WO2012063509A1

WO2012063509A1 - Amphipathic liquid crystal compound, micelle, and use of the compound or the micelle

Info

Publication number: WO2012063509A1
Application number: PCT/JP2011/060748
Authority: WO
Inventors: 隆志宮田; 忠浦上
Original assignee: 独立行政法人科学技術振興機構; 学校法人関西大学
Priority date: 2010-11-11
Filing date: 2011-05-10
Publication date: 2012-05-18
Also published as: JP5397822B2; JPWO2012063509A1

Abstract

Provided is a compound which can form a micelle in water, wherein a liquid crystal phase is formed in the micelle. This compound can form a micelle in water, wherein a liquid crystal phase is formed in the micelle.

Description

Amphiphilic liquid crystal compounds, micelles and their use

The present invention relates to a compound useful as, for example, a drug release carrier, an aqueous paint, a coating agent, an adhesive, an adsorbent, etc., a micelle containing the compound, and use thereof.

Amphiphilic molecules consisting of hydrophilic and hydrophobic chains are known to form micelles in water and are used in various fields.

For example, such micelles can hold hydrophobic drugs and the like in the inside, and application research to drug delivery systems (DDS) and the like has been vigorously conducted as drug carriers for controlling the release of various drugs. ing. Recently, a system that can control drug release by changing the stability of micelles due to changes in pH and temperature has been reported, and is expected to be applied to autonomous response type DDS, target-oriented type DDS, etc. Patent Document 1).

However, heretofore, no compound that forms micelles in water and forms a liquid crystal phase inside the micelle has been reported.

The present invention has been made in view of the above problems, and an object of the present invention is to realize a compound that forms a micelle in water and that forms a liquid crystal phase inside the micelle.

By realizing the above-mentioned compound, the present inventor forms a micelle that can encapsulate a substance and that can be released slowly for a certain period of time when the substance is released in response to a specific stimulus. I thought that a possible compound could be realized.

Specifically, when releasing a drug in response to a specific stimulus such as temperature, it may be effective to release it for a certain period of time rather than instantaneous release. Conventionally, micelles that respond to changes in physicochemical environment such as pH and temperature have already been reported, but most of them are accompanied by dramatic structural changes such as the collapse of micelles by external stimuli. For this reason, when such conventional micelles are used for drug release, drug release is often completed instantly. That is, in the case of using conventional micelles, since the release is controlled based on the micelle collapse in response to the stimulus, it is difficult to release the drug for a certain period of time after the stimulus response.

Therefore, in order to solve the above problems, the present inventor, as a micelle for use in drug release or the like, the molecular chain of the core portion is oriented and its orientation structure is changed by an external stimulus. A novel micelle that does not induce collapse is considered effective. However, in general micelles, hydrophobic chains aggregate in water to form a core, and hydrophilic chains contribute to stabilization of the micelle as a shell layer, and these molecular chains have a random structure. For this reason, there are no micelles in which molecular chains have molecular orientation in the core.

On the other hand, in general, liquid crystal molecules change from a liquid crystal state in which the molecules are aligned to an isotropic phase state due to a temperature change or the like, and the molecular alignment state greatly changes at the liquid crystal-isotropic phase transition point. Therefore, if the micelle core portion can form a micelle exhibiting a liquid crystal state, the present inventors will obtain a temperature-responsive micelle that changes the internal structure such as the molecular orientation state without destroying the micelle structure due to temperature change. Thought.

Furthermore, the present inventor has found that the above-mentioned novel compound forms a liquid crystal phase inside the micelle, so that it differs from conventional film-type liquid crystals and solvent-soluble liquid crystals as water-dispersed liquid crystals as aqueous paints, coating agents, adhesives, We thought that it could be applied in a wide range of fields such as adsorbents.

Therefore, the present inventor has intensively studied paying attention to liquid crystal molecules that have already been widely used for display elements and the like but have not been reported on medical materials. As a result, a compound that forms micelles in water and that forms a liquid crystal phase inside the micelle has been found, and the present invention has been completed.

That is, the compound according to the present invention is a compound that forms micelles in water in order to solve the above-mentioned problems, and is characterized by forming a liquid crystal phase inside the micelle.

