CN101394866B - Stabilizer for hydrophobic compounds - Google Patents
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Abstract
The present invention provides a stabilizer for hydrophobic compounds, particularly hinokitiol, which consists of a block copolymer comprising at least a hydrophilic segment and a hydrophobic segment as the essential components.
Description
Technical field
The present invention relates to make the unsettled hydrophobic compound of light and heat, particularly the stabilizing agent of Chinese juniper another name for (hinokitiol) stabilisation, the stabilizing agent of forming by the block copolymer that contains hydrophilic segment and hydrophobic chain segment at least and the antihunt means of utilizing it.
Background technology
No matter be natural goods or synthetic, also no matter owing to being that chemical compound has good activity, because the shortcoming of stability is a lot of in the situation that fields such as medicine, food and pesticide can not obtain to use actually.For example; have Chinese juniper another name for (hinokitiol) (β-arborvitae element (β-thujaplicin)) in the acid-soluble oil of blue or green gloomy Thujopsis dolabrata, and the tall and erect phenolic ketone of 4-isopropenyl (((α-thujaplicin) and 4-acetyl group tropolone (4-acetyltroplone) etc. have the chemical compound of 7 yuan of rings for γ-thujaplicin), α-arborvitae element for β-dolabrin), gamma-thujaplicin.Wherein, the Chinese juniper another name for is that people such as wild pair in 1963 purification from Taiwan juniper (hinoki) obtains, and determined its chemical structural formula, reported that the relevant antimicrobial acivity of its physiologically active, cell obstructive action, metalloproteases obstructive action, tryrosinase obstacle activity, plant growing hinder multiple physiologically active (medical journals of Chinese 39,1283-1294 (2003) such as activity; Antimicrob.Agents Chemother.49,2519-2521 (2005); Arch.Pharm.Res.22,335-339 (1999)).Because it has so various physiologically active, its at food preservation (spy opens flat 6-277019 communique, the spy opens flat 6-153788 communique .), prevent variable color (spy opens clear 59-085279 communique), the application that is combined into treatment of infection prescription face with zinc obtained research.Yet the Chinese juniper another name for itself is a kind of sublimate, and understands accelerated decomposition under the effect of light, has therefore limited its use under common environment, can not reach sufficient practicability (J.Am.Chem.Soc.83.1768-1769 (1961); Can.J.Microbiol.19,1177-1180 (1973); Biosci.Biotechnol.Biochem.67,1996-1998 (2003)).
About the stabilisation of Chinese juniper another name for, have cooperate organic acid, with PH be adjusted to 5.0-6.0 method (spy opens flat 9-188620 communique), use surfactant etc. emulsifying process for dispersing (spy opens flat 10-291906 communique), the Chinese juniper another name for is made aluminum salt or/and is made with the methods such as coordination compound (WO97/02025) of aluminium compound etc.Yet above arbitrary method all can not reach sufficient stability.
Summary of the invention
Problem of the present invention is the stabilisation about the hydrophobic compound of heat stability and light stability equistability difference.
The present application contains following embodiment.
To stablize the stabilizing agent that hydrophobic compound is a purpose, described stabilizing agent is made up of the block copolymer that contains hydrophilic segment and hydrophobic chain segment at least.
1 described stabilizing agent, described hydrophilic segment is a Polyethylene Glycol.
1 or 2 described stabilizing agents, described hydrophobic chain segment are the polyamino acid or derivatives thereofs.
3 described stabilizing agents, described polyamino acid are to choose from the group that is made up of polyglutamic acid, poly-aspartate, its derivant and one or more mixture thereof.
Any one described stabilizing agent in 1～4, the chemical formula of described block copolymer are (I) or (II):
Or
[above-mentioned various in R1 and R3 represent hydrogen atom respectively independently or by can the metathetical or not metathetical low alkyl group of protected functional group; R2 represents hydrogen atom, saturated or undersaturated C1～C29 aliphatic carbonyl or aromatic series carbonyl; R4 represents hydroxyl, saturated or undersaturated C1～C30 aliphatic oxygen base or aryl-lower alkoxy; R5 represents benzyl, alkyl benzyl or pi-allyl; L1 represent from by-NH-,-O-,-CO-,-CH2-,-O-Z-S-Z ,-O-Z-NH-and-the connection base selected in the group that O-CO-Z-NH-(Z be independently C1～C4 thiazolinyl) herein, is formed; L2 represent from by-OCO-Z-CO-and-NHCO-Z-CO-,-the connection base selected in the group that O-Z-NH-(Z be independently C1～C4 thiazolinyl) herein, is formed; N is 10～2500 integer; X and y be, identical or different, both sums are 10～300 integer, and x is in the scope of 1:1～0:1 than y, and x and y arbitrarily exist respectively; Q is 1 or 2 integer.]
