Surfactant composition comprising polyhydroxyalkanoate-based amphiphilic block copolymer

Abstract

The present invention relates to a surfactant composition comprising a polyhydroxyalkanoate (PHA)-based amphiphilic block copolymer. The surfactant composition has high stability for the human body and the environment due to excellent biodegradability and biocompatibility thereof, and a hemostatic agent and a medical adhesive which comprise same are effective in hemostasis, wound healing, tissue adhesion, and the inhibition of bacterial infection.

Description

Surfactant composition comprising a polyhydroxyalkanoate-based amphiphilic block copolymer

[0001] The present invention relates to a surfactant composition comprising a polyhydroxyalkanoate-based amphiphilic block copolymer and to a medical adhesive and cosmetic composition comprising the same.

[0002] Surfactants play a crucial role in the modern medical and cosmetic industries. Through cleansing, emulsifying, and dispersing functions, surfactants significantly improve the quality and performance of products such as cosmetics, medical products, and detergents. In cleansing, surfactants remove contaminants. In emulsifying, they stably bind immiscible substances like water and oil. Their dispersing function helps maintain product stability by evenly distributing particles.

[0003] However, existing synthetic surfactants pose various challenges in terms of environmental sustainability and human safety. Many synthetic surfactants are non-biodegradable, accumulating in the environment and causing pollution. Because these substances are difficult to break down in the natural environment, they can cause problems such as water and soil pollution. For example, if synthetic surfactants accumulate in aquatic ecosystems, they can cause water pollution, and if they accumulate in soil, they can harm soil health.

[0004] Furthermore, synthetic surfactants that do not break down in the body can act as potential toxic substances. These substances, once absorbed, can accumulate in the body over long periods of time, potentially causing negative health effects. For example, some synthetic surfactants can accumulate in the body, negatively affecting the liver and kidneys, and can even trigger immune responses. For these reasons, the medical and cosmetic industries are demanding the development of alternative surfactants that are biocompatible and biodegradable.

[0005] The present disclosure aims to provide an environmentally friendly surfactant composition that is degradable both in vivo and in vitro.

[0006] The present disclosure aims to provide a surfactant composition that can minimize an immune response caused by absorption of a surfactant into the body and achieve wound healing, infection suppression, and antibacterial effects.

[0007] The present disclosure provides a surfactant composition comprising an amphiphilic block copolymer comprising a hydrophobic block comprising polyhydroxyalkanoate (PHA); and a hydrophilic block.

[0008] The above polyhydroxyalkanoate may include a repeating unit derived from 3-hydroxybutyrate and / or a repeating unit derived from 4-hydroxybutyrate.

[0009] Based on the total weight of the polyhydroxyalkanoate, the content of the repeating unit derived from the 4-hydroxybutyrate may be 0.1 to 60 wt%.

[0010] The above polyhydroxyalkanoate may be a poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymer.

[0011] The hydrophilic block may include at least one selected from polyethylene glycol (PEG), polyglycerol (PG), hyaluronic acid, dextran, and mannan.

[0012] The above amphiphilic block copolymer may be manufactured by treating a hydrophilic material constituting the hydrophilic block with peroxide and then mixing it with polyhydroxyalkanoate.

[0013] The weight ratio of the hydrophobic block and the hydrophilic block may be 3000:1 to 1:10.

[0014] The number average molecular weight of the hydrophilic block may be 1000 to 40000 g / mol.

[0015] The above polyhydroxyalkanoate may have a molecular weight of 10,000 to 1,200,000 g / mol.

[0016] The concentration of the above amphiphilic block copolymer may be 0.1 to 75% (w / v).

[0017] The present disclosure provides a hemostatic agent comprising a surfactant composition according to one embodiment of the present disclosure.

[0018] The present disclosure provides a medical adhesive comprising a surfactant composition according to one embodiment of the present disclosure.

[0019] The present disclosure provides a cosmetic composition comprising a surfactant composition according to one embodiment of the present disclosure.

[0020] A surfactant composition according to one embodiment of the present invention has excellent biodegradability and biocompatibility, and thus has high safety for the human body and the environment.

[0021] A surfactant composition according to one embodiment of the present invention is effective in hemostasis, wound healing, tissue adhesion, and inhibition of fungal infection.

[0022] Figure 1 is a schematic diagram showing the manufacturing process of PHA(L6)-co-PEG.

[0023] Figure 2 shows (a) the results of measuring the interfacial energy at the water-chloroform interface and (b) the stability of the emulsion observed with an optical microscope.