According to the above configuration, the liquid crystal phase and the isotropic phase can be controlled inside the micelle by an external stimulus such as temperature. For example, if a substance such as a drug is contained inside the micelle, the temperature change etc. It is considered that the substance can be released little by little by external stimulation. Therefore, it is possible to provide a compound that can encapsulate a substance such as a drug and can form a micelle that can be sustainedly released for a certain time when releasing the substance in response to a specific stimulus. .

Furthermore, it can be expected to be used for new fields such as environment and energy, for example, water-based paints, coating agents, adhesives, adsorbents, etc., which are completely different from the fields where conventional liquid crystals are used.

As described above, the compound according to the present invention is a compound that forms a micelle in water, and is characterized by forming a liquid crystal phase inside the micelle.

For this reason, it is possible to provide a compound that forms micelles in water and that forms a liquid crystal phase inside the micelle.

It is a figure which shows the polarization micrograph of the PEG-g-LCP film in each temperature. It is a graph which shows the relationship between a PEG-g-LCP density | concentration and the fluorescence intensity of pyrene. It is a figure which shows the (a) SEM photograph, (b) TEM photograph, and (c) AFM photograph about the PEG-g-LCP polymer micelle in water. It is a figure which shows typically a PEG-g-LCP polymeric micelle. It is a graph which shows the temperature dependence of the particle size of the liquid crystal polymer micelle determined by light scattering.

Hereinafter, the present invention will be described in detail. In addition, unless otherwise indicated, the various physical properties mentioned in this specification mean values measured by the methods described in Examples described later.

(I) Compound The compound according to the present invention is a compound that forms a micelle in water, and forms a liquid crystal phase inside the micelle. In addition, the compound according to the present invention is an amphiphilic compound, exhibits a liquid crystal phase at a normal use temperature (100 ° C. or less), and can be rephrased as a compound having a molecular weight in the range of 500 to 5,000,000. Can do.

In the present specification, an “amphiphilic compound” is a compound having a hydrophilic group and a hydrophobic group in a molecule. Specifically, when an aqueous solution is used, micelles are added in an arbitrary concentration range. It means the compound that forms.

In the present specification, “micelle” means an aggregate formed by an amphiphilic compound in water, and includes aggregates of various shapes such as a spherical micelle, a layered micelle such as a vesicle, and a rod-like micelle.

So far, various amphiphilic polymers composed of hydrophilic and hydrophobic chains have been synthesized, and drug release utilizing their micelle formation has been reported. However, the core portion in which the hydrophobic chains serving as the drug holding sites are assembled has a random molecular chain, and no micelle having a high mobility and regularity like liquid crystal has been reported.

On the other hand, various liquid crystal molecules have been synthesized all over the world, but amphiphilic liquid crystal polymers exhibiting liquid crystallinity near room temperature were synthesized, and the formation of liquid crystal polymer micelles due to their self-assembly in water was completely reported. Not. The lyotropic liquid crystal formed in the coexistence with the solvent is completely different from the micelle state formed by the compound according to the present invention because the whole solution exhibits liquid crystallinity.

Therefore, if micelles whose core part is in a liquid crystal state can be prepared, there is a possibility of exhibiting unprecedented stimulus responsiveness, and wide application development as micelles that can be used in the medical field and environmental field such as DDS. Be expected. On the other hand, it is a completely new liquid crystal material in terms of liquid crystal that can be dispersed in water, and is expected to lead to the development of new fields of liquid crystal. That is, the compound according to the present invention is a material that is expected to be applied in various ways as a novel material having the characteristics of both conventional micelles and liquid crystal molecules.

The temperature range showing the liquid crystal phase in the compound is preferably in the range of 0 to 100 ° C., more preferably in the range of 15 to 60 ° C., and particularly preferably in the range of 25 to 45 ° C. preferable.

Similarly, the temperature range showing the liquid crystal phase inside the micelle is preferably in the range of 0 to 100 ° C., more preferably in the range of 15 to 60 ° C., and in the range of 25 to 45 ° C. It is particularly preferred that

In the liquid crystal phase inside the micelle, the transition temperature from the liquid crystal phase to the isotropic phase is preferably in the range of 20 to 60 ° C., more preferably in the range of 30 to 50 ° C., and 35 to 45 ° C. It is particularly preferable that the value falls within the range. Such a compound having a liquid crystal-isotropic phase transition point that becomes a liquid crystal state near room temperature and changes to an isotropic phase under appropriate conditions should be suitably used in the medical field such as DDS. Can do.