Any one described stabilizing agent in 1～5, described hydrophobic compound is selected from the group that is made up of antibiotic, antibiotics, antitumor agent, anti-inflammatory agent, antipyretic, analgesics, Antiswelling medicine, relieving cough and expelling phlegm agent, tranquilizer, muscle relaxant, Anti-epileptics, antiulcer agent, resist melancholy agent, anti-allergic agent, cardiac tonic, anti-arrhythmic agents, vasodilation, hypotensive agent, treatment diabetes agent, homoiostasis agent, polypeptide, hormone preparation, anti-acidulant, the agent of gums illness and vitamin.
Any one described stabilizing agent in 1～6, described hydrophobic compound is selected from the group that is made up of Chinese juniper another name for, coenzyme Q10, vitamin E or derivatives thereof, vitamin A or derivatives thereof, vitamin C derivatives, alpha-lipoic acid and polyphenol.
7 described stabilizing agents, described hydrophobic compound are the Chinese juniper another name fors.
The antihunt means of hydrophobic compound, comprise: the stabilizing agent of being made up of the block copolymer that contains hydrophilic segment and hydrophobic chain segment at least mixes mutually with aforementioned hydrophobic compound, makes this block copolymer and the interactional step of this hydrophobic compound; Perhaps, under the function of stabilizer of forming by the block copolymer that contains hydrophilic segment and hydrophobic chain segment at least, aforementioned hydrophobic compound sealed and form the step of microcapsule.
9 described methods, described hydrophilic segment is a Polyethylene Glycol.
9 or 10 described methods, described hydrophobic chain segment are the polyamino acid or derivatives thereofs.
11 described methods, described polyamino acid are selected from the group that is made up of polyglutamic acid, poly-aspartate or derivatives thereof and one or more mixture thereof.
Any one described method in 9～12, the chemical formula of block copolymer are (I) or (II):
Or
[above-mentioned various in R1 and R3 represent independently that respectively hydrogen atom or expression are by can the metathetical or not metathetical low alkyl group of protected functional group; R2 represents hydrogen atom, saturated or undersaturated C1～C29 aliphatic carbonyl or aromatic series carbonyl; R4 represents hydroxyl, saturated or undersaturated C1～C30 aliphatic oxygen base or aryl-lower alkoxy; R5 represents benzyl, alkyl benzyl or pi-allyl; L1 represent from by-NH-,-O-,-CO-,-CH2-,-O-Z-S-Z ,-O-Z-NH-and-the connection base selected in the group that O-CO-Z-NH-(Z be independently C1～C4 thiazolinyl) herein, is formed; L2 represent from by-OCO-Z-CO-and-NHCO-Z-CO-,-the connection base selected in the group that O-Z-NH-(Z be independently C1～C4 thiazolinyl) herein, is formed; N is 10～2500 integer; X and y be, identical or different, both sums are 10～300 integer, and x is in the scope of 1:1～0:1 than y, and x and y arbitrarily exist respectively; Q is 1 or 2 integer.]
9～13 any one described method, described hydrophobic compound is selected from the group that is made up of antibiotic, antibiotics, antitumor agent, anti-inflammatory agent, antipyretic, analgesics, Antiswelling medicine, relieving cough and expelling phlegm agent, tranquilizer, muscle relaxant, Anti-epileptics, antiulcer agent, resist melancholy agent, anti-allergic agent, cardiac tonic, anti-arrhythmic agents, vasodilation, hypotensive agent, treatment diabetes agent, homoiostasis agent, polypeptide, hormone preparation, anti-acidulant, the agent of gums illness and vitamin.
Any one described method in 9～14, described hydrophobic compound is selected from the group that is made up of Chinese juniper another name for, coenzyme Q10, vitamin E or derivatives thereof, vitamin A or derivatives thereof, vitamin C derivatives, alpha-lipoic acid and polyphenol.
15 described methods, described hydrophobic compound are the Chinese juniper another name fors.
