WO2007102608A1 - Stabilizer for hydrophobic compounds - Google Patents

Abstract

A stabilizer for hydrophobic compounds, particularly hinokitiol, which consists of a block copolymer comprising a hydrophilic segment and a hydrophobic segment as the essential components.

Description

Hydrophobic compound stabilizer

Technical field

 The present invention is a stabilizer for stabilizing hydrophobic compounds that are unstable to heat and light, particularly hinokitiol, and is at least hydrophilic.

The present invention relates to a stabilizer composed of a block copolymer having gummen and a hydrophobic segment, and a method for stabilizing ffl using the same.

 Background art

Regardless of whether they are natural products or synthetic products, there are many compounds that have excellent activity, but their practical use in medicine, food, agricultural chemicals, etc. is often avoided because of their lack of stability. For example, in Aomori Hiba's acidic oil, there are compounds with 7-membered rings such as hinokitiol (; 6-tyaprisin), -drabrin, a-tyaprisin, α-tyaprisin, and 4-acetylroborone. Among them, hinokitiol was isolated from Taiwan cypress by Nosaka et al. In 1963, its chemical structural formula was determined, regarding bioactivity, antimicrobial activity, cytotoxicity, metalloprotease inhibitory activity, tyrosinase Many physiological activities such as inhibitory activity and plant growth inhibitory activity have been reported (Pharmaceutical Journal 39, 1283-1294 (2003); Antimicrob. Agents Chemo ther. 49, 2519-2521 (2005); Arch. Pharm. Res. 22, 335-339 (1 999)). Due to its various physiological activities, food preservation (Japanese Patent Laid-Open Nos. 6-2 7 7 0 1 9 and 6- 1 5 3 7 8 8) and prevention of discoloration (Japanese Patent Laid-Open No. 5 9-0 8) No. 5 2 7 9), and its application to the treatment of infection (W 0 9 3/1 7 5 5 9) in combination with zinc has been studied. However, Nokithiol is an inherently sublimable substance and is further rapidly decomposed by light (Fig. 1), so its use under normal circumstances is limited and has not been fully put into practical use. Am. Chem. So 83, 17 68-1769 (1961); Can. J. Microbiol. 19, 1177-1180 (1973); Biosci. Biotechnol. Biochem. 67, 1996-1998 (2003)).

 Regarding stabilization of hinokitiol, emulsification and dispersion using a method of adding an organic acid and adjusting pH to 5.0 to 6.0 (JP-A-9 1 8 8 6 20), surfactants, etc. (Japanese Laid-Open Patent Publication No. Hei 10-2 9 1 90 6), a method in which hinokitiol is converted to a salt with aluminum or / and a complex compound with an aluminum compound (W097 / 0 2 0 2 5), etc. However, neither method is sufficiently stable. Disclosure of the invention

 An object of the present invention is to stabilize a hydrophobic compound having poor stability such as thermal stability and light stability.

 The present invention includes the following aspects.

 [1] A stabilizer for stabilizing a hydrophobic compound, comprising at least a block copolymer having a hydrophilic segment and a hydrophobic segment.

 [2] The stabilizer according to [1], wherein the hydrophilic segment is polyethylene glycol.

 [3] The stabilizer according to [1] or [2], wherein the hydrophobic segment is a polyamino acid or a derivative thereof.

 [4] The stabilizer according to [3], wherein the polyamino acid is selected from the group consisting of polyglutamic acid, polyaspartic acid, derivatives thereof, and one or more mixtures thereof.

[5] The block copolymer is represented by the following formula (I) or (II): 1;] Any of the stabilizers of [4]

L,一 [(C0CHNH) (C0CHNH) ( I ) ）。 (CH,) R,

L, one [(C0CHNH) (C0CHNH) (I))). (CH,)

C00H C00-R ₅ or

R ₃ R ₄ (II)

[In the above formulas and R ₃ each independently represents a hydrogen atom or a substituted or unsubstituted lower alkyl group substituted with an optionally protected functional group, and R ₂ represents a hydrogen atom, a saturated or unsaturated group. C ^ ~ C ₂₉ represents an aliphatic force Ruponiru group or Ariru force Lupo two Le group, R ₄ represents a hydroxyl group, an aliphatic Okishi group or Ariru one lower Arukiruokishi group saturated or unsaturated, R ₅ Habe Njiru group, Represents an alkylbenzyl group or an aryl group, is — NH—, — 0—, — CO—, 1 CH ₂ —, 1 O— Z— S— Z—, 10 1 Z— NH— and 10 CO − Z - NH- (wherein, Z is a is independently ^ C alkylene group) represents a linking group selected from the group consisting of, L ₂ is one OCO- Z- CO- Oyopi one NH CO- Z - CO-, - 0 - in Z -NH- (here, Z is C, and linking group selected from the group consisting of ~ C ₄ alkylene group And n is an integer from 1 0 to 2 5 0 0, and X and y are the same or different, and their sum is 1 0 to 3 0 0, and X vs. y is 1 : 1 to 0: within the range of 1, and X and y are each randomly present, and q is an integer of 1 or 2.]

