阅读说明：本技术 生物材料 (Biological material ) 是由 千叶幸介 高久浩二 富川晴贵 于 2020-02-26 设计创作，主要内容包括：本发明提供一种与水接触时的保持性优异的生物材料。生物材料包含：中性酰基脂质；及两亲性嵌段共聚物,其由亲水性链段及疏水性链段构成且亲水性链段与疏水性链段之间的ClogP值之差大于1.00,两亲性嵌段共聚物的含量相对于生物材料的固体成分的总质量为1.0～20质量％。(The invention provides a biomaterial having excellent retention properties when in contact with water. The biomaterial comprises: a neutral acyl lipid; and an amphiphilic block copolymer which is composed of a hydrophilic segment and a hydrophobic segment, wherein the difference in ClogP value between the hydrophilic segment and the hydrophobic segment is greater than 1.00, and the content of the amphiphilic block copolymer is 1.0 to 20 mass% relative to the total mass of the solid components of the biomaterial.)

1. A biomaterial comprising:

a neutral acyl lipid; and

an amphiphilic block copolymer composed of a hydrophilic segment and a hydrophobic segment and having a difference in ClogP value between the hydrophilic segment and the hydrophobic segment of more than 1.00,

the content of the amphiphilic block copolymer is 1.0 to 20 mass% with respect to the total mass of the solid components of the biomaterial.

2. The biomaterial of claim 1,

the number average molecular weight of the amphiphilic block copolymer is 1000-10000.

3. The biomaterial of claim 1 or 2, wherein,

the neutral acyl lipid comprises 30-100 mass% of neutral monoacyl lipid, 0-70 mass% of neutral diacyl lipid and 0-20 mass% of neutral triacyl lipid relative to the total mass of the neutral acyl lipid.

4. The biomaterial of any one of claims 1 to 3,

the number of carbon atoms of the acyl group of the neutral acyl lipid is 6-32.

5. The biomaterial of claim 4,

the number of carbon atoms of the acyl group is 16 to 22.

6. The biomaterial of any one of claims 1-5, further comprising: at least 1 selected from the group consisting of phospholipids and quaternary ammonium salts.

7. The biomaterial of claim 6,

the number of carbon atoms of the acyl group of the phospholipid is 12-22.

8. The biomaterial of claim 6 or 7,

the number of carbon atoms of the acyl group of the phospholipid is 16-18.

9. The biomaterial of claim 6,

the quaternary ammonium cation of the quaternary ammonium salt is represented by the following formula,

[ chemical formula 1]

In the above formula, R¹、R²、R³And R⁴Each independently represents an alkyl group having 1 to 22 carbon atoms, and a hydrogen atom of the alkyl group may be substituted with an alkoxy group, an acyl group or an acyloxy group.

10. The biomaterial of claim 9,

the number of carbon atoms of an alkoxy group, an acyl group or an acyloxy group which substitutes for a hydrogen atom of the alkyl group is 16 to 18.

11. The biomaterial of any one of claims 1 to 10,

the neutral acyl lipid is acylglycerol.

12. The biomaterial of claim 11,

the acylglycerol is oleic acid glycerol.

13. The biomaterial of any one of claims 1 to 12,

the number average molecular weight of the amphiphilic block copolymer is 1000-5000.

14. The biomaterial of any one of claims 1 to 13,

the difference in ClogP value between the hydrophilic segment and the hydrophobic segment is greater than 2.00.

15. The biomaterial of any one of claims 1-14, wherein,

the hydrophobic chain segment is composed of polycaprolactone.

16. The biomaterial of any one of claims 1-15,

the amphiphilic block copolymer is a triblock copolymer.

17. The biomaterial of claim 16,

the triblock copolymer is of a structure of polycaprolactone-polytetrahydrofuran-polycaprolactone.

18. The biomaterial of any one of claims 1-17,

a liquid crystal phase is formed by contacting the biomaterial with water.

19. The biomaterial of claim 18,

the liquid crystal phase is any 1 selected from the group consisting of a hexagonal columnar phase, a lamellar phase, a sponge phase, a bicontinuous cubic phase, and a mixed state of 2 or more of them.

20. The biomaterial according to any one of claims 1 to 19, which is for mucosal protection.

21. The biomaterial according to claim 20, which is for oral mucosal protection.

22. The biomaterial according to any one of claims 1 to 19 for sustained release of a pharmaceutical agent.

Technical Field

The present invention relates to a biomaterial.