The molecular weight of the above compound is preferably in the range of 500 to 5,000,000, more preferably in the range of 1,000 to 3,000,000, and 10,000 to 1,000,000. It is particularly preferable that the value falls within the range.

The above compound preferably contains a hydrophilic group and a mesogenic group, and the chain compound preferably has a structure containing a hydrophilic group and a mesogenic group as side chains.

As the main chain of the above compound, those having a flexible structure are preferable from the viewpoint of easily aligning mesogenic groups with each other to form a liquid crystal phase. Specific examples include a structure containing an oxygen atom such as an ether bond in the main chain, such as polysiloxane or the following formula HO— (OR ¹ ) _n —OH
(Where R ¹ is a divalent hydrocarbon group, n is an integer of 1 or more)
The polyalkylene glycol represented by these, and these derivatives are mentioned.

The polysiloxane is not particularly limited as long as it is a polymer containing a siloxane bond in a repeating unit. From the viewpoint of easily introducing a hydrophilic group and a mesogenic group, the following formula is used.

(In the formula, each R is independently an organic group, preferably a hydrocarbon group, more preferably a hydrocarbon group having 1 to 5 carbon atoms. N is an integer of 1 to 10,000.)
A polysiloxane having active hydrogen in the repeating unit is preferable, such as siloxane shown in FIG.

The polyalkylene glycol may be a homopolymer such as polyethylene glycol or a copolymer such as polyethylene glycol / propylene glycol. In the case of a copolymer, the polymerization form may be a block copolymer or a random copolymer.

The hydrophilic group is not particularly limited as long as it is a substituent having higher hydrophilicity than the mesogenic group. For example, —OH, the following formula — (OR ² ) _n —OH
(In the formula, R ² is a divalent hydrocarbon group, and n is an integer of 1 to 50.)
A nonionic group such as a polyalkylene glycol group represented by: an anionic group such as —COOH, —SO ₃ H, and an alkali metal salt thereof;
-NR ³ ₂
(In the formula, R ³ is hydrogen or a monovalent hydrocarbon group.)
And cationic groups such as quaternary ammonium salts thereof and polymer chains containing them.

From the viewpoint of biocompatibility, a polyalkylene glycol group represented by — (OR ² ) _n —OH is preferred, and a polyethylene glycol group is particularly preferred.

The polyalkylene glycol group may be a group made of a homopolymer such as polyethylene glycol or a group made of a copolymer such as polyethylene glycol / propylene glycol. In the case of a group comprising a copolymer, the polymerization form may be a block copolymer or a random copolymer.

As the mesogenic group, a group having a mesogenic structure, which is a basic skeleton of a conventionally known liquid crystal molecule, can be used. The liquid crystal molecules are usually composed of a hard partial structure and one or more flexible partial structures, and this hard partial structure is generally called a rod-like or plate-like rigid partial structure as a “mesogen”.

Examples of such a mesogenic group include the following general formula-(A ¹ -B) _m -A ² -C
(Wherein A ¹ and A ² are each independently a 1,4-phenylene group, a heterocyclic group in which one or more CH groups in the 1,4-phenylene group are replaced by N; , 4-cyclohexylene group, 1,4-cyclohexylene one CH ₂ group or non-adjacent two heterocyclic group CH ₂ group to which may be replaced by O and / or S groups, 1,4-cyclohexenylene group or naphthalene-2,6-diyl group, which may have a substituent, B represents —COO—, —OCO—, —CH ₂ CH ₂ —, —OCH ₂ —, —CH ₂ O—, —CH═CH—, —C≡C—, —CH═CH—COO—, —OCO—CH═CH—, or a single bond. A monovalent organic group, and m is an integer of 1 to 10.)
When a hydrophilic group such as polyalkylene glycol is used as the chain compound, a hydrophilic group may or may not be separately provided as a side chain.

The above-mentioned compounds can be synthesized by a conventionally known method. For example, (i) a method in which a main group of a chain compound is reacted with a hydrophilic group having a group capable of reacting with the main chain and a mesogenic group having a group capable of reacting with the main chain; And a method of polymerizing a hydrophilic group having a polymerizable group, a mesogenic group having a polymerizable group, and a monomer capable of forming a polymer main chain.

More specifically, as the method of (i), as shown in the examples described later, a polysiloxane having active hydrogen is reacted with a hydrophilic group having a vinyl group and a mesogenic group having a vinyl group. Is mentioned.