[6] Hydrophobic compounds are antibiotics, antibacterial agents, antitumor agents, anti-inflammatory agents, Antipyretic, analgesic, antiedema, antitussive agent, sedative, muscle relaxant, antiepileptic agent, antiulcer agent, antidepressant, antiallergic agent, cardiotonic agent, antiarrhythmic agent, vasodilator, Antihypertensive agent, antidiabetic agent, homeostatic agent, polypeptide, hormone agent, antioxidant, gingival disease agent and stabilizer selected from any of [1] to [5] .

 [7] The hydrophobic compound is selected from the group consisting of hinokitiol, CoQ10, vitamin E or derivatives thereof, vitamin A or derivatives thereof, vitamin C derivatives, a-lipoic acid and polyphenols [1] to [6] Any stabilizer.

 [8] The stabilizer according to [7], wherein the hydrophobic compound is hinokitiol.

 [9] A method for stabilizing a hydrophobic compound,

 A step in which a stabilizer comprising at least a hydrophilic segment and a block copolymer having a hydrophobic segment is mixed with the hydrophobic compound to cause the block copolymer to interact with the hydrophobic compound; or

 Encapsulating the hydrophobic compound with a stabilizer comprising a block copolymer having at least a hydrophilic segment and a hydrophobic segment to form a micelle;

 Comprising a method.

 [1 0] The method according to [93], wherein the hydrophilic segment is polyethylene glycol.

 [1 1] The method according to [9] or [1 0], wherein the hydrophobic segment is a polyamino acid or a derivative thereof.

 [1 2] The method according to [1 1], wherein the polyamino acid is selected from the group consisting of polyglutamic acid, polyaspartic acid or a derivative thereof, and one or more mixtures thereof.

[1 3] The block copolymer is represented by the following formula (I) or (II) Any method from [9] to [1 2]

R₅ または R, _y ] — R ₂ (I)

R ₅ or

R ₃ — OCH ₂ CH ₂ ^L 2 [(NHCHCO) _x (NHCHC0)

(II)

(II)

(G) _Q (CH

COOH C00-R ₅

[In the above formulas, R and R ₃ each independently represent a hydrogen atom or an optionally protected lower alkyl group substituted or unsubstituted, and R ₂ represents a hydrogen atom, saturated or unsaturated. Of saturation. ! ~. Represents an aliphatic carbonyl group or an arylcarbonyl group, and R ₄ is a hydroxyl group, saturated or unsaturated,. ^ Aliphatic oxy group or aryl — represents a lower alkyloxy group, R ₅ represents a benzyl group, an alkyl benzyl group or an aryl group, is —NH—, — O—, one CO—, — CH ₂ —, — O—Z—S—Z—, —0—Z—NH— and —OCO—Z—NH— (where Z is independently a linking group selected from the group consisting of (^ to alkylene groups)). represents, L ₂ is, - OCO- Z- C_〇 first and one NH CO- Z- CO-, - 0 - Z -NH - ( in here, Z is selected from the group consisting from C, ~ C ₄ alkylene group N is an integer from 1 0 to 2 5 0 0, X and y are the same or different, and their sum is 1 0 to 3 0 0, and X The pair y is in the range of 1: 1 to 0: 1, and X and y are each randomly present, and q is an integer of 1 or 2.]

[1 4] Hydrophobic compounds are antibiotics, antibacterial agents, antitumor agents, anti-inflammatory agents Antipyretic, analgesic, antiedema, antitussive agent, sedative, muscle relaxant, antiepileptic agent, antiulcer agent, antidepressant, antiallergic agent, cardiotonic agent, antiarrhythmic agent, vasodilator, blood pressure [9]-[13] The method according to any one of [9] to [13], which is selected from the group consisting of a hypotensive agent, an antidiabetic agent, a homeostatic agent, a polypeptide, a hormonal agent, an antioxidant, a gingival disease agent, and pivemin.

 [1 5] The hydrophobic compound is selected from the group consisting of hinokitiol, CoQ10, vitamin E or a derivative thereof, vitamin A or a derivative thereof, vitamin C derivative, α-lipoic acid and polyphenol [9] to [1 4 ] Either method.

 [1 6] The method according to [15], wherein the hydrophobic compound is hinokitiol. By using the block copolymer of the present invention, it is possible to stabilize a wide range of hydrophobic compounds that cause an isomerization reaction by light and / or heat. Brief Description of Drawings

 Figure 1 shows the structure of hinokitiol and its isomerization.