Background

In cancer patients, cancer treatment affects the oral mucosa and tends to cause stomatitis. For example, in anticancer agent therapy, when a drug which easily causes stomatitis is administered, in radiotherapy of head and neck cancer (cancer ranging from head to neck), stomatitis inevitably occurs when the oral mucosa is directly irradiated with radiation. Stomatitis is so painful that it cannot eat.

As symptomatic treatments for stomatitis, there are the following treatments: a patch that is directly attached to the affected part (for example,25 μ g, manufactured by Taisho Pharmaceutical co., ltd; triamcinolone acetonide (Triamcinolone acetonide) as an active ingredient, and an Ointment applied to an affected part (for example, dexamethasone Ointment for Oral administration (dexalton Oral increment), Nippon Kayaku co., ltd.; dexamethasone (Dexamethasone) as an active ingredient, and a spray for spraying onto an affected part (for example,capsules are applied externally with 50 μ g, made by TEIJIN PHARMA LIMITED; beclomethasone propionate (active ingredient) and the like.

However, these therapeutic agents contain steroids (steroids) as an immunosuppressive agent as an active ingredient, and therefore are not ideal for cancer patients.

Further, when a patient eats, the patch applied to the affected part peels off, or the ointment or spray applied to the affected part disappears, so that pain due to stomatitis cannot be suppressed.

Materials capable of suppressing such pain in stomatitis are expected.

For example, patent document 1 describes "a nonaqueous preformulation containing a low viscosity mixture of: i) a non-polymeric slow release matrix; ii) at least 1 living compatible (preferably oxygen containing) organic solvent; iii) at least 1 peptide active; and iv) at least 1 fat-soluble acid. "(claim 1).

Further, patent document 2 describes "an oil-in-water emulsion in which oil droplets having a diameter in the range of 5nm to several hundred micrometers exhibit a nano-sized self-assembled structure having hydrophilic regions having a diameter size in the range of 0.5 to 200nm due to the presence of a lipophilic additive, and which contains an active ingredient present in a range of 0.00001% to 79% based on the entire composition. "(claim 1).

Prior art documents

Patent document

Patent document 1: japanese Kokai publication No. 2010-536838

Patent document 2: japanese Kokai publication Hei-2009-516724

Disclosure of Invention

Technical problem to be solved by the invention

However, the non-aqueous preformulation described in patent document 1 and the oil-in-water emulsion described in patent document 2 do not satisfy the level of the retentivity upon contact with water (the adherence to the mucosa in the wet colorful environment) as shown by the comparative example described later, and there is room for improvement.

Accordingly, an object of the present invention is to provide a biomaterial having excellent retention properties when in contact with water.

Means for solving the technical problem

As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by using a biomaterial containing a predetermined component, and have completed the present invention.

(1) A biomaterial comprising

A neutral acyl lipid; and

an amphiphilic block copolymer composed of a hydrophilic segment and a hydrophobic segment and having a difference in ClogP value between the hydrophilic segment and the hydrophobic segment of more than 1.00,

the content of the amphiphilic block copolymer is 1.0 to 20 mass% based on the total mass of the solid components of the biomaterial.

(2) The biomaterial according to (1), wherein,

the amphiphilic block copolymer has a number average molecular weight of 1000 to 10000.

(3) The biomaterial according to (1) or (2), wherein,

the neutral acyl lipid comprises 30-100 mass% of neutral monoacyl lipid, 0-70 mass% of neutral diacyl lipid and 0-20 mass% of neutral triacyl lipid relative to the total mass of the neutral acyl lipid.

(4) The biomaterial according to any one of (1) to (3), wherein,

the neutral acyl lipid has 6-32 carbon atoms in the acyl group.

(5) The biomaterial according to (4), wherein,

the number of carbon atoms of the acyl group is 16 to 22

(6) The biomaterial according to any one of (1) to (5), further comprising at least 1 selected from the group consisting of phospholipids and quaternary ammonium salts.

(7) The biomaterial according to (6), wherein,

the number of carbon atoms of the acyl group is 16 to 22.

(8) The biomaterial according to (6) or (7), wherein,

the number of carbon atoms of the acyl group is 16 to 22.

(9) The biomaterial according to (6), wherein,

the quaternary ammonium cation of the quaternary ammonium salt is represented by the following formula.

(10) The biomaterial according to (9), wherein,

the number of carbon atoms of an alkoxy group, an acyl group or an acyloxy group which is a hydrogen atom of the substituted alkyl group is 16 to 18.

(11) The biomaterial according to any one of (1) to (10), wherein,

the neutral acyl lipid is acylglycerol.

(12) The biomaterial according to (11), wherein,

the acylglycerol is oleic glycerol.