Further, as the method (ii), there is a method of polymerizing an alkylene oxide such as ethylene oxide as a monomer in the presence of a hydrophilic group having a glycidyl group and a mesogenic group having a glycidyl group.

(II) Micelle The micelle according to the present invention contains the above compound according to the present invention.

As described above, the compound according to the present invention can control the liquid crystal phase and the isotropic phase inside the micelle by an external stimulus such as a temperature change. Therefore, the micelle contains a substance such as a drug. Then, the substance can be released little by little by an external stimulus such as a temperature change.

The micelles are formed in an aqueous solvent and may be composed only of the compound according to the present invention, but other surfactants, solvents, solutes, etc. may be used as long as they do not interfere with the formation of the liquid crystal phase. You may make it contain. Moreover, the said compound based on this invention which forms a micelle may use only 1 type, and may use 2 or more types together.

The shape and size of the micelle may be appropriately changed depending on the use. For example, when used as a drug release carrier, it may be appropriately changed according to the type of drug to be included.

The micelles may be formed by simply dispersing the compound according to the present invention in an aqueous solvent or by dialysis.

(III) Method for controlling drug release The method for controlling drug release according to the present invention comprises forming the drug release carrier in micelles in water, holding the drug inside the micelle, and releasing the drug by external stimulation. It is a method to control.

The external stimulus is not particularly limited as long as the liquid crystal phase inside the drug release carrier can be transferred to the isotropic phase, and examples thereof include temperature change and current.

Examples of drugs that can be held and released by the drug release carrier include plasticizers and anticancer agents.

(IV) Composition The composition according to the present invention is used for water-based paints, coating agents, adhesives or adsorbents, and contains the above-mentioned compound according to the present invention.

Since the composition contains the compound according to the present invention, it exhibits a liquid crystal phase at a normal use temperature (100 ° C. or lower). For this reason, the composition can utilize the characteristics of a liquid crystal structure having both high mobility and regularity in various applications, or the physical properties can be controlled by phase transition.

In addition to the amphiphilic compound according to the present invention, the composition contains various components generally used in water-based paints, coating agents, adhesives, adsorbents, etc., in accordance with the intended use. Can do.

That is, the present invention includes the following inventions.

In order to solve the above problems, the compound according to the present invention is a compound that forms micelles in water, and is characterized by forming a liquid crystal phase inside the micelle.

In order to solve the above problems, the compound according to the present invention is an amphiphilic compound, exhibits a liquid crystal phase at 100 ° C. or lower, and has a molecular weight in the range of 500 to 5,000,000. It is a feature.

According to the above configuration, the amphiphilic compound can form micelles in water and can form a liquid crystal phase inside the micelle. In addition, since the liquid crystal phase and the isotropic phase can be controlled by an external stimulus such as temperature inside the micelle, for example, if a substance such as a drug is contained inside the micelle, It is considered that the substance can be released little by little. Therefore, it is possible to provide a compound that can encapsulate a substance such as a drug and can form a micelle that can be sustainedly released for a certain time when releasing the substance in response to a specific stimulus. .

The compound according to the present invention preferably forms micelles in water and forms a liquid crystal phase inside the micelle.

In the compound according to the present invention, it is preferable that the inside of the micelle exhibits a liquid crystal phase at 100 ° C. or less, and the transition temperature from the liquid crystal phase to the isotropic phase is in the range of 20 to 60 ° C.

According to the above configuration, since the particle size of micelles can be controlled at a temperature close to body temperature, a compound more useful as a drug carrier for a drug delivery system (DDS) or the like can be provided. In addition, the micelles are in a liquid crystal state in the temperature range used for water-based paints, coating agents, adhesives, adsorbents, etc., and the high mobility and regularity can be used more easily.

The compound according to the present invention preferably contains a hydrophilic group and a mesogenic group.

The compound according to the present invention preferably contains a hydrophilic group and a mesogenic group as side chains in the main chain containing an oxygen atom.

In the compound according to the present invention, the main chain is preferably polysiloxane.

In the compound according to the present invention, the hydrophilic group is preferably a polyalkylene glycol group.

According to the above configuration, since the polyalkylene glycol group has high biocompatibility, a compound more useful as a drug carrier for a drug delivery system (DDS) or the like can be provided.