 Figure 2 shows the effect of various carriers on the photostability of hinokitiol.

 Figure 3 shows the effect of various carriers on the thermal stability of hinokitiol. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides a stabilizer that can be widely used for a hydrophobic compound comprising a block copolymer having a hydrophilic segment and a hydrophobic segment. In one embodiment, the stabilizer according to the present invention stabilizes hinokitiol, SDS micellar hinokitiol with sodium dodecyl sulfate (SDS), ribosomal hinokitiol with egg yolk lecithin, Compared with hinokitiol contained in the nanoparticles of remethyl methacrylate, it was confirmed that it showed higher stability to light and heat. The block copolymer that can be used in the present invention is a block copolymer comprising a hydrophilic segment and a hydrophobic segment, and these block copolymers may be any hydrophilic segment and any one as long as the purpose of the present invention is met. Forces that may contain a hydrophobic segment Specifically, the following are included. Without limitation, hydrophilic segments include poly (ethylene glycol) [or poly (ethylene oxide)], polysaccharides, poly (vinyl pyrrolidone), poly (vinyl alcohol), poly (acrylamide). ), Poly (acrylic acid), poly (methacrylic acid), poly (methacrylic acid), poly (methacrylic acid ester), poly (acrylic acid ester), polyamino acid, poly (malic acid), or their derivatives A segment of origin. Examples of polysaccharides include starch, dextran, fructan, and galactan. Of these, the poly (ethylene glycol) segment is preferably provided with various functional groups at one end, and a segment with a controlled size can be easily used.

On the other hand, the hydrophobic segment includes, but is not limited to, poly [(meth) alkyl acrylate- (meth) acrylic acid], poly (aspartic acid derivatives) and poly (glutamic acid derivatives), for example poly ( ) 8-Benzylspartate), Poly (? Benlulu L-aspartate-koaspartate), Poly (6-alkylspartate), Poly (3-alkylspartate-choaspartate), Poly (-allyl) Aspartate toca spartate), poly (ιδ — aralkyl spartate tose spartate ), Poly (iS-aralkylspartate), poly () S-aralkyl spartate-choaspartic acid, poly (iS-alkylspartamide), poly (iS-alkylspartami docosparpartic acid) ), Poly (/ 3-aralkylspartamide), poly (β-aralkylspartami docoaspartic acid), poly (a benzildar evening mate), poly (abenzyl yl L-daltam Mono-glutamic acid), poly (alkyl-alkaline mate), poly (alkyl mono-alcohol glutamate), poly (alkyl-glutamate), poly (alpha-alkyl dalmatate), poly (Faral Kildal Tame Toco Glutamate) Poly (r monoalkyl) Rutamid), Poly (r-alkylglutamidide-co-glutamate), Poly (Raralkyldultamide), Poly (Faralkyldalmitamide, Co-glutamate), Poly ( Can optionally mention poly (amino acid derivatives) such as lactide), poly (lactide coco ricoride), poly (ε_cabloractone), poly (δ-valerolactone) and poly (haplololactone) In addition, among such poly (amino acid derivative) segments, those having a forceful loxyl group in the side chain are known per se, for example,

, After removing the benzyl group of poly (iS-benzil L-aspartic acid) or poly (alpha-benzyl-L-monoglutamic acid) by hydrolysis and then ester or amino group with the corresponding alcohol or amine. In this case, by changing the reaction amount of alcohol or amine, it is possible to obtain a hydrophobic segment having a forceful loxyl group in the side chain at a desired ratio. At this time, poly (benzyl-L-aspartic acid) is converted to jS rearranged aspartic acid by hydrolysis. with aspartic acid without iS rearrangement; The aspartic acid ratio is known to be about 1: 3. Needless to say, the present invention includes a hydrophobic segment having aspartic acid and its derivatives that have undergone three rearrangements. Aspartic acid and glutamic acid can be of any optically active type or a mixture thereof. The hydrophilic segment and the hydrophobic segment can be connected via a linking group known per se, for example, an ester bond, an amide bond, an imino group, a carbon-carbon bond, an ether bond, and the like.

 In particular, examples of the block copolymer that is easy to produce and that can be conveniently used in the present invention include those represented by the following formulas (I) and (I I).