[0024] Figure 3 shows the size distribution of particles and the results of PDI (Polydispersity Index) measurement according to the number of times they passed through the microfludizer.

[0025] Figure 4 is a schematic diagram showing the manufacturing process of PHA(L6)-co-Dextran.

[0026] Figure 5 shows the FT-IR analysis results of PHA(L6)-co-Dextran.

[0027] Figure 6 shows the results of quantitative evaluation of (A), (B) the appearance of wound healing over time, (C) the histological course, and (D) the wound width when each sample was processed.

[0028] The present invention will be described in detail below. Terms used herein, unless specifically defined, should be interpreted as generally understood by those skilled in the art. The drawings and examples in this specification are intended to facilitate the understanding and practice of the present invention by those skilled in the art. Content that may obscure the gist of the invention may be omitted from the drawings and examples, and the present invention is not limited to the drawings and examples.

[0029] The singular forms used in this specification are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0030] Additionally, the numerical range used in the present invention includes lower and upper limits and all values ​​within that range, increments logically derived from the shape and width of the defined range, all doubly defined values, and all possible combinations of upper and lower limits of numerical ranges defined in different shapes. Unless otherwise specifically defined in the specification of the present invention, values ​​outside the numerical range that may arise due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0031] In this specification, terms such as include, have, and have mean that a feature or component described in the specification exists, and unless specifically limited, do not preclude the possibility that one or more other features or components may be added.

[0032] The present disclosure provides a surfactant composition comprising an amphiphilic block copolymer comprising a hydrophobic block comprising polyhydroxyalkanoate (PHA) and a hydrophilic block. The surfactant composition can bond living tissues while exhibiting hemostatic effects, wound healing effects, antimicrobial effects, and the like on living tissues.

[0033] The above surfactant composition may be a composition in which the amphiphilic block copolymer is dispersed in a conventional solvent or solution. Specifically, the solvent or solution is not particularly limited, but may specifically include purified water, saline solution, or PBS buffer solution. Specifically, the amphiphilic block copolymer included in the above surfactant composition may be in an amount of 0.01 to 5 wt% based on the total weight of the composition, but is not limited thereto.

[0034] The amphiphilic block copolymer included in the above surfactant composition may be an AB-type diblock copolymer, an ABA-type triblock copolymer, or an ABAB-type tetrablock copolymer, and A and B may be hydrophobic blocks or hydrophilic blocks, but are not limited thereto.

[0035] Specifically, the amphiphilic block copolymer may be a diblock copolymer connected with the [hydrophobic block]-[hydrophilic block], or may be a triblock copolymer connected with the [hydrophobic block]-[hydrophilic block]-[hydrophobic block] or [hydrophilic block]-[hydrophobic block]-[hydrophilic block].

[0036] Additionally, according to one embodiment, the weight ratio of the hydrophobic block and the hydrophilic block in the amphiphilic block copolymer may be 3000:1 to 1:10, specifically 2500:1 to 1:10, but is not limited thereto.

[0037] The hydrophilic block may include at least one selected from polyethylene glycol (PEG), polyglycerol (PG), polyvinyl alcohol (PVA), polyacrylamide (PAM), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), polyglutamic acid (PGA), levan, starch, amylose, amylopectin, cellulose, hyaluronic acid, and dextran, mannan, and specifically, polyethylene glycol (PEG), levan, It may be at least one selected from starch, amylose, amylopectin, cellulose, hyaluronic acid, dextran, and mannan, and according to one embodiment, it may include at least one selected from polyethylene glycol (PEG), hyaluronic acid, dextran, and mannan.

[0038] The number average molecular weight of the hydrophilic block may be 1000 to 40,000 g / mol, 2000 to 15000 g / mol, 3000 to 10000 g / mol or 4000 to 8000 g / mol, specifically 4000 to 5000 g / mol.

[0039] The above polyhydroxyalkanoate (PHA) may include repeating units derived from at least one selected from the group consisting of 3-hydroxybutyrate (3HB), 4-hydroxybutyrate (4HB), 3-hydroxypropionate (3HP), 3-hydroxyhexanoate (3HH), 3-hydroxyvalerate (3HV), 4-hydroxyvalerate (4HV), 5-hydroxyvalerate (5HV), and 6-hydroxyhexanoate (6HH).

[0040] According to one embodiment, the polyhydroxyalkanoate (PHA) may comprise a repeating unit derived from 3-hydroxybutyrate (3HB) and / or a repeating unit derived from 4-hydroxybutyrate (4HB).