(13) The biomaterial according to any one of (1) to (12), wherein,

the amphiphilic block copolymer has a number average molecular weight of 1000 to 5000.

(14) The biomaterial according to any one of (1) to (13), wherein,

the difference in ClogP values between the hydrophilic and hydrophobic segments is greater than 2.00.

(15) The biomaterial according to any one of (1) to (14), wherein,

the hydrophobic segment is composed of polycaprolactone.

(16) The biomaterial according to any one of (1) to (15), wherein,

the amphiphilic block copolymer is a triblock copolymer.

(17) The biomaterial according to (16), wherein,

the triblock copolymer is a structure of polycaprolactone-polytetrahydrofuran-polycaprolactone.

(18) The biomaterial according to any one of (1) to (17), wherein,

a liquid crystal phase is formed by contacting it with water.

(19) The biomaterial according to (18), wherein,

the liquid crystal phase is any 1 selected from the group consisting of a hexagonal columnar phase, a lamellar phase, a sponge phase, a bicontinuous cubic phase, and a mixed state of 2 or more of them.

(20) The biomaterial according to any one of (1) to (19), which is for mucosal protection.

(21) The biomaterial according to (20), which is for protecting oral mucosa.

(22) The biomaterial according to any one of (1) to (19), which is for mucosal protection.

Effects of the invention

According to the present invention, a biomaterial having excellent retention properties when in contact with water can be provided.

Detailed Description

In this specification, the range represented by the term "to" includes both ends of the term "to".

For example, the range represented by "a to B" includes a and B.

In the present specification, the solid component refers to a component contained in the biological material other than the dispersion medium component, and its state is calculated as a solid component even when it is in a liquid state.

The biomaterial of the invention comprises a neutral acyl lipid and a defined amphiphilic block copolymer.

The biomaterial of the present invention has excellent retention properties when in contact with water. In addition, in the biomaterial of the present invention, the use of the amphiphilic block copolymer suppresses the occurrence of "sagging" and improves the usability.

The components of the biomaterial of the present invention will be described below.

< neutral acyl lipid >

Neutral acyl lipids refer to acyl lipids that are electrically neutral. That is, the neutral acyl lipid does not contain a cation portion and an anion portion. In addition, acyl lipids refer to lipids that contain an acyl group.

Examples of the neutral acyl lipid include neutral monoacyl lipid, neutral diacyl lipid, and neutral triacyl lipid.

In the biomaterial of the present invention, the neutral acyl lipid includes a neutral monoacyl lipid and a neutral diacyl lipid, and the total content of the neutral monoacyl lipid and the neutral diacyl lipid is preferably 80 to 100% by mass, more preferably 90 to 100% by mass, and still more preferably 100% by mass, based on the total mass of the neutral acyl lipid.

The content of the neutral monoacyl lipid is not particularly limited, but is preferably 30 to 100% by mass, more preferably 40 to 100% by mass, and still more preferably 40 to 80% by mass, based on the total mass of the neutral acyl lipid.

The content of the neutral diacyl lipid is not particularly limited, but is preferably 0 to 70% by mass, more preferably 0 to 60% by mass, and still more preferably 20 to 60% by mass, based on the total mass of the neutral diacyl lipid.

The content of the neutral triacyl lipid is not particularly limited, but is preferably 0 to 20% by mass, more preferably 0 to 10% by mass, based on the total mass of the neutral acyl lipid.

Among these, the neutral monoacyl lipid composition preferably contains 40 to 100 mass% of neutral monoacyl lipid and 0 to 60 mass% of neutral diacyl lipid, and the neutral triacyl lipid composition contains 0 to 20 mass% of neutral triacyl lipid, and more preferably contains 40 to 80 mass% of neutral monoacyl lipid and 20 to 60 mass% of neutral diacyl lipid, and the neutral triacyl lipid composition contains 0 to 10 mass% of neutral triacyl lipid, from the viewpoint that the formed liquid crystal phase shows a more preferable phase (for example, hexagonal columnar (H2) phase).

The number of carbon atoms of the acyl group of the neutral acyl lipid is not particularly limited, but is preferably 6 to 32, and more preferably 16 to 22.

The hydrocarbon group of the carbonyl group other than the acyl group is preferably a saturated or unsaturated chain hydrocarbon group having 6 to 32 carbon atoms, and more preferably a saturated or unsaturated chain hydrocarbon group having 16 to 22 carbon atoms. Examples of the hydrocarbon group include CH₃(CH₂)₁₄-、CH₃(CH₂)₇CH＝CH(CH₂)₇-and CH₃(CH₂)₄(CH＝CHCH₂)₂(CH₂)₆-。

When the neutral acyl lipid has 2 or more acyl groups in 1 molecule, the acyl groups may be the same as or different from each other.