The micelle according to the present invention is characterized by including the above-mentioned compound according to the present invention.

According to the above configuration, the liquid crystal phase and the isotropic phase can be controlled inside the micelle by an external stimulus such as a temperature change. For example, if a substance such as a drug is contained inside the micelle, the temperature change It is considered that the substance can be released little by little by external stimulation such as. Accordingly, it is possible to provide a drug release carrier capable of enclosing a substance such as a drug and capable of forming a micelle capable of sustained release for a certain period of time when releasing the substance in response to a specific stimulus. it can.

The method for controlling the release of a drug according to the present invention is characterized in that the drug is held inside the micelle according to the present invention and the release of the drug is controlled by an external stimulus.

According to the above method, since the micelle according to the present invention is used, there is an effect that the drug can be gradually released for a certain period of time when the drug is released in response to a specific stimulus.

The composition according to the present invention is used for water-based paints, coating agents, adhesives or adsorbents, and is characterized by containing the above-mentioned compound according to the present invention.

According to the above configuration, since the present compound has characteristics that the liquid crystal polymer having a phase transition temperature in a relatively high temperature region does not have, the liquid crystal state is obtained at a normal use temperature (100 ° C. or lower). For example, a system capable of controlling physical property changes accompanying phase transition near room temperature can be provided.

Liquid crystals are widely used in the fields of display elements and high-strength fibers, and liquid crystal molecules having various structures are synthesized. Most of the liquid crystals so far are those in which the film itself forms a liquid crystal state or those that are dissolved in a certain solvent to show liquid crystals as a solution. However, when liquid crystal is used for DDS as described above, and further when used for water-based paints, coating agents, adsorbents, etc., it is not a film type liquid crystal or a solvent-soluble type liquid crystal as in the prior art, but a micelle. Thus, liquid crystal micelles in which fine liquid crystal aggregates are dispersed in an aqueous solution are useful.

Further, in the case of a conventional film type liquid crystal or solvent-soluble type liquid crystal, it is difficult to use it for DDS or the like as described above. Furthermore, even when used in water-based paints, coating agents, adhesives, adsorbents, etc., conventional film-type liquid crystals have the disadvantage of low formability because they are film-like, and are solvent-soluble. In the case of liquid crystals, a liquid crystal state is exhibited only in the presence of a solvent, so that it is necessary to use a solvent. In addition, unlike low-molecular liquid crystals, high-molecular liquid crystals often enter a liquid crystal state only at a temperature considerably higher than room temperature. The only liquid crystal polymer that can utilize the regularity and mobility of liquid crystal near room temperature is the liquid crystalline polysiloxane with side chain mesogenic groups introduced, but the liquid crystalline polysiloxanes reported so far are not amphiphilic. It was difficult to form micelles.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to the following examples.

[Synthesis Example 1: Synthesis of mesogenic group-containing monomer]
A mesogenic group-containing monomer was synthesized according to the following synthesis route.

Specifically, first, 27.6 g (0.20 mol) of p-hydroxybenzoic acid was dissolved in 70 ml of methanol, and 130 ml of a methanol solution of 33.7 g (0.60 mol) of potassium hydroxide was dissolved in the solution. The solution was added dropwise over 1 hour. To the resulting solution, 18 ml (0.22 mol) of allyl chloride was added and reacted for 6 hours under reflux conditions (70 ° C.).

After completion of the reaction, the methanol solvent and unreacted allyl chloride were removed with an evaporator and extracted several times with brine / diethyl ether. Since unreacted p-hydroxybenzoic acid is present in the ether phase and the target product p-allyloxybenzoic acid is present in the aqueous phase as a potassium salt, the aqueous phase is neutralized with hydrochloric acid, and p-allyloxybenzoic acid is obtained. The acid was precipitated and the precipitate was separated by suction filtration. The resulting precipitate was recrystallized several times with isopropanol to obtain white crystalline p-allyloxybenzoic acid.

About 330 ml of thionyl chloride was added to 11.2 g (62.9 mmol) of the obtained p-allyloxybenzoic acid, and the mixture was stirred at room temperature for 2 hours, and then unreacted thionyl chloride was removed by an evaporator. The obtained acid chloride (pale yellow liquid) was diluted with dichloromethane and added dropwise to a solution of 7.8 g (62.9 mmol) of p-methoxyphenol in dichloromethane in an ice bath over 1 hour and reacted at room temperature for 6 hours. I let you. After completion of the reaction, dichloromethane was removed with an evaporator to obtain a white solid. This was extracted several times with ethyl acetate / sodium hydroxide aqueous solution.