[0041] Based on the total weight of the polyhydroxyalkanoate (PHA), the content of the repeating unit derived from 4-hydroxybutyrate may be 0.1 to 60 wt%, and specifically 1 to 48 wt%.

[0042] In one embodiment, the polyhydroxyalkanoate (PHA) may be a poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymer.

[0043] According to one embodiment, the amphiphilic block copolymer may be manufactured by treating a hydrophilic material constituting the hydrophilic block with a peroxide and then mixing the treated material with polyhydroxyalkanoate (PHA). Specifically, the hydrophilic material may be treated with a peroxide to introduce an aldehyde group (-CHO), and the produced aldehyde group may react with polyhydroxyalkanoate (PHA) to form a copolymer. Specifically, the peroxide may be sodium peroxide (NaIO4), hydrogen peroxide (H2O2), potassium persulfate (K₂S₂O), or ammonium persulfate ((NH₄)₂S₂O), and more specifically, may be sodium peroxide (NaIO4).

[0044] The above polyhydroxyalkanoate may have a molecular weight (weight average molecular weight) of 10,000 to 1,200,000 g / mol, specifically 20,000 to 1,100,000 g / mol, 30,000 to 1,000,000 g / mol, 40,000 to 900,000 g / mol, 45,000 to 850,000 g / mol, 50,000 to 800,000 g / mol, 60,000 to 750,000 g / mol, 70,000 to 700,000 g / mol, 80,000 to 600,000 g / mol, 90,000 to 500,000 g / mol, 100,000 to The molecular weight of the polyhydroxyalkanoate (PHA) may be 400,000 g / mol, 200,000 to 800,000 g / mol, or 300,000 to 700,000 g / mol. As the molecular weight of the polyhydroxyalkanoate (PHA) is within the above range, the adhesive performance to living tissue can be improved.

[0045] The concentration of the amphiphilic block copolymer in the surfactant composition of the present disclosure may be 0.1 to 75% (w / v), and specifically, 0.2 to 70% (w / v), 0.2 to 60% (w / v), 0.2 to 50% (w / v), 0.3 to 40% (w / v), 0.3 to 30% (w / v), 0.3 to 25% (w / v), 0.3 to 16% (w / v), 0.35 to 15.6% (w / v), 0.7 to 13% (w / v), 3 to 11% (w / v), or 6 to 9% (w / v). When the concentration of the amphiphilic block copolymer in the surfactant composition is within the above range, the hemostatic efficacy, wound healing efficacy, and adhesive performance of the surfactant composition of the present disclosure can be significantly improved.

[0046] The present disclosure provides a hemostatic agent comprising a surfactant composition according to one embodiment of the present disclosure. The hemostatic agent has low immunogenicity, excellent biocompatibility, and can effectively stop bleeding. The surfactant composition of the present disclosure can effectively stop bleeding in injured biological tissue by including the amphiphilic block copolymer.

[0047] The above hemostatic agent may be formulated in various forms. Specifically, the hemostatic agent according to one embodiment of the present disclosure may have a formulation such as a powder, liquid, gel, or sheet (film) form.

[0048] The present disclosure provides a medical adhesive comprising a surfactant composition according to one embodiment of the present disclosure. The medical adhesive may have a tissue adhesion strength of 15 kPa or more, as measured at 100% relative humidity and room temperature (e.g., 20±5°C, specifically 25°C). Specifically, the medical adhesive may have an adhesion strength to a living tissue of 1 to 50 kPa, 2 to 50 kPa, 3 to 40 kPa, or 5 to 30 kPa. Since the adhesion strength to a living tissue is within the above range, the medical adhesive may exhibit high adhesion performance not only to a living tissue without moisture but also to a living tissue with moisture (e.g., a tissue with a wet surface, or a tissue in water).

[0049] In one embodiment of the present disclosure, a medical adhesive may further comprise a biocompatible polymer and / or adhesive material in addition to the surfactant composition comprising the amphiphilic block copolymer. The biocompatible polymer may be, specifically, a polysaccharide polymer such as catechol, caffeic acid, gallic acid, tannin; chitosan, hyaluronic acid, alginic acid, dextran, etc.; or a protein polymer such as collagen, gelatin, etc. The adhesive material may specifically be protamine, mussel adhesive protein, or squid sucker tooth protein (suckerin).

[0050] Additionally, the medical adhesive may further comprise a commonly known pharmacologically active substance. The pharmacologically active substance may be, specifically, an analgesic, anti-inflammatory, antibacterial, or antifungal agent.