R, — OCH, CH, L,-((I)

Or

上記各式中 および R₃は、 それぞれ独立して、 水素原子または 保護されていてもよい官能基が置換したもしくは未置換低級アルキ ル基を表し、 R₂は水素原子、 飽和もしくは不飽和の C ,〜 C₂₉脂肪 族力ルポニル基またはァリ一ルカルポ二ル基を表し、 1^は水酸基 、 飽和もしくは不飽和の C ,〜 C_{3 Q}脂肪族ォキシ基またはァリール 一低級アルキルォキシ基を表し、 R₅はべンジル基、 アルキルベン ジル基またはァリル基を表す。 （但し、 R₅は 1つのブロックコポ リマー内の各アミノ酸ユニッ トにおいて任意に選択可能である。 ）-0CH ₂ CH ₂ --L2 (II)

In the above formulas and R ₃ each independently represents a hydrogen atom or a substituted or unsubstituted lower alkyl group substituted with an optionally protected functional group, R ₂ represents a hydrogen atom, saturated or unsaturated C , ~ C _{29 represents an} aliphatic group or arylcarbonyl group, 1 ^ represents a hydroxyl group, a saturated or unsaturated C, ~ C _{3 Q} aliphatic oxy group or an aryl lower alkyloxy group, R ₅ represents a benzyl group, an alkyl benzyl group or an aryl group. (However, R ₅ is one block copy. It can be arbitrarily selected for each amino acid unit in the remer. )

L and L ₂ each independently represent a linking group, n is an integer from 1 0 to 2 5 0 0, X is an integer from 1 0 to 3 0 0, and y is 1 or 2 Represents an integer. Examples of the functional group which may be protected include a hydroxyl group, an acetal, a ketal, an aldehyde, and a sugar residue. In the case where R and R ₃ represent a lower alkyl group substituted with a functional group which may be protected, the hydrophilic segment is, for example, W09 6/3 3 2 3 3 or W0 9 6 Z 3 2 4 3 4 The method described in WO 9 7 Z 0 62 0 2 can be followed. Lower alkyl means a linear or branched alkyl group having, for example, 7 or less carbon atoms, preferably 4 or less carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl groups and the like.

The linking group is not limited because it can be changed mainly by the production method of the block copolymer, but as specific examples, L i is —NH—, —0—, 100—Z—NH—, — CO—, 1 CH ₂ —, — O— Z— S — Z— and 10 CO— Z— NH— (where Z is independently a C ₄ to C ₄ alkylene group). A group selected from the group consisting of: L ₂ is 10 C 0 1 Z—CO— and 1 NH 2 CO—Z—CO— (where Z is (^ to (^ alkylene group)) Can be mentioned.

A particularly preferred block copolymer that can be used in the present invention may be abbreviated as “polyethylene glycol (PEG) -poly () 6-benzyl-L-asparagic acid) block copolymer (hereinafter“ PEG-PBLA ”). ) PEG— PBLA is, for example, PEG— PBLA— 5— 2 0 — 1 0 0 (PEG molecular weight is 5, 0 0 0, Asno \ ° Laginic acid has a degree of polymerization of 20 and benzylation rate is 100%. ), PEG— PBLA— 1 2 — 4 0 — 5 0 (PEG molecular weight 1 2, 0 0 0, false The degree of polymerization of paraformic acid is 40, the benzylation rate is 50%), PEG—PBLA—1 2—5 0—50 (the molecular weight of PEG is 12,00,00, the degree of polymerization of aspartic acid is One aspect of the present invention is that the hydrophobic compound is stabilized by micellization with a block copolymer (the drug is encapsulated in the micelle). Is possible. For example, hinokitiol is decomposed by isomerization reaction by light and / or heat, but inhibition of isomerization reaction by block copolymer is based on hinokitiol / ^ block copolymer 1 mg / 1.2 mg (hinokitiol) In a large excess of the block copolymer). Therefore, it is considered that hinokitiol is stabilized by steric inhibition of the catabolism reaction only by causing the block copolymer to interact with hinokitiol. Therefore, the stabilizer comprising the block copolymer of the present invention can be used for a wide range of hydrophobic compounds in which an isomerization reaction is caused by light and / or heat.

Therefore, the compound stabilized by the block copolymer according to the present invention is not limited to hinokitiol, but includes, for example, a wide range of compounds that cause isomerization reaction by light and Z or heat, and is not particularly limited. Antibacterial agent, Antibacterial agent, Antitumor agent, Anti-inflammatory agent, Antipyretic agent, Analgesic agent, Antiedema agent, Antitussive foot sedative agent, Sedative agent, Muscle relaxant, Antitensile agent, Antiulcer agent, Antidepressant agent Antiallergic agents, cardiotonic agents, antiarrhythmic agents, vasodilators, antihypertensive agents, antidiabetic agents, homeostatic agents, polypeptides, hormone agents, antioxidants, gingival disease agents and vitamins. Specifically, hinokitiol, amphotericin B, nice statin, pyruvinum pamoate, methotrexate, mitomycin C, daunorubicin, adriamycin, cisbratin, DACH Bratin, paclitaxel and its derivatives, vincristine, camptothecin and its derivatives, sterolide, indomethacin, methyl salicylate, phenevenyl, hinokitiol, CoQ10, pitamine E or its derivatives, vitamin A or its derivatives Derivatives, vitamin C derivatives, hylipoic acid and polyphenols.