Since unreacted p-allyloxybenzoic acid and p-methoxyphenol are present in the aqueous phase as Na salts, the ethyl acetate phase is separated, dehydrated with anhydrous sodium sulfate, and then the solvent is removed with an evaporator. did. Finally, it was recrystallized several times with ethanol to obtain white crystal mesogen group-containing monomers.

[Example 1]
PEG-g-LCP was synthesized according to the following synthesis route.

First, 1.3 g (4.57 mmol) of the mesogenic group-containing monomer obtained in Synthesis Example 1 and 0.253 g (0.81 mmol) of polyethylene glycol methacrylate (PEGMA) (trade name: polyethylene glycol methacrylate, SIGMA-ALDRICH) and 0.339 g (97.8 μmol) of polymethylsiloxane (PMS) (trade name: SH1107, manufactured by Toray Dow Corning) were dissolved in 20 ml of toluene, and Speier catalyst (H ₂ PtCl). ₆ ) PEG-g-LCP was synthesized by reacting with 3 mg under nitrogen atmosphere at 110 ° C. for 24 hours. The PMS used was calculated by ¹ H-NMR to have an average degree of polymerization n of 55.

After completion of the reaction, the obtained yellow solution was centrifuged, and further filtered using a glass filter to remove the Speier catalyst.

The solution from which the Speier catalyst had been removed was dropped into about 100 ml of methanol to precipitate PEG-g-LCP. This utilizes the difference in solubility of the polymer in toluene and methanol. By repeating this several times, PEG-g-LCP was purified and sufficiently dried under reduced pressure.

The composition of the obtained PEG-g-LCP was determined by ¹ H-NMR, and the thermal properties were further examined by a differential scanning calorimeter (DSC).

The PMS used had a molecular weight distribution of about 500 to 5,500 from the MALDI-MS spectrum. When the average degree of polymerization n is 55, the number average molecular weight of PMS is 3,500. Since 82 mol% of mesogenic groups having a molecular weight of 284 and 10 mol% of PEGMA having a number average molecular weight of 360 are added to this PMS, the total molecular weight of the obtained PEG-g-LCP is about 18,300. Calculated.

Table 1 shows the amount of PEG chain and mesogenic group introduced into the synthesized PEG-g-LCP, its glass transition temperature (T _g ), and liquid crystal (nematic) -isotropic phase transition temperature (T _NI ). For reference, the value of polymethylsiloxane used as a raw material is also shown in Table 1.

[Comparative Example 1]
A polymer was obtained in the same manner as in Example except that PEGMA was not used and the addition amount of the mesogen group-containing monomer was changed to 0.92 g. Table 1 shows the amounts of introduced PEG chains and mesogenic groups, the glass transition temperature (T _g ), and the liquid crystal (nematic) -isotropic phase transition temperature (T _NI ).

[Comparative Example 2]
A polymer was obtained in the same manner as in Example except that PEGMA was not used and the addition amount of the mesogenic group-containing monomer was changed to 1.25 g. Table 1 shows the amounts of introduced PEG chains and mesogenic groups, the glass transition temperature (T _g ), and the liquid crystal (nematic) -isotropic phase transition temperature (T _NI ).

[Comparative Example 3]
A polymer was obtained in the same manner as in Example except that PEGMA was not used and the addition amount of the mesogen group-containing monomer was changed to 1.53 g. Table 1 shows the amounts of introduced PEG chains and mesogenic groups, the glass transition temperature (T _g ), and the liquid crystal (nematic) -isotropic phase transition temperature (T _NI ).

In Table 1, “mesogen group content” means the ratio of introduced mesogen groups to the total number of active hydrogens in PMS, and “PEG group content” means PEG relative to the total number of active hydrogens in PMS. It means the rate at which groups are introduced.

As shown in Table 1, it was found that mesogenic groups and PEG chains could be introduced into PMS by the method of Example 1. Moreover, the DSC measurement, PEG-g-LCP obtained in Example 1, the peak due to _{T g} and _{T NI} was observed.