[0051] The above medical adhesive may be formulated in various forms. Specifically, the medical adhesive according to one embodiment of the present disclosure may have a formulation such as a powder, liquid, gel, or sheet (film) form.

[0052] The present disclosure provides a cosmetic composition comprising a surfactant composition according to one embodiment of the present disclosure.

[0053] The above cosmetic composition may contain 0.5 to 50 wt% of the surfactant composition based on the total weight, and specifically, may contain 1.0 to 55 wt%, 1.5 to 45 wt%, 2.0 to 30 wt%, 2.5 to 25 wt%, or 3.0 to 20 wt%.

[0054] Hereinafter, the surfactant composition according to the present invention will be described in more detail through specific examples. However, the following examples are merely references for further explanation of the present invention and are not intended to limit the present invention, which may be implemented in various forms. Furthermore, the terminology used in the description of the present invention is merely for the purpose of effectively describing specific examples and is not intended to limit the present invention.

[0055]

[0056] [Example 1] Preparation of PHA(L6)-co-PEG

[0057] As shown in the reaction scheme in Fig. 1, a copolymer was synthesized in which the hydrophobic substance was PHA (L6: 6% of 4-hydroxybutyrate (4HB) based on 3-hydroxybutyrate (3HB)) and the hydrophilic substance was PEG (polyethylene glycol). Specifically, PHA (L6) and polyethylene glycol (polyethylene glycol, 4 kDa) were quantified at a molar ratio of 1:1.7 or 1:17, and a mixture was prepared so that the weight ratio of the total solid reactant and the solvent, 2-methoxyethyl ether, was 1:5. The mixture was then stirred at 140 °C under a nitrogen atmosphere for about 20 minutes. Dibutyltin dilaurate, the reaction catalyst, was prepared with 1 mL of the solvent, and then added to the stirred mixture at a concentration of 0.79 mM, and the reaction was continued for 1 hour. Afterwards, the reaction mixture was poured into cold water to form a precipitate, ultrasonicated at 50 °C, and the precipitate was filtered, and the washing process was repeated 2-3 times, and the final product was dried under vacuum.

[0058]

[0059] [Example 2] Preparation of PHA-co-PEG

[0060] Example 1 was performed in the same manner as Example 1, except that the composition of PHA was 3-hydroxybutyrate (3HB) alone.

[0061]

[0062] [Comparative Example 1]

[0063] PHA (L6: 3-hydroxybutyrate (3HB) content of 4-hydroxybutyrate (4HB) was 6% of that of Example 1 as Comparative Example 1.

[0064]

[0065] interfacial energy

[0066] The results of measuring the interfacial energy at the water and chloroform interface of Example 1 and Comparative Example 1 are shown in Fig. 2.

[0067] According to Fig. 2(a), Comparative Example 1 can be confirmed to have a continuous decrease in interfacial energy as the concentration of the polymer increases, whereas Example 1 can be confirmed to have a constant interfacial energy when the concentration of the copolymer is 0.25 wt%, and thus, the critical micelle point (CMC) can be confirmed to be formed at a concentration of 0.25 wt%.

[0068] In addition, as shown in Fig. 2(b), unlike Comparative Example 1, it can be confirmed that the emulsion of Example 1 is stable even after 1 day. Accordingly, it is believed that Example 1 effectively functions as a surfactant that stabilizes the interface of the emulsion compared to Comparative Example 1, which did not form a copolymer.

[0069]

[0070] Emulsion stability

[0071] In Example 1, the emulsion stability was confirmed when the molar ratio of PHA (L6) and polyethylene glycol (4 kDa) was 1:1.7 or 1:17. Specifically, in the experiment, an emulsion was formed using only the copolymer of Example 1 and distilled water using a microfluidizer, and then particles were generated by evaporating the chloroform. The size distribution of the particles and the PDI (Polydispersity Index) measurement results for each number of times they passed through the microfluidizer are shown in Figure 3.

[0072] According to Fig. 3, when the molar ratio of PHA (L6) and PEG is 1:1.7, it can be confirmed that as the number of times passing through the microfluidizer increases, the particle size becomes smaller and the distribution becomes more homogeneous. On the other hand, when the molar ratio of PHA (L6) and PEG is 1:17, it can be confirmed that the particle size and distribution are unbalanced regardless of the number of times passing through the microfluidizer.

[0073]

[0074] [Example 3] Preparation of PHA(L6)-co-Dextran

[0075] As shown in the reaction formula in Fig. 4, the same procedure as Example 1 was performed except that the hydrophilic substance was changed to dextran.