 A particularly preferred hydrophobic compound is hinokitiol. According to the present invention, hinokitiol can be effectively used for various purposes by minimizing the influence of the superoxy sided two-ion radical generated during the thermal decomposition and photolysis of hinokitiol, and the hydroxyl radical. A composition can be provided.

 The amount of the block copolymer used as the stabilizer can be appropriately changed depending on the molecular weight of the block copolymer and the kind of the compound, and is not particularly limited, but the block copolymer with respect to the compound 1 in a molar ratio is 0.0.0. 0 1 to 10, preferably 0.0 0 1 to 1 can be used.

In the case where a micelle is produced by encapsulating a hydrophobic compound with a stabilizer comprising the block copolymer according to the present invention as one of the stabilization methods which are embodiments of the present invention, the method is not particularly limited. This can be carried out according to the method disclosed in Japanese Patent Application Laid-Open No. 2 0 0 3 — 2 6 8 1 2 or Japanese Patent Application Laid-Open No. 2 0 3 — 3 4 2 1 6 8. Specific examples include a block copolymer composed of a hydrophilic segment and a hydrophobic segment and a hydrophobic compound in a volatile organic solvent such as methyl alcohol, isopropyl alcohol, acetone, acetonitrile, methyl acetate, acetic acid. After dissolving in volatile solvents such as ethyl, tetrahydrofuran, jetyl ether, cyclohexane, and mixed solvents thereof at room temperature, the organic solvent is removed, and the resulting film is uniformly dispersed in water. Enough time, for example 2 hours to 2 4 o'clock During this period, stir at an appropriate temperature, for example, 4 ° C to room temperature. The obtained solution is appropriately irradiated with ultrasonic waves, particle size is measured using a dynamic light scattering photometer (eg, Otsuka Electronics DLS-7000DH), and gel filtration (eg, PD-10 columns, GE Healthcare Biotechnology) is performed. Science Co., Ltd.) isolates compounds that have not been incorporated into micelles.

 In addition, when a hydrophobic compound is allowed to interact with the block copolymer stabilizer according to the present invention for stabilization, both are mixed in an appropriate solvent, and a hydrophobic compound that does not interact (free compound). Can be removed.

 The stabilizer of the present invention is suitable for various uses such as pharmaceuticals, agricultural chemicals and foods. For example, the dosage form of the pharmaceutical is not particularly limited, and examples thereof include pills, granules, syrups, capsules, injections, suppositories, inhalants, and patches.

 Hereinafter, the present invention will be described specifically by showing comparative examples and examples. Example

 In the following, polyethylene glycol monopoly (j8-benzil monoL-aspartic acid) block copolymer is abbreviated as PEG-PBLA. Also, for example, when the average molecular weight of the PEG chain of the block copolymer is 12,00, polyamino acid chain 40 residues, and the benzylation rate of the polyamino acid side chain is 50%, after each block copolymer, 1 2 — 4 0-5 0

Example 1. Stabilization of Hinokitiol with Plock Copolymer

Hinokitiol (Wako, Osaka) 1 mg and PEG— PBLA— 5 1 2 0— 1 0 0, PEG— PBLA— 1 2— 4 0— 5 0 or PEG— PBLA— 1 2— 5 0 — 5 0, 1 O Weigh mg in a screw tube and dissolve it in dichloromethane. The film consisting of hinokitiol and block copolymer was obtained. To this film, 3 ml of ultrapure water was added and stirred for 12 hours at 4 ° C in the dark. The obtained micelle solution was subjected to ultrasonic irradiation for 5 minutes, the particle size was measured, and the micelle was separated from hinokitiol that was not incorporated by gel filtration (PD-10 column s). 'Hinokitiol shows maximum absorption at 3 30 nm in water, while hinokitiol encapsulated in block copolymer micelles shows maximum absorption at 3 24 nm and 3 72 nm. Table 1 below shows the hinokitiol incorporation rate (ratio of the amount of drug incorporated into the micelle relative to the starting amount, wt / wt%), encapsulation rate, and micelle size in the obtained micelles. The drug uptake rate is obtained from the molar absorption coefficient of the amount of drug not taken in, and the value obtained by subtracting this value from the starting amount of the drug as the value of the drug taken into the micelle. The encapsulation rate is the ratio (wt / w) of the amount of drug taken into the micelle relative to the starting amount of polymer. The particle size of the polymer micelle can be measured by a method well known to those skilled in the art. For example, a dynamic light scattering photometer (Otsuka Electronics Co., Ltd., DLS-7000DH) can be used according to the instructions. Table 1. Micellized hinokitiol