Neutral acyl lipids are lipids obtained by ester-bonding a fatty acid with a polyhydric alcohol such as glycerol, diglycerol, sugar (e.g., inositol), and succinic acid. Among them, acylglycerol is preferable, and oleic acid glycerol is more preferable.

Examples of the acylglycerol include monoacylglycerol, diacylglycerol, and triacylglycerol.

Examples of the oleic acid glycerol include monooleic acid glycerol, dioleic acid glycerol, and triolein.

In addition, monoacylglycerol and monoolein correspond to one form of the neutral monoacyl lipid, diacylglycerol and dioleoyl glycerol correspond to one form of the neutral diacyl lipid, and triacylglycerol and triolein correspond to one form of the neutral triacyl lipid.

In the present specification, the content ratio of the neutral monoacyl lipid, the neutral diacyl lipid and the neutral triacyl lipid in the neutral acyl lipid is measured by a High Performance Liquid Chromatography (HPLC) method.

HPLC measurement conditions

Pipe column: imtakt Cadenza CD-C18(4.6 mm. times.300 mm)

Eluent: tetrahydrofuran water

Flow rate: 1.0mL/min

And (3) detection: corona CAD (Corona charged particle detector)

Temperature of the pipe column: 50 deg.C

The content of the neutral acyl lipid in the biomaterial of the present invention is not particularly limited, but is preferably 35 to 85 mass%, more preferably 55 to 75 mass%, based on the total mass of the solid components of the biomaterial of the present invention.

< amphiphilic Block copolymer >

The biomaterial of the invention comprises an amphiphilic block copolymer.

The amphiphilic block copolymer is a block copolymer comprising a hydrophilic segment and a hydrophobic segment. Therefore, when the amphiphilic block copolymer is used in the biomaterial of the present invention, the hydrophilic segment is disposed in the core (aqueous phase) of the liquid crystal micelle formed by the neutral acyl lipid, and the hydrophobic segment is disposed in the oil phase. By disposing the hydrophilic segment and the hydrophobic segment of the amphiphilic block copolymer in the aqueous phase and the oil phase of the liquid crystal micelle as described above, the amphiphilic block copolymer functions as a linker of the liquid crystal micelle, thereby stabilizing the liquid crystal micelle, and thus the liquid crystal phase is advanced, and the retentivity of the biomaterial of the present invention when it is contacted with water is improved. Further, by using the amphiphilic block copolymer, the viscosity of the material before contact with water (in a preformulation state) increases, and sagging of the material can be suppressed.

The segment is a structural unit constituting each block in the block copolymer and is composed of a specific repeating unit.

The hydrophilic segment is a segment showing hydrophilicity. In particular, hydrophilic segments are segments having a ClogP value of less than-0.60. From the viewpoint of further improving the effect of the present invention, the ClogP value of the hydrophilic segment is preferably-0.70 or less, more preferably-0.80 or less. The lower limit is not particularly limited and is preferably-3.00 or more.

The hydrophobic segment is a segment showing hydrophobicity. Specifically, the hydrophobic segment means a segment having a ClogP value of-0.60 or more. From the viewpoint of further improving the effect of the present invention, the ClogP value of the hydrophobic segment is preferably 0.00 or more, and more preferably 1.00 or more. The upper limit is not particularly limited, but is preferably 4.00 or less.

In the above definition, polypropylene oxide (PPO) was treated as a hydrophobic segment (Japan Oil Chemists' Society impurity, volume 49, No. 10 (2010)), and set based on the ClogP value of PPO being-0.55.

In addition, ClogP value is distribution based on the ratio of the concentrations of the organic compounds distributed respectively in the two-phase system of water and octanol, and is an index representing the hydrophobicity of the organic compound.

In the present specification, the ClogP value of a segment is a value obtained by calculating the ClogP value of a 3-mer of the repeating units constituting the segment using chemfice Professional 2016.

Further, a 3-mer of the repeating units constituting the segment corresponds to a compound in which 3 repeating units are connected and hydrogen atoms are arranged at both ends. More specifically, for example, the repeating unit is- (OCH)₂CH₂) The hydrophilic segment composed of polyethylene oxide represented by the formula-has a ClogP value corresponding to H- (OCH) in which 3 repeating units are connected and hydrogen atoms are arranged at both ends₂CH₂)-(OCH₂CH₂)-(OCH₂CH₂) ClogP of the compound represented by the formula-H.