Furthermore, from the results of Comparative Examples 1 to 3, the introduction rate of the mesogenic groups of the PMS is increased, T _g and T _NI of LCP it was confirmed to be increased gradually. On the other hand, from the results of Comparative Example 2 and Example 1, T _g and T _NI be introduced PEG as a hydrophilic chain PMS having a mesogenic group hardly changed.

Moreover, when the polymer micelle aqueous solution was prepared using the polymers obtained in Comparative Examples 1, 2, and 3 according to the preparation of the polymer micelle aqueous solution described later, precipitation was observed in any polymer. The supernatant of this aqueous polymer micelle solution was measured by dynamic light scattering, but no micelles were present in the supernatant. From this, it was found that micelles were not formed in the polymers obtained in Comparative Examples 1, 2, and 3.

<Observation with a polarizing microscope in film state>
The results of observing the liquid crystal structure of PEG-g-LCP at various temperatures with a polarizing microscope are shown in FIG.

As is clear from FIG. 1, a birefringence pattern in a polarization microscope is observed in the temperature range between T _g and T _NI of PEG-g-LCP, determined by DSC measurement, and forms a nematic phase. It was confirmed. This result also revealed that PEG-g-LCP is an amphiphilic liquid crystal polymer that exhibits a liquid crystal transition (nematic liquid crystal-isotropic phase transition) at 43 ° C.

<Critical micelle concentration (CMC)>
Generally, when a polymer micelle is formed, a hydrophobic molecule such as pyrene is incorporated into a core portion where hydrophobic chains are assembled. In the case of a hydrophobic molecule that emits fluorescence, such as pyrene, the fluorescence intensity varies greatly depending on the environment around the pyrene molecule. Therefore, the presence or absence of polymer micelles can be examined by measuring the fluorescence intensity. Using this principle, critical micelle concentration (CMC) measurement was performed.

FIG. 2 shows a change in the fluorescence intensity ratio (I ₃₇₄ / I ₃₈₅ ) of ₃₇₄ nm to 385 nm of pyrene when the PEG-g-LCP concentration is changed. From FIG. 2, it was found that the fluorescence intensity ratio gradually decreased as the PEG-g-LCP concentration increased, and the CMC was 5.0 × 10 ⁻⁴ mg / ml from the change. In addition, since the fluorescence intensity ratio I ₃₇₄ / I ₃₈₅ depends on the interaction between the dipole moment of the solvent and the excited singlet of pyrene, it is considered that there was a sharp change in the fluorescence intensity ratio near the critical micelle concentration.

In addition, the specific measuring method of CMC is as follows.

[Preparation of polymeric micelle aqueous solution]
1 mg of PEG-g-LCP was dissolved in 4 ml of dimethyl sulfoxide (DMSO), and 0.2 ml of ultrapure water was further added and sealed in a dialysis tube. The solvent exchange rate of DMSO and ultrapure water is very fast, and in order to prevent abnormal formation of self-assemblies due to abrupt changes in hydrophilicity / hydrophobicity, dialysis is carried out in a state where water is replaced with about several percent of DMSO in advance. Started. By dialysis for 48 hours in ultrapure water, an aqueous polymer micelle solution in which a self-assembly of PEG-g-LCP was formed was prepared.

The amphiphilic compound prepared in this example is a very hydrophobic compound in view of the introduction ratio of the mesogenic group, which is a hydrophobic group, and hardly dissolves simply by placing it in ultrapure water. It will cause precipitation and aggregation. For this reason, in order to form micelles at the molecular level, this compound is once dissolved in DMSO, which is a good solvent, and ultrapure water, which is a poor solvent, is uniformly diffused in the system. A dialysis method was used.

[Critical micelle concentration (CMC) measurement]
An acetone solution of 3.6 mg / 100 ml of pyrene was prepared, and 4 μl of this pyrene solution was dropped into each of the prepared polymer micelle aqueous solutions at various concentrations, at room temperature and in a dark place. Allowed to stand overnight. Thereafter, the fluorescence intensity was measured for each solution, and the critical micelle concentration (CMC) of PEG-g-LCP was determined by the change in fluorescence intensity.

<Micelle particle size>
The polymer micelle aqueous solution prepared according to [Preparation of polymer micelle aqueous solution] described above was freeze-dried, and the polymer micelle was analyzed by a scanning electron microscope (SEM), a transmission electron microscope (TEM), and an atomic force microscope (AFM). The structure was observed. As a result, as shown in FIG. 3, spherical polymer micelles of about 100 nm to 200 nm were observed. Incidentally, the scale bar in FIG. 3 is 200 nm.