 No. Polymer Hinokitiol Uptake Rate Encapsulation Size Size

 (¾) (w t / wt ¾) (nm)

1 PEG-PBLA-5-20- 100 l Omg 46. 8 4. 7 47. 8

2 PEG-PBLA- 12-40 '-50 lOmg 48. 7 4. 9 55.5

3 PEG-PBLA- 12-50- -50 l Orag 46. 8 4. 7 65. 2

4 PEG-PBLA-12-50- -50 5mg 35. 2 7. 0 63. 8

5 PEG-PBLA-12-δΟ-50 -5 2.5 mg 29. 2 1 1. 7 71. 3

6 PEG-PBLA-12-50- -50 1. 2mg 34. 9 29. 1 102.4

7 PEG-PBLA- 12-δΟ -50 0. 5rag 37. 8 75. 6 21 1. 9

8 PEG-PBLA- 12-50- -50 0. lmg 32. 2 322 158.3 3 Hinokitiol 1 rag was used in all experiments. When 10 mg of polymer and lmg of hinokitiol are used as starting materials, the incorporation rate of hinokitiol is PEG— PBLA— 5— 2 0 — 1 0 0, PEG— PBLA— 1 2-5 0— 5 0, PEG— PBLA- It was highest when 1 2 — 4 0 — 5 0 was used, 4 7 — 4 9%, and the encapsulation rate was 4.7 to 4. 9% (see Table 1).

 When the amount of hinokitiol used as a starting material is 1 mg and the amount of PEG — PBLA— 1 2— 5 0 — 50 is 5 mg, 2.5 mg, 1.2 mg, 0.5 mg, 0.1 mg The amount of hinokitiol incorporated decreases as the polymer amount decreases, but the polymer amount is almost constant at 2.5 mg, 1.2 mg, and 0.5 mg, and the encapsulation rate increases. The micelle size has increased (see Table 1). Example 2. Stability of hinokitiol to light by block copolymer

An aqueous solution of micellized hinokitiol (samples from Experiments 1 to 6 shown in Table 1) was stored at room temperature under laboratory light, and changes in absorption intensity over time were measured. As shown in Figure 2, The absorption intensity at 3 24 nm was 85% after 1 day, 53% after 7 days, and 40% after 14 days, and the photodegradation of hinokitiol was suppressed by micellization. It has been shown. The results shown in Fig. 2 show the average value of absorption at 3 24 nm for micelles in Experiments 1 to 6. In other words, the isomerization reaction shown in Fig. 1 appears to be sterically hindered by micellization. This inhibition of isomerization is also observed when hinokitiol / block copolymer 1 mg / 1.2 mg is used as the starting material (hinokitiol is in a large excess relative to the block copolymer). It is suggested that steric hindrance to the isomerization reaction occurs even when is interacting with the block copolymer. Example 3. Thermal stability of micellized hinokitiol with block copolymer

 When an aqueous solution of micellized hinokitiol (samples from Experiments 1 to 6 shown in Table 1) was stored at 37 ° C in the dark and measured for changes in absorption intensity over time, the maximum absorption at 3 24 nm was It was maintained at 97% even after 14 days, indicating that the thermal decomposition of hinokitiol was completely suppressed by micellization (Fig. 3). Since the spectral change in the case of thermal decomposition is exactly the same as that in the case of photolysis, the degradation product is a wrinkled pentene derivative in both cases of photolysis and pyrolysis. Comparative example that seems to have occurred by the same mechanism 1. Stability of free hinokitiol to light or heat The stability of free hinokitiol to light or heat was evaluated in the same manner as in Examples 2 and 3. When a free hinokitiol aqueous solution was stored at room temperature under laboratory light, and the absorption intensity at 330 nm was measured over time, the absorption intensity was already reduced to 64% after 1 day. It decreased to 9% after 8 days and to 6% after 14 days (Fig. 2). At 37 ° C under shading, the absorption intensity of free hinokitiol at 30 30 nm decreased to 57% after 8 days and to 41% after 14 days (Fig. 3).