The amphiphilic block copolymer may have a hydrophilic segment and a hydrophobic segment, and may be, for example, a diblock copolymer (so-called AB-type block copolymer) composed of 1 hydrophilic segment and 1 hydrophobic segment, or a triblock copolymer (so-called ABA-type block copolymer) composed of 3 segments, i.e., a hydrophilic segment-a hydrophobic segment-a hydrophilic segment or a hydrophobic segment-a hydrophilic segment-a hydrophobic segment.

The type of the polymer constituting the hydrophilic segment is not particularly limited, and examples thereof include polyethylene oxide (PEO) (ClogP value: -1.48) and Polytetrahydrofuran (PTHF) (ClogP value: -0.81).

The kind of the polymer constituting the hydrophobic segment is not particularly limited, and examples thereof include polylactic acid (PLA) (ClogP value: 2.46), Polycaprolactone (PCL) (ClogP value: 0.19), and polypropylene oxide (PPO) (ClogP value: 0.55).

The difference in ClogP values between the hydrophilic and hydrophobic segments is greater than 1.00. Among them, from the viewpoint of further improving the effect of the present invention, the difference in ClogP value is preferably greater than 2.00, and more preferably 3.00 or more. The upper limit is not particularly limited, but is preferably 5.00 or less, and more preferably 4.50 or less.

Examples of the amphiphilic block copolymer include a polyethylene oxide (PEO) -polylactic acid (PLA) diblock copolymer, a Polycaprolactone (PCL) -polyethylene oxide (PEO) -Polycaprolactone (PCL) triblock copolymer, and a Polycaprolactone (PCL) -Polytetrahydrofuran (PTHF) -Polycaprolactone (PCL) triblock copolymer.

The number average molecular weight of the amphiphilic block copolymer is not particularly limited, but is preferably 1000 to 10000, more preferably 1000 to 5000, from the viewpoint of further improving the effect of the present invention.

In the present invention, the number average molecular weight of the amphiphilic block copolymer is a value measured by GPC (gel permeation chromatography) under the following measurement conditions.

Pipe column: TOSOH TSK guardcolumn Super HZ-H

TOSOH TSK gel Super HZM-H

TOSOH TSK gel Super HZ 4000

TOSOH TSK gel Super HZ 2000

Eluent: tetrahydrofuran (containing stabilizer)

Flow rate: 0.35mL/min

Temperature: 40 deg.C

A detector: RI (differential refractor)

The content of the amphiphilic block copolymer in the biomaterial of the present invention is 1.0 to 20 mass%, preferably 5.0 to 15 mass%, based on the total mass of the solid components of the biomaterial of the present invention.

< other ingredients >

The biomaterial of the invention may comprise other components in addition to the components described above.

(phospholipid)

The biomaterial of the invention may comprise phospholipids.

The phospholipid is not particularly limited as long as it is a lipid having a phosphate structure in its molecular structure, and typical examples thereof include glycerophospholipids having a glycerol skeleton (glycerophospholipids) and sphingophospholipids having a sphingosine skeleton (sphingophospholipids).

Whether the phospholipid is a glycerophospholipid or a sphingomyelin, it has an acyl group derived from a fatty acid in the molecule.

The number of carbon atoms of the acyl group of the phospholipid is not particularly limited, and is preferably 12 to 22, more preferably 16 to 18.

The hydrocarbon group other than the carbonyl group of the acyl group is preferably a saturated or unsaturated chain hydrocarbon group having 11 to 21 carbon atoms, and more preferably a saturated or unsaturated chain hydrocarbon group having 15 to 17 carbon atoms. Examples of the hydrocarbon group include CH₃(CH₂)₁₄-、CH₃(CH₂)₇CH＝CH(CH₂)₇-and CH₃(CH₂)₄(CH＝CHCH₂)₂(CH₂)₆-。

When the phospholipid has 2 or more acyl groups in 1 molecule, the acyl groups may be the same as or different from each other.

Specific examples of the phospholipid include phosphatidylcholine. Acyl of phosphatidyl choline is excellentSelected from palmitic acid (CH)₃(CH₂)₁₄COOH), oleic acid (CH)₃(CH₂)₇CH＝CH(CH₂)₇COOH), or linoleic acid (CH)₃(CH₂)₄(CH＝CHCH₂)₂(CH₂)₆COOH). Specific examples of the phosphatidylcholine include PO phosphatidylcholine (phosphatidylcholine having hexadecanoic acid at the 1-position (α -position), oleic acid at the 2-position (β -position), and choline at the 3-position (γ -position)), DL phosphatidylcholine (phosphatidylcholine having linoleic acid at the 1-position (α -position), linoleic acid at the 2-position (β -position), and choline at the 3-position (γ -position)), and Dipalmitoylphosphatidylcholine (Dipalmitoylphosphatidylcholine).