By the use of block copolymer of the present invention, can realize under the condition of light and/or heat, causing the stabilisation of hydrophobic compound of the wide scope of isomerization reaction.
Description of drawings
Fig. 1 represents the structure and the isomerization thereof of Chinese juniper another name for.
Fig. 2 represents the influence of various carriers for the light stability of Chinese juniper another name for
Fig. 3 represents the influence of various carriers for the heat stability of Chinese juniper another name for
The specific embodiment
The invention provides, by containing the stabilizing agent that can be common to hydrophobic compound that hydrophilic segment and hydrophobic chain segment block copolymer are formed.Stabilizing agent of the present invention as a kind of embodiment, can make the Chinese juniper another name for stable, compare with the Chinese juniper another name for that in the micro encapsulation Chinese juniper another name for that forms under SDS micro encapsulation Chinese juniper another name under the effect of sodium lauryl sulphate (SDS), the effect, nanoparticle, contains, confirm to demonstrate high stability light and heat at polymethyl methacrylate at yolk lecithin.
The block copolymer that can use among the present invention is to contain the block copolymer of hydrophilic segment and hydrophobic chain segment.These block copolymers so long as purpose according to the invention can be the block copolymer that contains any hydrophilic segment and any hydrophobic chain segment, but comprise following substances specifically.
Hydrophilic segment can list but be not limited to following substances: the segment that poly-(ethylene glycol) (or poly-(oxirane)), polysaccharide, poly-(vinylpyrrolidone), poly-(vinyl alcohol), poly-(acrylamide), poly-(acrylic acid), poly-(Methacrylamide), poly-(methacrylic acid), poly-(methacrylate), poly-(acrylate), polyamino acid, poly-(malic acid) or their derivant etc. constitute.Herein, polysaccharide has: starch, dextran, levan, galactan etc.In these materials, the Polyethylene Glycol segment has various functional groups and segmental size at an end can be controlled and can utilize easily, so preferred Polyethylene Glycol.
On the other hand, hydrophobic chain segment can list but be not limited to following substances: poly-(methacrylate-co-methacrylic acid), poly-(aspartame) and poly-(glutamate derivatives), for example, poly-(aspartic acid-beta-benzyl ester), poly-(L-aspartic acid-beta-benzyl ester-co-aspartic acid), poly-(aspartic acid β-alkane ester), poly-(aspartic acid β-alkane ester-co-aspartic acid), poly-(aspartic acid-beta-allyl ester-co-aspartic acid), poly-(aspartic acid-beta-aralkyl ester-co-aspartic acid), poly-(aspartic acid-beta-aralkyl ester), poly-(aspartic acid-beta-aralkyl ester-co-aspartic acid), poly-(β-alkyl agedoite), poly-(β-alkyl agedoite-co-aspartic acid), poly-(β-aralkyl agedoite), poly-(β-aralkyl agedoite-co-aspartic acid), poly-(glutamic acid-γ-benzyl ester), poly-(L-glutamic acid-γ-benzyl ester-co-glutamic acid), poly-(glutamic acid-γ-alkane ester), poly-(glutamic acid-γ-alkane ester-co-glutamic acid), poly-(polyglutamic acid-γ-allyl ester-co-glutamic acid), poly-(glutamic acid-γ-aralkyl ester), poly-(glutamic acid-γ-aralkyl ester-co-glutamic acid), poly-(γ-alkyl glutamine), poly-(γ-alkyl glutamine-co-glutamic acid), poly-(γ-aralkyl glutamine), poly-(γ-aralkyl glutamine-co-glutamic acid), poly-(lactide), poly-(lactide-co-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(6-caprolactone), poly-(amino acid derivativges) of poly-(δ-Wu Neizhi) and poly-(gamma-butyrolacton) etc.