[0076] Specifically, PHA powder (L6, 50 kDa) and dextran (Dextran from 쪧Leuconostoc쪧spp. 40 kDa) were quantified at a molar ratio of 1:10, and a mixture was prepared so that the weight ratio of the solid reactant and the solvent, dimethyl sulfoxide, was approximately 1:5. The mixture was stirred at 100 °C for approximately 1 hour. After confirming that the solid reactant was partially dissolved in the solvent, a reflux condenser was connected. The reactant connected to this device was prepared with 1 mL of the reaction catalyst, p-Toluenesulfonic acid, and the solvent at 100 °C under an argon atmosphere, and then 149.4 mM was added to the stirred mixture and the reaction was continued for 4 hours. After that, 1 g of magnesium sulfate was added, the reaction was continued for 2 hours. The reactant was filtered under reduced pressure, the solid obtained was washed with distilled water, the liquid obtained was poured into cold water to precipitate, and the final obtained was dried under vacuum.

[0077]

[0078] FT-IR analysis

[0079] The FT-IR analysis results of PHA(L6)-co-Dextran synthesized through Example 3 are shown in Fig. 5. According to Fig. 5, dextran is bound to the PHA polymer and the FT-IR spectra are obtained at 3300 cm -1 Nearby and 980 cm -1 It is believed that a copolymer of PHA and dextran was formed, as a polysaccharide pattern was observed together with a PHA pattern in the vicinity.

[0080]

[0081] [Experimental Example 1] Tissue adhesion and wound healing effects

[0082] A wound of approximately 2 cm was made on the back skin of a mouse, and the adhesive effect of the wound when it was bonded with the copolymer dispersion (P8) of Example 1, a bioadhesive material (fibrin glue, FG), and when it was not treated at all (No treatment, NT) is shown in Figure 6.

[0083] In summary, it can be seen from FIGS. 6A to 6C that Example 1 heals and attaches the wound site more cleanly than FG and NT, and in particular, it can be seen from FIG. 6D that the wound area is effectively reduced.

[0084]

[0085] As described above, the present invention has been described through specific matters and limited examples and comparative examples, but these are provided only to help a more general understanding of the present invention, and the present invention is not limited to the above examples, and those skilled in the art to which the present invention pertains can make various modifications and variations based on this description.

[0086] Therefore, the idea of ​​the present invention should not be limited to the described embodiments, and all things that are equivalent or equivalent to the following claims as well as the claims are considered to fall within the scope of the idea of ​​the present invention.

Claims

1. A surfactant composition comprising an amphiphilic block copolymer comprising a hydrophobic block comprising polyhydroxyalkanoate (PHA); and a hydrophilic block.

2. In paragraph 1, A surfactant composition wherein the polyhydroxyalkanoate comprises a repeating unit derived from 3-hydroxybutyrate and / or a repeating unit derived from 4-hydroxybutyrate.

3. In paragraph 2, A surfactant composition having a content of repeating units derived from 4-hydroxybutyrate of 0.1 to 60 wt% based on the total weight of the polyhydroxyalkanoate.

4. In paragraph 1, A surfactant composition wherein the above polyhydroxyalkanoate is a poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymer.

5. In paragraph 1, A surfactant composition, wherein the hydrophilic block comprises at least one selected from polyglycerol (PG), polyethylene glycol (PEG), hyaluronic acid, dextran, and mannan.

6. In paragraph 1, The above amphiphilic block copolymer is, A surfactant composition prepared by treating a hydrophilic material constituting the hydrophilic block with peroxide and then mixing it with polyhydroxyalkanoate.

7. In paragraph 1, A surfactant composition wherein the weight ratio of the hydrophobic block and the hydrophilic block is 3000:1 to 1:

10.

8. In paragraph 1, A surfactant composition wherein the number average molecular weight of the hydrophilic block is 1000 to 40000 g / mol.

9. In paragraph 1, A surfactant composition wherein the polyhydroxyalkanoate has a molecular weight of 10,000 to 1,200,000 g / mol.

10. In paragraph 1, A surfactant composition wherein the concentration of the amphiphilic block copolymer is 0.1 to 75% (w / v).

11. A hemostatic agent comprising a surfactant composition according to any one of claims 1 to 10.

12. A medical adhesive comprising a surfactant composition according to any one of claims 1 to 10.

13. A cosmetic composition comprising a surfactant composition according to any one of claims 1 to 10.

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