Comparative Example 2. Micelleization of hinokitiol with sodium dodecyl sulfate (S D S)

SDS (Wako, Osaka) 7.2 mg and hinokitiol 45 3 g were dissolved in 2.5 ml of ultrapure water, stirred and purified by gel filtration to obtain micelles with a particle size of 130 nm. The uptake rate of hinokitiol was 12.4%, the encapsulation rate was 0.8%, and the micellized hinokitiol by SDS showed absorption maxima at 3 2 8 11111 and 3 8 7 11111. SDS Thus, the stability of micellized hinokitiol to light or heat was evaluated in the same manner as in Examples 2 and 3 and Comparative Example 1, but the absorption intensity at 3 28 nm was measured. The absorption intensity at 3 28 nm of SDS micellar hinokitiol decreases to 65% after 1 day when stored at room temperature under laboratory light, and 40%, 14% after 7 days. Later it decreased to 30% (Fig. 2). At 37 ° C under shading, the absorption intensity at 3 28 nm decreased to 33% after 1 day, 17% after 7 days, and 14% after 14 days (Fig. 3). )

Comparative Example 3. Hinokitiol-containing ribosome

 Egg yolk lecithin (Wako, Osaka) 3 O mg was dissolved in 2 ml of dichloromethane, and then dichloromethane was volatilized under a nitrogen stream to obtain an egg yolk lecithin film. Add 1 mg of hinokitiol dissolved in 3 m 1 of ultrapure water to this film, stir at 4 ° C in the dark, and sonicate for 15 minutes and purify by gel filtration. Particles were obtained. The uptake rate of hinokitiol was 23.7%, the encapsulation rate was 0.8%, and the ribosomal hinokitiol showed absorption maxima at 3242 nm and 372 nm. The stability of ribosomal hinokitiol with egg yolk lecithin against light or heat was evaluated in the same manner as in Examples 2 and 3 and Comparative Example 1. The absorption intensity of ribosomal hinokitiol at 3 24 nm decreased to 3 8% after 1 day and was already 0% after 3 days when stored at room temperature under laboratory light (Figure 2). ) At 37 ° C under shading, the absorption intensity at 3 24 nm decreased to 75% after 1 day, to 25% after 7 days, and to 10% after 14 days (Figure 3). )

Comparative Example 4. Hinokitiol-containing polymethylmethacrylate (PMM A) nanoparticles

Hinokitiol 10 Omg and PMMA (Wako, Osaka) 2 g Dissolve in 2 ml of chloromethane, add it to 200 ml of ultrapure water containing 1 g of SDS, stir, and then put it in an ultrahigh pressure homogenizer (Microfluidizer, MicroiliUdics Corporation, MA, USA). Prepare an emulsion under the conditions of 0 0 0 bar, flow rate 1 500 m 1 / min, evaporate and remove dichloromethane, and then remove SDS and unincorporated hinokitiol by dialysis to obtain particles with a particle size of approximately 55 nm was gotten. Hinokitiol encapsulated in PMMA nanoparticles had absorption maxima at 3 24 nm and 3 66 nm, and stability evaluation against light or heat was performed in the same manner as in Examples 2 and 3 and Comparative Example 1. The absorption intensity at 3 24 nm of hinokitiol contained in PMMA nanoparticles decreases to 72% after 1 day and 25% after 7 days when stored at room temperature under laboratory light. After 14 days, it decreased to 22% (Fig. 2). At 37 ° C under shading, the hinokitiol contained in the PMMA nanoparticles was stable and maintained an absorption intensity of 92% even after 14 days. (Fig. 3).

Claims

The scope of the claims 1. a stabilizer for stabilizing a hydrophobic compound, comprising a block copolymer having at least a hydrophilic segment and a hydrophobic segment.  2. The stabilizer according to claim 1, wherein the hydrophilic segment is polyethylene glycol.  3. The stabilizer according to claim 1 or 2, wherein the hydrophobic segment is a polyamino acid or a derivative thereof.  4. The stabilizer according to claim 3, wherein the polyamino acid is selected from the group consisting of polyglutamic acid, polyaspartic acid, derivatives thereof, and one or more mixtures thereof.  5. The stabilizer according to claim 14, wherein the block copolymer is represented by the following formula (I) or (I I): R, (I)