At random, in so poly-(amino acid derivativges) segment, the material that on side chain, has carboxyl, itself be known, for example, the benzyl of poly-(L-aspartic acid-γ-benzyl ester-co-glutamic acid) or poly-(L-glutamic acid-γ-benzyl ester-co-glutamic acid) is by adding after water decomposition is removed, by with corresponding ethanol or ammonia react, be exchanged into ester group or amide groups, at this moment, by changing the response magnitude of ethanol and ammonia, just can obtain the hydrophobic chain segment that on side chain, has carboxyl of desired proportion.At this moment, poly-(L-aspartic acid-γ-benzyl ester) generates the aspartic acid that β resets under the effect that adds water decomposition.The ratio that β aspartic acid of resetting and the aspartic acid that the β rearrangement has taken place do not take place approximately is 1:3, and this is known.Naturally, contain and aspartic acid that β resets has taken place and the hydrophobic chain segment of derivant is included among the present invention.Aspartic acid, glutamic acid can be any optical activity type materials, or their mixture.Above hydrophilic segment is by itself known base that is connected with hydrophobic chain segment, for example ester bond, amido link, imino group, carbon-carbon bond, ehter bond etc. and connection.
Particularly, make easily, the block copolymer that the present invention can conveniently use, can list have following chemical formula (I) or (II) shown in material.
Or
Above-mentioned various in R1 and R3 represent independently that respectively hydrogen atom or expression are by can the metathetical or not metathetical low alkyl group of protected functional group; R2 represents hydrogen atom, saturated or undersaturated C1～C29 aliphatic carbonyl or aromatic series carbonyl; R4 represents hydroxyl, saturated or undersaturated C1～C30 aliphatic oxygen base or aryl-lower alkoxy; R5 represents benzyl, alkyl benzyl or pi-allyl; Yet (, R5 is that select arbitrarily in each aminoacid unit in 1 block copolymer may.) L1 and L2 respectively independently expression is connected basicly, n is 10～2500 integer, x is 10～300 integer, y represents 1 or 2 integer.Can protected functional group be hydroxyl, acetal radical, ketal group, aldehyde radical, saccharide residue for example.R1 and R3 represent can be protected hydrophilic segment under the low alkyl group situation after functional group's displacement be can basis, for example method of putting down in writing among WO96/33233, WO96/32434, the WO97/06202.Low alkyl group is a carbon number for example below 7, preferentially be the expression carbon number at the straight or branched alkyl below 4, comprise for example methyl, ethyl, propyl group, isopropyl, butyl and isobutyl group etc.
Connect that base generally speaking changes because of the difference of the manufacture method of block copolymer so be not limited, particularly, the connection base that can enumerate has, L1 can be selected from-NH-,-O-,-O-Z-NH-,-CO-,-CH2-,-O-Z-S-Z and-group that O-CO-Z-NH-(Z be independently C1～C4 thiazolinyl) herein, is formed; L2 can-OCO-Z-CO-and-group that NHCO-Z-CO-, (Z be independently C1～C4 thiazolinyl) herein, are formed.
The operable good especially block copolymer of the present invention is Polyethylene Glycol (PEG)-poly-(L-aspartic acid-beta-benzyl ester) block copolymer (following slightly be called " PEG-PBLA ").PEG-PBLA can be, for example, (molecular weight of PEG is 5 to PEG-PBLA-5-20-100,000, the degree of polymerization of aspartic acid is 20, the benzyl rate is 100%), PEG-PBLA-12-40-50 (molecular weight of PEG is 12,000, the degree of polymerization of aspartic acid is 40, and the benzyl rate is 50%), (molecular weight of PEG is 12 to PEG-PBLA-12-50-50,000, the degree of polymerization of aspartic acid is 50, and the benzyl rate is 50%).
An embodiment of the invention are, hydrophobic compound under the block compound effect by micro encapsulation (medicine is enclosed in the microcapsule), thereby its stabilisation can realize.For example, the Chinese juniper another name for is under light and/or heat condition isomerization reaction to take place, the obstruction to isomerization reaction of block copolymer is, assert under with the situation of Chinese juniper another name for/block copolymer 1mg/1.2mg for the material that sets out (the Chinese juniper another name for is in respect to block copolymer and surpasses surplus state).Therefore can think that making Chinese juniper another name for and block copolymer only is to interact also to play three-dimensional obstruction to isomerization reaction, makes Chinese juniper another name for stabilisation.Therefore, the stabilizing agent of being made up of the block copolymer among the present invention is the hydrophobic compound that can be used for being initiated the wide scope of isomerization reaction under light and heat.