The content of the phospholipid in the biomaterial of the present invention is not particularly limited, and is preferably 15 to 65% by mass, more preferably 25 to 45% by mass, in total, based on the total mass of the solid components of the biomaterial of the present invention, and the quaternary ammonium salt described below.

(Quaternary ammonium salt)

The biomaterial of the invention may comprise a quaternary ammonium salt.

The quaternary ammonium salt is an ionic compound composed of a quaternary ammonium cation and an anion.

The quaternary ammonium cation is of the formula NR₄ ⁺The indicated positively charged polyatomic ion. Here, R represents an alkyl group or an aryl group, and each of the R groups may be the same or different.

Among them, the quaternary ammonium cation of the quaternary ammonium salt is preferably a quaternary ammonium cation represented by the following formula.

[ chemical formula 1]

In the above formula, R¹、R²、R³And R⁴Each independently represents an alkyl group having 1 to 22 carbon atoms, and a hydrogen atom of the alkyl group may be substituted with an alkoxy group, an acyl group or an acyloxy group.

The number of carbon atoms of an alkoxy group, an acyl group or an acyloxy group which is a hydrogen atom of the substituted alkyl group is preferably 16 to 18.

The quaternary ammonium salt is preferably a di-long alkyl quaternary ammonium salt.

The di-long-chain alkyl quaternary ammonium salt is represented by the formula NR₄ ⁺2 of the R of the quaternary ammonium cations represented are salts of long chain alkyl groups. The other 2R are each independently lower alkyl or aryl. Here, the long-chain alkyl group represents an alkyl group having 8 or more carbon atoms, and the short-chain alkyl group represents an alkyl group having 1 to 7 carbon atoms.

In the biomaterial of the present invention, the number of carbon atoms in the long chain alkyl group of the quaternary ammonium cation of the di-long chain alkyl quaternary ammonium salt is preferably 12 to 22, and more preferably 16 to 18.

Examples of such a long chain alkyl group include a hexadecyl group, a heptadecyl group (heptadeceyl group), and an octadecyl group. The 2 long-chain alkyl groups may be the same as or different from each other.

Examples of the quaternary ammonium salts include dioleoyloxytrimethylpropane ammonium chloride (DOTAP), dioctadecyltrimethylpropane ammonium chloride (DOTMA), didecyldimethylammonium chloride, didecyldimethylammonium bromide, dicocoyldimethylammonium chloride, dicocoyldimethylammonium bromide, dilauryldimethylammonium chloride, diethyldimethylammonium chloride, hexacosyldimethylammonium bromide, distearyldimethylammonium chloride, distearyldimethylammonium bromide, dioleyldimethylammonium chloride, behenyldimethylammonium bromide, dialkyldimethylammonium chloride, dialkyldimethylammonium bromide, dicocoylethylethylhydroxyethylmethylammonium methylsulfate, dipalmitoylethylhydroxyethylmethylammonium methylsulfate, and distearoylethylhydroxyethylmethylammonium methylsulfate.

These quaternary ammonium salts may be used in combination of 2 or more.

The content of the quaternary ammonium salt in the biomaterial of the present invention is not particularly limited, and is preferably 15 to 65% by mass, more preferably 25 to 45% by mass, in total, based on the total mass of the solid components of the biomaterial of the present invention, in terms of the sum with the aforementioned phospholipid.

(nonaqueous Dispersion Medium)

The biomaterial of the invention may comprise a non-aqueous dispersion medium.

The nonaqueous dispersion medium is not particularly limited, and is preferably an alcohol-based solvent, and more preferably ethanol, cetyl alcohol, stearyl alcohol, or propylene glycol, from the viewpoint of not adversely affecting the human body.

The concentration of the solid content in the biomaterial of the present invention is not particularly limited, but is preferably 80% by mass or more, and more preferably 90% by mass or more, based on the total mass of the biomaterial of the present invention. The upper limit is 100% by mass.

The biomaterial of the invention preferably comprises substantially no water. The substantial absence of water means that the content of water is 1.0 mass% or less with respect to the total mass of the biomaterial. The content of water is preferably 0.1 mass% or less with respect to the total mass of the biomaterial. The lower limit is not particularly limited, and is 0% by mass.

The biomaterial of the invention is capable of forming a liquid crystalline phase upon contact with water.

