DEG C of ultracentrifugation for continuing 3 hours to obtain purifying
Transferrins combination lipoid plastid.The preparation of all lipoid plastids all carries out (- 84 DEG C of freezing dry process;24 hours) with generation
Stable powder.
Embodiment 3
Determine the drug encapsulation efficiency of transferrins combination nano particle
Based on encapsulation efficiency, size, zeta potential and form, the nano particle of preparation is optimized.Drug encapsulation efficiency quilt
The ratio between medicine total amount added in the medicine and such Liposomal formulation that are described as encapsulating in lipoid plastid, and drug loading efficiencies
It is the mass ratio for the drug quality and total carrier system being encapsulated in the lipoid plastid.Use the efficient liquid for vitamin E
Phase chromatogram (HPLC) quantitative approach determines the encapsulation efficiency and drug loading of nano-carrier.Size and zeta potential use Zetasizer
Nano ZS (a kind of system of the technology of particle diameter for being combined with measure protein, zeta potential and molecular weight) are measured.It is responsible for grain
The Brownian movement of the quantitative particle of the technical Analysis in footpath.Zeta potential is between the fixation liquid level around decentralized medium and discrete particles
Potential difference.It provides the estimation of the magnitude of the attraction and repulsive force between discrete particles.Therefore, by measuring zeta potential,
The stability of dispersion can be predicted.Use the form of transmission electron microscope (TEM) detection nano particle.TEM is related to high energy
Electron beam penetrates thin sample.The electronics interacts with the sample, subsequently forms image, there is provided than conventional light microscope more
High resolution ratio.
The present invention can produce particle diameter less than 150nm and the lipoid plastid of high uniformity (polydispersity index is less than 0.3).
According to display, encapsulation efficiency depends on the ratio between AP and cholesterol (as shown in table 2).
With the reduction of ratio, from 24.67% (preparation A1) to 3.51%, (preparation A5) is drastically reduced encapsulation efficiency.This
It was found that result with being proposed in Gopinath etc. (2004) is consistent, wherein using AP, cholesterol and cetyl phosphate to close
Into lipoid plastid.All lipoid plastids are all anion, because they have negative zeta potential value.
However, when the cholesterol level being incorporated to is higher than AP (preparation A4 and A5), zeta potential value become it is big (negative value diminishes,
become less negative).Because preparation A1 has highest encapsulation efficiency, therefore select the mol ratio of AP and cholesterol
Carry out further encapsulatings of the vitamin E TPGS into preparation.
Table 2:The physical characteristic of the lipoid plastid of different preparations.Data represent average value ± SD.
Preparation | Particle diameter/d.nm | Polydispersity index | Zeta potential/mV | Encapsulation efficiency/% |
A1 | 124±9 | 0.18±0.03 | -72±9 | 24.7±1.5 |
A2 | 130±1 | 0.22±0.01 | -79±2 | 22.2±1.4 |
A3 | 116±7 | 0.20±0.03 | -72±9 | 14.1±1.0 |
A4 | 131±3 | 0.15±0.03 | -62±7 | 8.0±0.5 |
A5 | 135±1 | 0.15±0.03 | -68±1 | 3.5±0.1 |
Embodiment 4
Hydrophilic polymer being incorporated into nanoparticle formulations
Hydrophilic polymer (TPGS) is incorporated in lipoid plastid preparation, causes encapsulation efficiency to be brought up to from 24.7%
42.9% (as shown in table 3).When TPGS mol ratio doubles, encapsulation efficiency improves up to 20%.Therefore, for synthesizing target
0.2 is fixed as to the TPGS of lipoid plastid mol ratio.
Table 3:The physical characteristic of the lipoid plastid coated with hydrophilic polymer.Data represent average value ± SD.
Embodiment 5
Functionalized polymeric being incorporated into nanoparticle formulations
According to table 4, the optimum mole ratio of DSPE-PEG (2000) carboxylic acid needed for synthesis targeting lipoid plastid is formulation C 2,
And joint efficiency is 13.13%, next to that C3 (11.80%) and C1 (7.84%).Therefore, mole of particle diameter and bridging agent lipid
Than indirectly proportional.In addition, there is moderate polydispersity by the targeting lipoid plastid of three kinds of different preparation generations, because
Their polydispersity index is fallen into 0.08-0.7.It is worth noting that, C2 also have in these three preparations it is minimum more
Monodispersity index.The lipoid plastid obtained is labeled as DSPE-PEG lipoid plastids.