Therefore, the chemical compound that can be stabilized under the effect of block copolymer of the present invention is not limited to the Chinese juniper another name for, can list the hydrophobic compound that for example under light and heat, is initiated the wide scope of isomerization reaction, there is no particular limitation, but can list for example antibiotic, antibiotics, antitumor agent, anti-inflammatory agent, antipyretic, analgesics, Antiswelling medicine, the relieving cough and expelling phlegm agent, tranquilizer, muscle relaxant, Anti-epileptics, antiulcer agent, resist melancholy agent, anti-allergic agent, cardiac tonic, anti-arrhythmic agents, vasodilation, hypotensive agent, the treatment diabetes agent, the homoiostasis agent, polypeptide, hormone preparation, anti-acidulant, agent of gums illness and vitamin etc.Specifically, there are Chinese juniper another name for, amphotericin B, nystatin, pamoic acid to pounce on pinworm peaceful (pyrvinium pamoate), methotrexate, ametycin, daunomycin, adriamycin, cisplatin, DACH platinum, taxol and derivant, vincristine, camptothecine and derivant thereof, steroid, indomethacin, methyl salicylate, sweet smell too slave, Chinese juniper another name for, coenzyme Q10, vitamin E and derivant, vitamin A and derivant thereof, vitamin C and derivant thereof, alpha-lipoic acid and polyphenol etc.
Good especially hydrophobic compound is the Chinese juniper another name for.According to the present invention, can do one's utmost to suppress the ultra-oxygen anion free radical that the Chinese juniper another name for takes place and the influence of hydroxy radical in thermal decomposition, photolysis, the constituent of effective use of the various purposes that can realize the Chinese juniper another name for is provided.
The amount of the block copolymer that uses as stabilizing agent, can carry out suitable variation according to the molecular weight of block copolymer and the kind of chemical compound, there is no particular limitation, but calculate with mol ratio, with respect to chemical compound is that 1 block copolymer is 0.0001～10, preferably can be 0.001～1.
Make the situation of microcapsule as hydrophobic compound being enclosed in the stabilizing agent of forming by block compound of the present invention of one of stabilization method of embodiments of the invention, this method is not special qualification, for example opens in the 2003-342168 communique disclosed method and just can carry out according to open 2003-26812 or spy the spy.A concrete example is, the block copolymer and the hydrophobic compound that will constitute by hydrophilic segment and hydrophobic chain segment, be dissolved in volatile organic solvent, for example methanol, isopropyl alcohol, acetone, acetonitrile, methyl acetate, ethyl acetate, oxolane, diethyl ether, encircle in the solvent that has fluidization property under amine etc. and their room temperature such as mixed solvent after, the film that is obtained after this organic solvent removed is dispersed in the water equably, in adequate time as stirring under as 4 ℃～room temperature 2 hours～24 hours, preference temperature.The solution that is obtained shines under suitable ultrasound wave, use dynamic light photometer at random (for example Da mound electronics DLS-7000DH) to carry out the mensuration in particle footpath, do not wrap into the chemical compound of microcapsule by gel (for example PD-10columns, GE healthcare bioscience limited company) isolated by filtration.
In addition, make under the situation of hydrophobic compound block copolymer stabilizers interaction related to the present invention and realization stabilisation, both can be mixed in appropriate solvent, can remove interactional hydrophobic compound (free compound) does not take place.
Stabilizing agent of the present invention is applicable to multiple uses such as pharmaceuticals, pesticide, food, for example as the dosage form of medicine is but is not limited to pill, granule, syrup, capsule, injection, suppository, inhalant, ointment etc.
Below specifically represent the present invention with comparative example and embodiment.
Embodiment
Below, poly-(L-aspartic acid-beta-benzyl ester) block copolymer of Polyethylene Glycol-co-slightly is called PEG-PBLA.In addition, for example at the mean molecule quantity 12,000 of the PEG of Polyethylene Glycol chain, 40 residues of polyamino acid chain, the benzyl rate of polyamino acid side chain is under 50% the situation, labelling 12-40-50 after each block copolymer.