Or R ₃ ~ 0CH ₂ CH ₂ 1 KNH R (ID

[In the above formulas and R ₃ each independently represents a hydrogen atom or a substituted or unsubstituted lower alkyl group substituted with an optionally protected functional group, and R ₂ represents a hydrogen atom, a saturated or unsaturated group. (^ ~ (Represents an aliphatic group or arylcarbonyl group, R ₄ represents a hydroxyl group , A saturated or unsaturated c, to C _{3 Q} aliphatic oxy group or an aryl single lower alkyloxy group, R ₅ represents a benzyl group, an alkyl benzyl group or an aryl group, L! Represents one NH—, one O—, — CO—, 1 CH ₂ —, — O— Z— S— Z—, 101 Z— NH— and — OCO — Z — NH— (where Z is independently C 1, C ₄ represents a linking group selected from the group consisting of an alkylene group is a), L ₂ is one OCO- Z- CO- and single NH CO- Z- CO-, - 0 - Z - NH- ( in here, Z represents a linking group selected from the group consisting of (^ to ^! Alkylene groups, n is an integer from 1 0 to 2 5 0 0, X and y are the same or different, and their sum is 1 0 to 3 0 0, and X vs. y is in the range of 1: 1 to 0: 1, and X and y are randomly present, and q is 1 or 2 Is an integer].  6. Hydrophobic compounds are antibiotics, antibacterial agents, antitumor agents, anti-inflammatory agents, antipyretic agents, analgesics, antiedema agents, antitussive heels, sedatives, muscle relaxants, antiepileptic agents, Antiulcer agent, Antidepressant agent, Antiallergic agent, Cardiotonic agent, Antiarrhythmic agent, Vasodilator, Antihypertensive agent, Antidiabetic agent, Homeostasis agent, Polypeptide, Hormone agent, Antioxidant agent, Gingival disease agent The stabilizer according to any one of claims 1 to 5, which is selected from the group consisting of and vitamins.  7. The hydrophobic compound of claim 1-6, wherein the hydrophobic compound is selected from the group consisting of hinokitiol, CoQ10, vitamin E or a derivative thereof, vitamin A or a derivative thereof, vitamin C derivative, hylipoic acid and polyphenol. The stabilizer in any one.  8. The stabilizer according to claim 7, wherein the hydrophobic compound is hinokitiol.  9. A method for stabilizing a hydrophobic compound, comprising: A stabilizer comprising at least a hydrophilic segment and a block copolymer having a hydrophobic segment is mixed with the hydrophobic compound. The step of interacting the block copolymer with the hydrophobic compound; or  Encapsulating the hydrophobic compound with a stabilizer comprising a block copolymer having at least a hydrophilic segment and a hydrophobic segment to form a micelle;  Comprising a method.  10. The method of claim 9, wherein the hydrophilic segment is polyethylene dalycol.  11. The method according to claim 9 or 10, wherein the hydrophobic segment is a polyamino acid or a derivative thereof.  12. The method according to claim 11, wherein the polyamino acid is selected from the group consisting of polyglutamic acid, polyaspartic acid, derivatives thereof, and one or more mixtures thereof.  13. The method according to any one of claims 9 to 12, wherein the block copolymer is of the following formula (I) or (I I): ( _y — R ₂ (I)

R ₅ or _{R 3 - 0CH 2 CH 2 L} 2 one _{l (NHCHCO) (NHCHC0) y} j- R 4 (II) (卜) a (CH ₂ ) _a COOH COO— K ₅ [In the above formulas, R and ₃ each independently represent a hydrogen atom or an optionally protected lower alkyl group substituted or unsubstituted, and R ₂ represents a hydrogen atom, saturated or Unsaturated (:, ~ ( ₂₉ fat R ₄ represents a hydroxyl group, a saturated or unsaturated C aliphatic oxy group or an aryl-lower alkyloxy group, R ₅ represents a benzyl group, an alkyl benzyl group or Lj represents —NH—, —O—, —CO—, 1 CH ₂ —, 1 O—Z— S—Z—, 10—Z—NH— and —OCO-Z -NH- ( here, Z is represents a linking group selected from the group consisting of 〇 independently ～〇 a ₄ alkylene group), L ₂ is one OCO- Z- CO- and single NH CO- Z- CO-, -0-Z -NH- (where Z represents a linking group selected from the group consisting of C i ^ alkylene groups, n is an integer from 1 0 to 2 5 0 0, and X and y are the same Or an integer whose sum is between 10 and 300, and X vs. y is in the range of 1: 1 to 0: 1, and X and y are respectively Present in random, q is an integer of 1 or 2].  14. Hydrophobic compounds are antibiotics, antibacterial agents, antitumor agents, anti-inflammatory agents, antipyretic agents, analgesics, antiedema agents, antitussive heels, sedatives, muscle relaxants, antiepileptic agents, Antiulcer agent, Antidepressant agent, Antiallergic agent, Cardiotonic agent, Antiarrhythmic agent, Vasodilator, Antihypertensive agent, Antidiabetic agent, Homeostasis agent, Polypeptide, Hormone agent, Antioxidant agent, Gingival disease agent The method according to any one of claims 9 to 13, which is selected from the group consisting of: and vitamins.  15. The hydrophobic compound is selected from the group consisting of hinokitiol, CoQ10, vitamin E or a derivative thereof, vitamin A or a derivative thereof, vitamin C derivative, 0! -Lipoic acid and polyphenol. ~ The method according to any one of 1 to 4.  16. The method according to claim 15, wherein the hydrophobic compound is hinokitiol.