Table 4:Target the physical characteristic of lipoid plastid.Data represent average value ± SD.
It can conclude that by the above results, the optimum proportioning for the nano-carrier not targetted is AP:Cholesterol:TPGS mol ratios are
1.0:0.5:0.2.For targetting lipoid plastid, AP:Cholesterol:TPGS:The optimum mole ratio of DSPE-PEG (2000) carboxylic acid is
1.0:0.5:0.2:0.04.The lipoid plastid meets spherical under the tem.
Embodiment 6
The stability test of nanoparticle formulations
DSPE-PEG lipoid plastids and transferrins combination lipoid plastid powder (every kind of 24mg) are dissolved separately in general
In 12mL PBS (2mg/mL) in bottle.By nano suspending liquid in the 3-5 DEG C of bottle for being stored in capping and lucifuge 2 months.Make
Parameter by the use of the percentage of the tocotrienols remained in lipoid plastid as evaluation lipoid plastid stability, because unstable
Property will be reflected in drug leakage and retain percent of drug reduction.To such after 2 weeks, 1 month and the Storage period of 2 months
Liposome is sampled.The color change of nano suspending liquid is observed, and is encapsulated in using HPLC methods measure in lipoid plastid
Tocotrienols content.The percentage of the tocotrienols of reservation is by the encapsulation efficiency after storing and the initial bag of tocotrienols
The ratio of envelope efficiency is calculated.
A collection of new DSPE-PEG lipoid plastids and transferrins combination lipoid plastid have been synthesized, has been existed with evaluating lipoid plastid
Stability during 3-5 DEG C of preservation.After production DSPE-PEG lipoid plastids and transferrins combination lipoid plastid, HPLC is used immediately
The content of standard measure tocotrienols.The encapsulation efficiency of DSPE-PEG lipoid plastids and transferrins combination lipoid plastid is respectively
41.35% and 26.82%.After 3-5 DEG C stores 2 months, 96.4% fertility triolefin is remained in DSPE-PEG lipoid plastids
Phenol, and 90.9% tocotrienols is remained in transferrins combination lipoid plastid, as shown in Figure 1.DSPE-PEG lipoids
Plastid and transferrins combination lipoid plastid keep stable in whole Storage period, because difference is not observed in tocotrienols content
It is different.Moreover, after the storage of 2 months, both without the coalescence that nano suspending liquid occurs, color change does not also occur.Therefore, can be with
Presumption, tocotrienols is encapsulated in the duplicature of lipoid plastid, rather than is adsorbed on the surface of lipoid plastid.
Embodiment 7
Use the quantitative tocotrienols of positive liquid chromatogram
Chromatographic isolation is carried out on 25 ± 1 DEG C of the analytical column based on silica is held in.Mobile phase by n-hexane, 1,
4- dioxanes and isopropanol (97.5:2:Mixture composition 0.5%v/v/v).Volume injected is set as 100 μ L, and flow velocity is fixed
It is set as that excitation wavelength is 295nm and launch wavelength is 325nm for 1mL/min, and detection.Before use, mobile phase ultrasound is de-
Gas 30 minutes.
The standard stock solution for γ-tocotrienols that concentration is 2000ppm is prepared in 20mL mobile phases.By using mobile phase
Appropriate serial dilution standard stock solution preparation work titer (200,100,50,10,5,0.1,0.05ppm).By using mobile phase
20mg PMC powder is dissolved to ultimate density and prepares 2,2,5,7,8- pentamethyl -6- hydroxy benzo dihydro pyrroles for 2000ppm
Mutter (PMC) be used as internal standard (IS) stoste.By using the mobile phase serial dilution IS stoste preparation work IS solution (100,10 and
1ppm)。
The method being previously reported by according to Nesaretnam et al., tocotrienols and IS are extracted from nano particle.Slightly
Modification.The nano suspending liquid of 1.0mL volumes is added in universal bottle, then adds 1ppm IS.The solution is vortexed 10 seconds, so
1.0mL 0.9% (w/v) NaCl is added afterwards.The mixture is vortexed again for other 10 seconds, then add 1.0mL ethanol and
5.0mL n-hexane.Then the mixture is ultrasonically treated 1 hour.In order to which the mixture is separated into water and organic phase, this is mixed
Compound is centrifuged 15 minutes for 4 DEG C in temperature with 2500rpm.Top organic phase is transferred in Y-pipe, and with vaporized nitrogen to dry,
Flow phase reconstruction with 0.5mL again afterwards.