Embodiment 1: the stabilisation of the Chinese juniper another name under the block copolymer effect
Chinese juniper another name for (Wako with 1mg, Osaka) and the PEG-PBLA-5-20-100 of 10mg, PEG-PBLA-12-40-50 or PEG-PBLA-12-50-50 weighing in the screw-cap test tube bottle, after in dichloromethane, dissolving, dichloromethane is volatilized under nitrogen current, obtain the film that Chinese juniper another name for and block copolymer form.The ultra-pure water that adds 3ml in this film under shading, under 4 ℃, stirred 12 hours.With the microcapsule solution that obtains ultrasonic irradiation with 5 minutes, carry out the mensuration of particle diameter, the Chinese juniper another name for that will not be wrapped into microcapsule by gel filtration (PD-10columns) general is separated.The Chinese juniper another name for is to present the 330nm place maximum absorption band is arranged in water, and the Chinese juniper another name for that wraps into the block copolymer microcapsule is at 324nm and 372nm maximum absorption band to be arranged.The embedding rate that following table 1 is depicted as the Chinese juniper another name in the microcapsule that is obtained (is embedded into the ratio of the medication amount and the medicine amount of setting out of microcapsule, wt/wt%), the size of inclosure rate, microcapsule.Again, the embedding rate of medicine is, tries to achieve the medicine value that not embedding is advanced by molar absorption coefficient, and will be worth and deduct the medicine value that the difference that obtained advances microcapsule as embedding try to achieve from medicine amount.The inclosure rate is meant that the medication amount ratio (wt/wt%) shared with respect to the amount of setting out of polymer of microcapsule advanced in embedding.The particle diameter of polymer microcapsule can adopt the known method of those skilled in the art to measure, and for example uses dynamic light photometer (at random Da mound electronics (strain), DLS-7000DH), can measure according to its description.
Table 1. micro encapsulation Chinese juniper another name for
All 1mg Chinese juniper another name for is used in experiment
Under polymer 10mg, Chinese juniper another name for 1mg situation as the material that sets out, the embedding rate of Chinese juniper another name for is, the highest under the situation of using PEG-PLBA-5-20-100, PEG-PLBA-12-50-50, PEG-PLBA-12-40-50, reach 47-49%, the inclosure rate is 4.7-4.9% (reference table 1).
The Chinese juniper another name for that uses as setting out material is 1mg, the amount of PEG-PLBA-12-50-50 is under the situation of 5mg, 2.5mg, 1.2mg, 0.5mg, 0.1mg, though the amount by the Chinese juniper another name for of embedding reduces along with the minimizing of amount of polymers, and amount of polymers is an almost fixed when 2.5mg, 1.2mg, 0.5mg, the inclosure rate uprises, and it is big that the size of microcapsule also becomes.
Chinese juniper another name under the embodiment 2 block copolymer effects is to the stability of light
The aqueous solution of micro encapsulation Chinese juniper another name for (sample of the 1-6 of experiment shown in the table 1), under breadboard light, at room temperature preserve, to their absorption intensity change through the time measure, as shown in Figure 2, the absorption intensity at 324nm place is maintaining 85%, maintaining 40% after maintaining 53%, 14 day after 7 days after one day, show that micro encapsulation makes the photolysis of Chinese juniper another name for be suppressed.Again, result shown in Figure 2 represents is the meansigma methods of absorption at 324nm place of the microcapsule of experiment 1-6.That is, can think that isomerization reaction shown in Figure 1 is, has been hindered three-dimensionally under the micro encapsulation effect.In addition, the obstruction of this isomerization reaction is that (being that the Chinese juniper another name for is to be in to surpass surplus state with respect to block polymer) also can be observed under the situation that Chinese juniper another name for/block polymer is 1mg/1.2mg as the material that sets out, and this shows the three-dimensional obstruction that also can cause isomerization reaction under Chinese juniper another name for and the interactional state of block copolymer.
Embodiment 3: the micro encapsulation Chinese juniper another name under the block copolymer effect is to the stability of heat
The aqueous solution of micro encapsulation Chinese juniper another name for (sample of the 1-6 of experiment shown in the table 1), under shading, preserve down for 37 ℃, to their absorption intensity change through the time measure, the absorption maximum at 324nm place still remained on 97% after 14 days, show that the micro encapsulation effect makes the thermal decomposition of Chinese juniper another name for be suppressed (Fig. 3) fully.Because the spectrum under the situation when spectrum under the pyrolysated situation and photolysis is identical, can think that the analyte under photolysis situation and the thermal decomposition situation is a cyclopentene derivatives, thermal decomposition obstruction and photolysis obstruction are what to be caused by same mechanism.