The water is not limited to pure water, and may be water (moisture) contained in an aqueous fluid other than water. Examples of the aqueous fluid other than water include saliva, interstitial fluid, blood, and lymph fluid.

The amount of water to be contacted with the biomaterial of the present invention is not particularly limited, and is preferably 20 to 1000 mass%, more preferably 30 to 500 mass%, based on the total mass of the biomaterial of the present invention.

Here, the liquid crystal phase is not particularly limited, and is 1 kind selected from the group consisting of a hexagonal (H2) phase, a lamellar (La) phase, a sponge (V2) phase, a bicontinuous cubic (L3) phase, and a mixed state of 2 or more kinds thereof, and is preferably a hexagonal columnar phase.

The temperature at which the biomaterial of the present invention is contacted with water is not particularly limited, but is preferably 20 to 40 ℃, and more preferably 35 to 40 ℃.

< method for producing biomaterial >

The biomaterial of the present invention can be produced by mixing the neutral acyl lipid, the amphiphilic block copolymer, and other components as necessary.

The method of mixing is not particularly limited, and conventionally known methods can be used.

Use and method of use of < biomaterial >

The biomaterial of the present invention is a material used in a living body, and for example, a material used in a living body for the purpose of assisting or repairing a living body which cannot exhibit its original function due to injury, disease, or the like, or a living body whose function has decreased.

The biomaterial of the present invention can be preferably used for protecting mucosa, particularly oral mucosa.

When the biomaterial of the present invention is applied to a mucous membrane, the biomaterial of the present invention is placed on the mucous membrane, and water or a solution containing water is added as necessary, so that the biomaterial of the present invention absorbs water to form a liquid crystal phase and adheres to the mucous membrane.

In particular, when the biomaterial of the present invention is applied to the oral mucosa, the biomaterial of the present invention is easy to use because it forms a liquid crystal phase from the moisture in saliva when it is attached to the oral mucosa. When the amount of saliva is small, the biomaterial of the present invention may be attached to the oral mucosa and then water may be supplied by spraying water or the like.

The biomaterial of the present invention has a low viscosity that is suppressed, and therefore can be sprayed by a sprayer to adhere to a mucous membrane.

Examples

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the following examples.

< example 1 to example 8, comparative example 1 to comparative example 9 >

(preparation of biomaterial)

The biological materials of examples 1 to 8 and comparative examples 1 to 8 were prepared by mixing the components shown in table 1 in the mixing amounts shown in table 1.

In addition, in comparative example 7, formulation a of table 1 of patent document 1 (japanese patent application publication No. 2010-536838) was prepared and used as a biomaterial.

In comparative example 8, formulation B of table 1 of patent document 1 (japanese patent application publication No. 2010-536838) was prepared and used as a biomaterial.

In comparative example 9, a biomaterial was prepared according to the procedure of example 1 of patent document 2 (japanese patent application laid-open No. 2009-516724).

< results and evaluation >

(confirmation of formation of liquid Crystal phase)

The prepared biological material (20. mu.L) was loaded on a glass slide, water (about 200. mu.L) was sprayed from above, and after removing excess water, it was covered with a cover glass, and initial observation was performed using a polarized light microscope (Nikon ECLIPSE E600 POL).

Thereafter, the liquid crystal phase was confirmed by heating together with the slide glass using a hot stage (INSTEC STC200) heated to 40 ℃.

(preparation of simulated Living body film)

A solution obtained by dissolving TDAB (tetradecylammonium bromide, manufactured by FUJIFILM Wako Pure Chemical Corporation; 50mg), polyvinyl chloride (manufactured by FUJIFILM Wako Pure Chemical Corporation; 800mg), and DOPP (di-n-octylphosphonate, manufactured by FUJIFILM Wako Pure Chemical Corporation; 0.6mL) in THF (manufactured by tetrahydrofuran, FUJIFILM Wako Pure Chemical Corporation; 10mL) was dried at room temperature in a petri dish to obtain a lipid membrane (about 200 μm thick).

The prepared lipid film was then attached to a hydrogel composed of agar (Karikorikan (registered trademark), Ina Food Industry co., ltd.; 0.5g), gellan gum (kelgel (registered trademark), CP Kelco u.s., inc.; 0.1g), and distilled water (49.4 g).

Subsequently, the surface of the lipid membrane was coated with MPC (2-methacryloyloxyethyl phosphorylcholine) polymer (LIPIDURE (registered trademark) -CM5206, manufactured by NOF corporation) to obtain a pseudo living membrane.