Moreover, as a result of measuring the particle size of the polymer micelle in water by dynamic light scattering (DLS), the presence of particles having a diameter of about 270 nm was confirmed.

The particle size measured by light scattering showed a larger value than the polymer micelle particle size observed by SEM, TEM, or AFM, which formed a structure in which hydrophilic PEG chains spread greatly in water. This is probably because of this.

Therefore, as shown in FIG. 4, PEG-g-LCP forms polymer micelles having a diameter of about 270 nm having a hydrophobic mesogen group in water and a hydrophilic PEG chain in the shell portion in water. I understood it. Furthermore, it is considered that mesogenic groups are gathered in the core portion and show liquid crystallinity near room temperature.

Furthermore, the relationship between the particle size and temperature of the PEG-g-LCP polymer micelles was examined by DLS, and the results are shown in FIG.

As is apparent from FIG. 5, the particle size of the PEG-g-LCP polymer micelles with increasing temperature up to around 43 ° C. is T _NI is gradually decreased and became almost constant at 43 ° C. or higher. Accordingly, a liquid crystal structure in which the mesogen groups forming the core portion are aligned is formed below T _NI , but changes to an isotropic phase above T _NI , and the polymer micelle grains change with the structural change. It was thought that the diameter also changed.

From these results, it was found that PEG-g-LCP, which is an amphiphilic liquid crystal polymer, showed CMC in the vicinity of 5.0 × 10 ⁻⁴ mg / ml and formed polymeric micelles in water. Furthermore, the micelle size gradually decreased with temperature change and became constant above the liquid crystal phase transition temperature. Therefore, unlike the conventional temperature-responsive polymer micelle, the polymer micelle composed of PEG-g-LCP is a novel liquid crystal in which the regularity of the internal structure of the micelle changes greatly without the micelle collapsing at the transition point. It is considered to be a polymer micelle.

As described above, the amphiphilic liquid crystal polymer obtained in Example 1 exhibits liquid crystallinity near room temperature, and the ordered structure is greatly changed by the liquid crystal-isotropic phase transition at a predetermined temperature. In addition, since it has a hydrophobic mesogenic group and a hydrophilic polyethylene glycol (PEG) chain, it can form a polymer micelle that is stable in water.

Such polymer micelles can control the orientation of the liquid crystal structure by temperature change or the like, and can be used as a new drug release carrier that can control the release of the encapsulated drug. Further, unlike the conventional liquid crystal polymer, the present invention relates to a water-dispersed liquid crystal in which polymer micelles having an internal liquid crystal state are dispersed in water. Use in completely different new fields can also be expected.

The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention.

The compounds of the present invention are not only in the medical field such as drug-release carriers in drug delivery systems (DDS), but also in new fields such as the environment and energy, which are completely different from fields where conventional liquid crystals are used, such as It can also be used for water-based paints, coating agents, adhesives, adsorbents and the like.

Claims

A compound that forms micelles in water,
A compound that forms a liquid crystal phase inside the micelle.
An amphiphilic compound,
Showing liquid crystal phase below 100 ° C,
A compound having a molecular weight in the range of 500 to 5,000,000.
The compound according to claim 2, which forms micelles in water and forms a liquid crystal phase inside the micelles.
The inside of the micelle shows a liquid crystal phase at 100 ° C. or lower,
The compound according to claim 1 or 3, wherein a transition temperature from the liquid crystal phase to the isotropic phase in the liquid crystal phase in the micelle is in the range of 20 to 60 ° C.
The compound according to any one of claims 1 to 4, comprising a hydrophilic group and a mesogenic group.
The compound according to any one of claims 1 to 5, wherein the main chain containing an oxygen atom contains a hydrophilic group and a mesogenic group as side chains.
The compound according to claim 6, wherein the main chain is polysiloxane.
The compound according to any one of claims 5 to 7, wherein the hydrophilic group is a polyalkylene glycol group.
A micelle comprising the compound according to any one of claims 1 to 8.
10. A method for holding a drug inside the micelle according to claim 9 and controlling the release of the drug by an external stimulus.
A composition comprising the compound according to any one of claims 1 to 8, which is used in water-based paints, coating agents, adhesives or adsorbents.