Use the standard liquid in ten concentration range 0.05-200ppm and IS structure calibration curves.By tocotrienols
Peak area ratio mapped relative to nominal concentration.Linear regression analysis is carried out using linear equation y=mx, wherein y is fertility three
The peak area ratio of alkene phenol, x is tocotrienol concentration, and m is the slope of calibration curve.Coefficient correlation (R2) is used to determine the school
The linearity of directrix curve.Tocotrienol concentration in sample determines according to following formula:
Test limit (LOD) is to produce to have mark-on (spiked) standard of signal and the peak of baseline noise (S/N) ratio >=3 molten
The least concentration of tocotrienols in liquid.Quantitative limit (LOQ) is defined as on calibration curve to be reported with height confidence level and produced
Concentration at the quantitative result at the peak of raw S/N ratios >=10 (184).
Mark-on sample by analyzing nano suspending liquid evaluates the precision and the degree of accuracy of this method.By intraday three
Each sample of individual different time analysis similar concentration level repeats to evaluate in a few days precision and the degree of accuracy three times.Continuous three days
Identical program is followed to determine precision in the daytime and the degree of accuracy.In a few days and in the daytime accuracy representing is the nano suspending liquid concentration of measure
Percentage than standard deviation (RSD):
The degree of accuracy is studied by analyzing nano suspending liquid, and is denoted as the recovery percentage of mark-on sample.For
It is worth in acceptable day and in the daytime, the degree of accuracy should be within ± the 10% of nominal concentration.
Under described chromatographic condition, tocotrienols separates well with IS, retention time be respectively about 16.1min and
10.9min.The total run time of each sample is 30 minutes.Fig. 2 show the tocotrienols that is extracted from nano particle and
PMC chromatogram.
As shown in table 5, the detector response of the tocotrienols and PMC standard items that are extracted from nano particle is in 0.05-
It is linear, wherein R2 in the range of 200ppm>0.99.Both tocotrienols and PMC LOD are 0.05ppm, and give birth to three
Alkene phenol and PMC LOQ values are respectively 0.1ppm and 0.05ppm.
The method validation quantitative γ-T3 of table 5. and PMC
* data represent average value.
Precision and accuracy data are summarized in table 6.Tocotrienols and the PMC rate of recovery are respectively about 97.41% He
94.66%.The RSD values of tocotrienols and PMC Daytime varieties are respectively 1.41% and 3.23%.For in a few days analyzing essence
Degree, γ-T3 %RSD is 2.31%, and PMC %RSD is 3.93%.By the tocotrienols and PMC concentration that are detected
Deviation be less than the 10% of nominal concentration, thus the measure of the checking is considered as accurate, accurate and reliable.
In table 6.HPLC method validations γ-T3 and PMC in the daytime and in a few days precision and the degree of accuracy
* data represent average value ± SD.
Embodiment 8
Stability test based on the publications of 2009 and 2011 using Span 60 nanoparticle formulations
At the 0th, 4,7,14,21 and 30 day, the lipoid plastids of Span 60 of the storage at 4 DEG C were small with 40,000rpm centrifugations 2
When.Lipoid plastid pill is redispersed in PBS, in this case with 1:100 dilution factors with isopropanol rupture vesica it
Afterwards, in λExcite295nm and λTransmittingFluorescence derived from tocotrienols is determined at 325nm.
The stability of tocotrienols encapsulating in the quantitative lipoid plastids of Span 60, with during providing 4 DEG C of vesica storages again
Possibility tocotrienols seepage universal.At the 7th day, about 10-15% tocotrienols was from transferrins combination class
Discharged in liposome and control lipoid plastid.It is interior at following 3 weeks all to observe in addition to explosive release in first 7 days
Sustained release.The average release less than 1% daily is all recorded for transferrins combination lipoid plastid and control lipoid plastid
Rate.At the 30th day, the tocotrienols content remained in vesica did not had between control group and transferrins combination lipoid plastid
There were significant differences:Up to 33.3 ± 4.9% Hes are released respectively from control lipoid plastid and transferrins combination lipoid plastid
23.8 ± 4.5% tocotrienols.