The simple Chinese juniper another name for of comparative example 1 is to the stability of light or heat
The evaluation of stability to light or heat of simple Chinese juniper another name for is to adopt with the same method of embodiment 2,3 to carry out.Simple Chinese juniper another name for aqueous solution is preserved under the room temperature under breadboard light, to the absorption intensity at 330nm place through the time measure, absorption intensity is reduced to 6% (Fig. 2) be reduced to 9%, 14 after being reduced to 64%, 8 after 1 day after.Under the shading, under 37 ℃ of conditions, the absorption intensity of simple Chinese juniper another name at the 330nm place is to be reduced to 41% (Fig. 3) after being reduced to 57%, 14 after 8 days.
Comparative example 2: the micro encapsulation of the Chinese juniper another name under sodium lauryl sulphate (SDS) effect
(Wako, Osaka) 7.2 grams are dissolved among the ultra-pure water 2.5ml with Chinese juniper another name for 453 micrograms, stir the back and make with extra care by gel filtration, obtain the microcapsule of particle diameter 130 nanometers with SDS.The embedding rate of Chinese juniper another name for is 12.4%, has very big absorption value at 328nm and 387nm place.The evaluation of stability to light or heat of the micro encapsulation Chinese juniper another name under the SDS effect is to adopt the method identical with embodiment 2,3 and comparative example 1 to carry out, and still measures the absorption intensity at 328nm place.The absorption intensity of SDS micro encapsulation Chinese juniper another name at the 328nm place be, under laboratory light, room temperature is preserved down, is reduced to 30% (Fig. 2) be reduced to 40%, 14 after being reduced to 65%, 7 after 1 day after.Under the shading, under 37 ℃ of conditions, the absorption intensity at 328nm place is to be reduced to 33% after 1 day, to be reduced to 17% after 7 days, to be reduced to 14% (Fig. 3) after 14 days.
Comparative example 3: the liposome that contains the Chinese juniper another name for
(Wako, Osaka) 30mg is dissolved in after the dichloromethane of 2ml, and dichloromethane is volatilized under nitrogen current, obtains the film of yolk lecithin with yolk lecithin.In this film, add the Chinese juniper another name for that is dissolved in the 3ml ultra-pure water, under shading, 4 ℃ of stirrings, 15 minutes ultrasonic irradiations are by the refining particle that obtains the about 200nm of particle diameter of gel filtration.The embedding rate of Chinese juniper another name for is 23.7%, and the inclosure rate is 0.8%, and liposome Chinese juniper another name for is to show very big absorption at 324nm and 372nm place.Liposome Chinese juniper another name under the yolk lecithin effect adopts the method identical with embodiment 2,3 and comparative example 1 to carry out to the estimation of stability of light and heat.The absorption intensity of liposome Chinese juniper another name at the 324nm place be, under the breadboard light, room temperature is preserved down, is reduced to 0% Fig. 2 after being reduced to 38%, 3 after 1 day).Under the shading, under 37 ℃ of conditions, the absorption intensity at 328nm place is to be reduced to 75% after 1 day, to be reduced to 25% after 7 days, to be reduced to 10% (Fig. 3) after 14 days.
Comparative example 4: polymethyl methacrylate (PMMA) nanoparticle that contains the Chinese juniper another name for
With Chinese juniper another name for 100mg and PMMA (Wako, Osaka) 2g is dissolved in the dichloromethane of 28ml, again after wherein adding the ultra-pure water 200ml and stirring that contains SDS1g, put into supertension tissue grinder (Microfluidizer, Microfluidics Corporation, MA USA), makes emulsion under the condition of pressure 1000bar and flow velocity 150ml/min.Behind the dichloromethane evaporative removal, by dialysis will be for SDS and do not removed by the Chinese juniper another name for of embedding after, obtain the particle that particle diameter is 55 nanometers.The Chinese juniper another name for that wraps in the PMMA nanoparticle has very big absorption at 324nm and 366nm place, is to adopt the method identical with embodiment 2,3 and comparative example 1 to carry out to the evaluation of stability of light or heat.The absorption intensity of Chinese juniper another name at the 324nm place contained in the PMMA nanoparticle be, under laboratory light, room temperature is preserved down, is reduced to 22% (Fig. 2) be reduced to 25%, 14 after being reduced to 72%, 7 after 1 day after.Under the shading, under 37 ℃ of conditions, Chinese juniper another name for contained in the PMMA nanoparticle is stable, still keeps 92% absorption intensity (Fig. 3) after 14 days.
Claims (3)
1. the application of stabilizing agent in stablizing the Chinese juniper another name for of forming by the block copolymer of Polyethylene Glycol, poly-(L-aspartic acid-beta-benzyl ester).