(evaluation of Retention)

The prepared biomaterial (1 cm. phi., 500 μm thick) was applied to the prepared simulated living membrane, and after artificial saliva (Salibate (registered trademark), manufactured by TEIJIN PHARMA LIMITED., Inc.) was sprayed, the membrane was allowed to stand for 1 minute to allow the biomaterial to absorb water, thereby preparing a sample for evaluation.

The prepared sample for evaluation was placed in a petri dish, and artificial saliva (salibat) was filled up to submerge the sample for evaluation. The petri dish was placed in a constant temperature shaker (37 ℃) and shaken so that the evaluation sample repeatedly contacted the wall of the petri dish. In this test, the time until the biomaterial that simulated the water absorption of the living body membrane disappeared by peeling or dissolution was measured, and the retentivity was evaluated according to the following criteria. The evaluation results are shown in the "evaluation" column of table 1.

AA: the material remained after shaking for 6 hours

A: disappearance of material after 6 hours of shaking

B: the material disappears after the oscillation is less than 6 hours

(evaluation of viscosity)

The biological material was loaded on the plate using a flow meter (MCR 302, manufactured by Anton Paar Japan K.K.) and the viscosity was measured at a gap0.105mm and a shear rate 1(1/s) using a conical plate of CP 25-2.

The relative viscosity of each of the examples and comparative examples was evaluated according to the following criteria, assuming that the viscosity at shear rate 1(1/s) of the liquid crystal material (comparative example 1) to which no amphiphilic polymer was added was 1. The evaluation results are shown in the "evaluation" column of table 1.

AA: more than 2 times

A: more than 1.5 times and less than 2 times

B: more than 1.1 times and less than 1.5 times

C: 1.1 times of

In table 1, the ingredients are as follows.

Oleic acid glycerol (1): 1-oleyl-rac-glycerol (> 99%, manufactured by Sigma-Aldrich Co., Ltd.)

Oleic acid glycerol (2, 3): mixed oleic acid glycerol (1), (4)

Oleic acid glycerol (4): dioleic acid (> 99%, manufactured by NU-CHECK-PREP Inc.)

Oleic acid glycerol (5): monooleic acid (> 40%, Tokyo Chemical Industry Co., Ltd.; manufactured by Ltd.)

Phosphatidylcholine: lipoid S100 (manufactured by Lipoid Co., Ltd.)

PLA-PEO-PLA: triblock copolymer comprising 3 segments of polylactic acid-polyethylene oxide-polylactic acid (Sigma Aldrich Co., Ltd.)

PCL-PEO: (manufactured by PolyScitech Co., Ltd.)

PCL-PEO-PCL: triblock copolymer comprising 3 segments of polycaprolactone-polyethylene oxide-polycaprolactone (Nu Chemie, Inc.)

PCL-PTHF-PCL: triblock copolymer comprising 3 segments of polycaprolactone-polytetrahydrofuran-polycaprolactone (Sigma Aldrich Co., Ltd.)

PEO-PPO-PEO (1): pluronic P123(Sigma-Aldrich Co., Ltd.)

PEO-PPO-PEO (2): pluronic L122 (manufactured by BASF corporation)

PPO-PEO-PPO: pluronic RPE1740 (manufactured by BASF corporation)

PEG: polyethylene glycol (manufactured by FUJIFILM Wako Pure Chemical Corporation)

PE: polyethylene (manufactured by Sigma-Aldrich Co., Ltd.)

In table 1, the type of liquid crystal phase is represented by the following abbreviation.

La: lamellar phase

H2: hexagonal columnar phase

The numerical values in the columns of the respective components in table 1 mean "parts by mass". For example, example 1 used "10 parts by mass" of PLA-PEO-PLA.

In table 1, ". star.1" in the column of "comparative example 7" means that the formulation a of table 1 of patent document 1 (japanese patent publication No. 2010-536838) was used as the biomaterial.

In table 1, "x2" in the column of "comparative example 8" means that the formulation B of table 1 of patent document 1 (japanese patent publication No. 2010-536838) was used as the biomaterial.

And ". about.3" in the column of "comparative example 9" refers to the biomaterial prepared according to the procedure of example 1 of patent document 2 (japanese patent application laid-open No. 2009-516724).

[ Table 1]

Table 1(1/2)

[ Table 2]

Table 1(2/2)

The retention of the biomaterials of examples 1 to 8 was good.

Among them, the comparison of examples 4 to 8 shows that the effects are more excellent when the neutral monoacyl lipid is contained in an amount of 40 to 100 mass% and the neutral diacyl lipid is contained in an amount of 0 to 60 mass% based on the total mass of the neutral acyl lipids, and when the neutral triacyl lipid is contained in an amount of 0 to 20 mass%.