The progress of the tocotrienols release of the lipoid plastids of Span 60 is shown in Fig. 3.
As above-described embodiment, particularly shown in embodiment 6 and 8, it is clear that nanoparticle formulations of the invention with according to reality
Apply 2009 of example 8 and the preparation delivered in 2011 is compared and has bigger stability, i.e. with the present invention according to embodiment 6
In compared after 2 months less than 5% tocotrienols release rate, up to 30% tocotrienols release rate after 30 days.
As those skilled in the art will be readily apparent that, the present invention can easily with without departing from the scope other are specific
Form produces.
Claims (27)
1. a kind of nano-carrier delivery system of lyophobic dust, comprising Nanoparticulate compositions, the nano particle include with
Lower component:
Surfactant comprising ascorbyl palmitate;
Cholesterol;
Hydrophilic polymer;
Functionalized polymeric containing carboxyl end groups;
Chemical linking agent;With
Targeting proteins,
Wherein, the targeting proteins form the targeted nano for strengthening targeted delivery of the lyophobic dust in mammal body
Particle;And
Wherein, the nano particle has improved storage stability, has the degradation rate less than about 5%.
2. nano-carrier delivery system according to claim 1, wherein, the nano particle is lipoid plastid.
3. according to the nano-carrier delivery system described in claim 1 and 2, wherein, the shape of the lipoid plastid is substantially
Spherical.
4. the nano-carrier delivery system according to any one of claim 1-3, wherein, the lipoid plastid, which has, to be less than
About 150nm particle diameter.
5. nano-carrier delivery system according to claim 1, wherein, the mol ratio of the ascorbyl palmitate is
About the 0.5 to about 1.00 of the Nanoparticulate compositions.
6. the nano-carrier delivery system according to any one of claim 1-5, wherein, the cholesterol be 3 beta-hydroxies-
5- cholestene, the β -ol of 5- cholestene -3.
7. nano-carrier delivery system according to claim 6, wherein, the mol ratio of the cholesterol is the nanometer
About the 0.5 to about 1.00 of grain composition.
8. the nano-carrier delivery system according to any one of claim 1-8, wherein, the hydrophilic polymer is dimension
Raw plain E TPGS (TPGS).
9. nano-carrier delivery system according to claim 8, wherein, the mol ratio of the TPGS is the nano particle
About the 0.1 to about 0.2 of composition.
10. the nano-carrier delivery system according to any one of claim 1-9, wherein, the functionalized polymeric is
DSPE-PEG (2000) carboxylic acid.
11. nano-carrier delivery system according to claim 10, wherein, mole of DSPE-PEG (2000) carboxylic acid
Than be the Nanoparticulate compositions about 0.02 to about 0.06.
12. the nano-carrier delivery system according to any one of claim 1-11, wherein, the chemical linking agent is 1-
Ethyl -3- [3- dimethylaminopropyls] carbon imidodicarbonic diamide hydrochloride (EDC) and/or Sulfo-N-hydroxy succinimide
(Sulfo-NHS)。
13. nano-carrier delivery system according to claim 12, wherein, the molar concentration of the chemical linking agent is institute
State the about 0.09M of Nanoparticulate compositions.
14. the nano-carrier delivery system according to any one of claim 1-13, wherein, the targeting proteins are to turn iron
Albumen.
15. nano-carrier delivery system according to claim 14, wherein, the molar concentration of the transferrins is described
The about 60mg/ml of Nanoparticulate compositions.
16. a kind of method for producing nano-carrier delivery system according to any one of the preceding claims, methods described
Comprise the following steps:
I) lyophobic dust is dissolved in organic solvent to form hydrophobic sol;
Ii) hydrophobic sol is mixed to produce with the surfactant, the cholesterol and the hydrophilic polymer
Unpurified solution;
Iii) excessive organic solvent is removed to form desciccator diaphragm from the unpurified solution;
Iv) by the dry film hydration into suspension;
V) chemical linking agent in cushioning liquid is provided separately to produce buffering liquid suspensions;
Vi) the unpurified lipoid plastid is mixed into the buffering liquid suspensions;
Vii targeting proteins solution) is then added;
Viii obtained mixture) is purified;And
Ix) mixture obtained is freeze-dried,
Wherein, the mixture of the acquisition is the Nanoparticulate compositions described in claim 1.