2. the antihunt means of a Chinese juniper another name for is characterized in that comprising: will be mixed mutually with the Chinese juniper another name for by the stabilizing agent that Polyethylene Glycol, the block copolymer of poly-(L-aspartic acid-beta-benzyl ester) are formed, make this block copolymer and the interactional step of this Chinese juniper another name for.
3. the antihunt means of a Chinese juniper another name for is characterized in that comprising: under the function of stabilizer of being made up of the block copolymer of Polyethylene Glycol, poly-(L-aspartic acid-beta-benzyl ester) the Chinese juniper another name for sealed and form the step of microcapsule.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| JP059552/2006 | 2006-03-06 | ||
| JP2006059552 | 2006-03-06 | ||
| PCT/JP2007/054741 WO2007102608A1 (en) | 2006-03-06 | 2007-03-05 | Stabilizer for hydrophobic compounds |
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| CN101394866B true CN101394866B (en) | 2011-07-27 |
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| JP (1) | JPWO2007102608A1 (en) |
| KR (1) | KR20080106219A (en) |
| CN (1) | CN101394866B (en) |
| HK (1) | HK1126690A1 (en) |
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| WO (1) | WO2007102608A1 (en) |
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| JP7409759B2 (en) * | 2017-10-11 | 2024-01-09 | 小林製薬株式会社 | Oral composition |
| WO2020098981A1 (en) * | 2018-11-16 | 2020-05-22 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Surfactant-stabilized fluid interface and dispersion comprising one or more droplets having a surfactant stabilized fluid interface |
| CN110184316A (en) * | 2019-05-24 | 2019-08-30 | 华南理工大学 | A method of strengthening lignocellulosic using modified beta-glucosidase and digests |
| CN110538149B (en) * | 2019-09-24 | 2021-10-01 | 太原理工大学 | Anticancer drug carrier with pH response and tumor targeting and preparation method thereof |
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| IE66830B1 (en) * | 1987-08-12 | 1996-02-07 | Hem Res Inc | Topically active compositions of double-stranded RNAs |
| RU2193574C2 (en) * | 1995-04-14 | 2002-11-27 | Казунори Катаока | Polyoxyethylene with sugar by one end and other functional group by other end and method of its synthesis |
| AU5346896A (en) * | 1995-04-19 | 1996-11-07 | Kazunori Kataoka | Heterotelechelic block copolymers and process for producing the same |
| WO1997002025A1 (en) * | 1995-06-30 | 1997-01-23 | P And Pf Co., Ltd. | Antibacterial/bactericidal/antiseptic agent, dermatologic preparation, and detergent composition |
| CA2229068A1 (en) * | 1995-08-10 | 1997-02-20 | Masao Kato | Block polymer having functional groups on its both ends |
| JP3615721B2 (en) * | 2001-07-13 | 2005-02-02 | ナノキャリア株式会社 | Method for producing drug-containing polymer micelle |
| JP2003342168A (en) * | 2002-05-24 | 2003-12-03 | Nano Career Kk | Method for producing polymer micelle preparation containing drug for injection |
| JP2005008614A (en) * | 2003-03-28 | 2005-01-13 | Nano Career Kk | Drug delivery system for ophthalmology by using macromolecular micelle |
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Non-Patent Citations (3)
| Title |
|---|
| G. Kwon, et al.Block copolymer micelles for drug delivery: loading and release of doxorubicin.《Journal of Controlled Release》.1997,第48卷(第2-3期),摘要，第195页左栏第1段，第196页左栏第4段，第201页左栏第2段. * |
| Kazunori Kataoka,et al.Block copolymer micelles as vehicles for drug delivery.《Journal of Controlled Release》.1993,第24卷(第1-3期),第123页右栏第1段-第125页右栏第1段. * |
| Masayuki Yokoyama, et al.Preparation of Micelle-Forming Polymer-Drug Conjugatesl.《Bioconjugate Chemistry》.1992,第3卷(第4期),第295页左栏第1段-第296页左栏第2段. * |
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| JPWO2007102608A1 (en) | 2009-07-23 |
| HK1126690A1 (en) | 2009-09-11 |
| KR20080106219A (en) | 2008-12-04 |
| WO2007102608A1 (en) | 2007-09-13 |
| TW200812641A (en) | 2008-03-16 |
| CN101394866A (en) | 2009-03-25 |
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