17. according to the method for claim 16, wherein, the organic solvent is hexane and methanol.
18. according to the method for claim 17, wherein, the organic solvent of hexane and methanol is with by volume about 9:1
Ratio add.
19. according to the method any one of claim 16-18, wherein, make in the hydration step of step (iv)
With phosphate buffer (PBS).
20. according to the method any one of claim 16-19, wherein, the cushioning liquid is 2-ethanesulfonic acid (MES).
21. according to the method any one of claim 16-20, wherein, the targeting proteins solution includes transferrins
And PBS.
22. nano-carrier delivery system according to any one of the preceding claims, wherein, the lyophobic dust is
γ-tocotrienols.
23. nano-carrier delivery system according to any one of the preceding claims, wherein, the mammal is people.
24. nano-carrier delivery system according to any one of the preceding claims is controlled in preparation for giving mammal
Treat the purposes in the medicine of cancer and cancer related disorders.
25. purposes according to claim 24, wherein, the medicine is by oral administration or through intravenous administration.
26. the purposes according to claim 24 or 25, wherein, the medicine is with about 5mg/kg to about 500mg/kg body weight
Effective dose is given.
27. according to the purposes any one of claim 24-26, wherein, the treatment phase of the medicine is about 10 days to about
60 days.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MYPI2015700198 | 2015-01-23 | ||
MYPI2015700198A MY197126A (en) | 2015-01-23 | 2015-01-23 | Nanocarrier delivery system for hydrophobic substances |
PCT/MY2016/050004 WO2016118001A1 (en) | 2015-01-23 | 2016-01-21 | Nanocarrier delivery system for hydrophobic substances |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107427471A true CN107427471A (en) | 2017-12-01 |
CN107427471B CN107427471B (en) | 2020-07-31 |
Family
ID=56417447
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680017476.3A Active CN107427471B (en) | 2015-01-23 | 2016-01-21 | Nanocarrier delivery systems for hydrophobic substances |
Country Status (5)
Country | Link |
---|---|
CN (1) | CN107427471B (en) |
AU (1) | AU2016209724B2 (en) |
GB (1) | GB2551453B (en) |
MY (1) | MY197126A (en) |
WO (1) | WO2016118001A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112180079A (en) * | 2020-09-25 | 2021-01-05 | 上海睿康生物科技有限公司 | Stable liposome particles and application thereof in immunoturbidimetric assay |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019094625A1 (en) * | 2017-11-09 | 2019-05-16 | Nexien Biopharma, Inc. | Methods and compositions for parenteral administration of cannabidiol in the treatment of convulsive disorders |
CN113318217A (en) * | 2021-06-02 | 2021-08-31 | 厦门大学 | BTZ-TPGS compound, nano preparation, preparation and application thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003053407A1 (en) * | 2001-12-19 | 2003-07-03 | Research Development Foundation | Liposomal delivery of vitamin e based compounds |
CN101569607A (en) * | 2009-06-16 | 2009-11-04 | 中国药科大学 | Di-demethoxycurcumin precursor liposome and preparation method thereof |
-
2015
- 2015-01-23 MY MYPI2015700198A patent/MY197126A/en unknown
-
2016
- 2016-01-21 AU AU2016209724A patent/AU2016209724B2/en active Active
- 2016-01-21 CN CN201680017476.3A patent/CN107427471B/en active Active
- 2016-01-21 WO PCT/MY2016/050004 patent/WO2016118001A1/en active Application Filing
- 2016-01-21 GB GB1713495.8A patent/GB2551453B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003053407A1 (en) * | 2001-12-19 | 2003-07-03 | Research Development Foundation | Liposomal delivery of vitamin e based compounds |
CN101569607A (en) * | 2009-06-16 | 2009-11-04 | 中国药科大学 | Di-demethoxycurcumin precursor liposome and preparation method thereof |
Non-Patent Citations (5)
Title |
---|
D. GOPINATH等: "Ascorbyl palmitate vesicles (Aspasomes): formation,", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
JU YEN FU等: "Novel tocotrienol-entrapping vesicles can eradicate solid tumors", 《JOURNAL OF CONTROLLED RELEASE》 * |
JU YEN FU等: "Tumor regression after systemic administration of tocotrienol entrapped in", 《JOURNAL OF CONTROLLED RELEASE》 * |
JU-YEN FU等: "Tumor-targeted niosome as novel carrier for", 《ASIAN JOURNAL OF PHARMACEUTICAL S C I E N C E S》 * |
陈正明等: "维生素C棕榈酸酯泡囊作为维A酸载体的研究", 《中国医药工业杂志》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112180079A (en) * | 2020-09-25 | 2021-01-05 | 上海睿康生物科技有限公司 | Stable liposome particles and application thereof in immunoturbidimetric assay |
CN112180079B (en) * | 2020-09-25 | 2024-04-19 | 上海睿康生物科技有限公司 | Stable liposome particle and application thereof in immune turbidimetry detection |
Also Published As
Publication number | Publication date |
---|---|
MY197126A (en) | 2023-05-26 |
GB201713495D0 (en) | 2017-10-04 |
GB2551453A (en) | 2017-12-20 |
AU2016209724B2 (en) | 2021-03-11 |
AU2016209724A1 (en) | 2017-09-14 |
WO2016118001A1 (en) | 2016-07-28 |
CN107427471B (en) | 2020-07-31 |
GB2551453B (en) | 2020-09-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Majumder et al. | Nanocarrier-based systems for targeted and site specific therapeutic delivery | |
Yang et al. | Dual-targeting liposome modified by glutamic hexapeptide and folic acid for bone metastatic breast cancer | |
Guo et al. | Functional alginate nanoparticles for efficient intracellular release of doxorubicin and hepatoma carcinoma cell targeting therapy | |
Li et al. | Aptamer-conjugated chitosan-anchored liposomal complexes for targeted delivery of erlotinib to EGFR-mutated lung cancer cells | |
Wang et al. | Preparation and evaluation of anti-neuroexcitation peptide (ANEP) loaded N-trimethyl chitosan chloride nanoparticles for brain-targeting | |
Zhu et al. | Glycyrrhetinic acid-modified TPGS polymeric micelles for hepatocellular carcinoma-targeted therapy | |
US20090004278A1 (en) | Enzymatically Crosslinked Protein Nanoparticles | |
Zheng et al. | Targeted paclitaxel delivery to tumors using cleavable PEG-conjugated solid lipid nanoparticles | |
Fang et al. | Novel hydrophobin-coated docetaxel nanoparticles for intravenous delivery: in vitro characteristics and in vivo performance | |
Wu et al. | Preparation and characterization of nanoparticles based on histidine–hyaluronic acid conjugates as doxorubicin carriers | |
Kushwaha et al. | Novel drug delivery system for anticancer drug: a review | |
Taneja et al. | Rational design of polysorbate 80 stabilized human serum albumin nanoparticles tailored for high drug loading and entrapment of irinotecan | |
Jha et al. | DNA biodots based targeted theranostic nanomedicine for the imaging and treatment of non-small cell lung cancer | |
CN102327230A (en) | Protein nanometer granules wrapped with taxane medicaments and preparation method for nanometer granules | |
JP2010132609A (en) | Casein nanoparticle | |
Zhao et al. | Transferrin conjugated poly (γ-glutamic acid-maleimide-co-L-lactide)-1, 2-dipalmitoylsn-glycero-3-phosphoethanolamine copolymer nanoparticles for targeting drug delivery | |
US8187571B1 (en) | Pharmaceutical composition of nanoparticles | |
Shirani et al. | Redox responsive polymeric micelles of gellan gum/abietic acid for targeted delivery of ribociclib | |
CN108339124B (en) | Preparation method and application of two-stage brain-targeted polymer micelle drug delivery system | |
Muralidharan et al. | Synthesis and characterization of naringenin-loaded chitosan-dextran sulfate nanocarrier | |
CN107427471A (en) | The nano-carrier delivery system of lyophobic dust | |
Fan et al. | Reduction-responsive crosslinked micellar nanoassemblies for tumor-targeted drug delivery | |
Campos et al. | Liquid crystalline nanodispersion functionalized with cell-penetrating peptides improves skin penetration and anti-inflammatory effect of lipoic acid after in vivo skin exposure to UVB radiation | |
US11260031B2 (en) | Protein particle with a poorly water-soluble drug encapsulated therein and preparation method thereof | |
Eskandari et al. | Targeting breast cancer using pirarubicin-loaded vasoactive intestinal peptide grafted sterically stabilized micelles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |