PH responsive polymer nano-micelle as well as preparation method and application thereof

Abstract

The invention relates to a pH responsive polymer nano-micelle as well as a preparation method and application thereof. The pH-responsive polymer nano-micelle based on a polyethylene glycol unit and a diisopropylamino unit forms a compact nano-micelle protection perfume in the storage process, fundamentally solves the problem of poor stability of the perfume, and when the pH value is lower than the critical pH value, the stability of the perfume is greatly improved due to the accurate switching performance in the use process. The effect of controlling the release of the perfume is achieved through the depolymerization of the compact nano-micelles; meanwhile, the perfuming agent has excellent universality, meets the requirement for precise release of different perfumes under different environmental conditions, and is suitable for various perfuming products such as hydrophilic daily cosmetics, cleaning products and indoor air fresheners. Compared with the prior art, the amphiphilic block polymer has the advantages that the stability and the selectivity of the amphiphilic block polymer are improved, and the high sensitivity and the precise controlled release performance of the amphiphilic block polymer as a nano-micelle are also improved.

Description

Technical Field

[0001] The invention relates to the technical field of spices and flavors, and in particular to a pH-responsive polymer nano-micelle and a preparation method and application thereof. Background Art

[0002] Spices and flavors are widely used in many fields such as food, textiles, leather, papermaking, cosmetics and detergents. However, the rich variety of natural or synthetic spices has high volatility, which greatly limits their industrial applications; at the same time, most spices are organic compounds with functional groups, which are easily oxidized or decomposed into other molecules during storage and transportation. Therefore, it is of vital importance to achieve the controlled release and stabilization of spices. With the rapid development of nanomaterial technology and chemical synthesis technology, physical encapsulation-type sustained-release capsules based on polysaccharides such as chitosan and cellulose or porous materials such as silica and MOF have been widely used in the field of spices and flavors. They not only improve the stability of spices, but also extend the release time of spices (Journal of Coatings Technology and Research 2015,12,793-799). However, it is difficult to accurately control the structure of such sustained-release capsules, and the problem of spices leakage often occurs during transportation and storage; at the same time, most of these sustained-release microcapsules are in passive controlled release, and active controlled release under different conditions cannot be achieved. Therefore, improving the stability of spices and achieving precise controlled release of spices are currently challenging research hotspots in the field of spices and flavors.

[0003] pH value plays a key role in many aspects of the environment, chemistry and biology, and pH-responsive polymer nano-micelles can be amphiphilic in high pH state and then form nano-micelles, and protonate in low pH state, so that the polymer is transformed between ON (single chain) and OFF (micelle) state, so as to achieve the effect of switch controlled release. Because the polymer has ultra-sensitive response performance and excellent switching performance, it has been used in materials for drug delivery systems (Biomacromolecules 2023,24,11,4958-4969). Therefore, hydrophilic units such as polyethylene glycol are introduced, and the amino units of the hydrophobic components are introduced as protonizable hydrophobic blocks, amphiphilic block polymers are constructed, and multiple spices are self-assembled into nano-scale micelles to form stable nano-micelles to protect spices, which can fundamentally solve the problem of poor stability of spices, and release spices under acidic conditions, with excellent universality, to meet the precise release of different spices under different environmental conditions.

[0004] So far, there is no commercially available pH-responsive polymer nano-micelles for flavors and fragrances to solve the problem of compromise between flavor storage stability and release effectiveness. Therefore, there is an urgent need to develop a switchable polymer nano-micelle preparation technology and products that can achieve precise responsive release of flavors. Summary of the invention

[0005] The purpose of the present invention is to provide a pH-responsive polymer nano-micelle and its preparation method and application. The pH-responsive polymer nano-micelle based on polyethylene glycol units and diisopropylamino units has excellent switching performance, precise controlled release performance, high stability and universality, and is suitable for various flavoring products such as slightly acidic daily cosmetics, cleaning products and indoor air fresheners.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] A pH-responsive polymer nano-micelle, wherein the pH-responsive polymer nano-micelle is prepared from a pH-responsive polymer and a fragrance substance R2.

[0008] Wherein, the aromatic substance R2 is selected from any one or more of hydrocarbons, alcohols, esters, ketones or ethers;

[0009] The structure of the pH responsive polymer is shown in Formula I'-5:

[0010]

[0011] In formula I'-5, R1 is selected from any one or more of chemical groups such as alkyl, phenyl, alkoxy, amino, amide or nitro.

[0012] The n (polymerization degree of ethylene glycol monomer) is 20 to 200,

[0013] The x (pH responsive monomer polymerization degree) is 30-100.

[0014] Furthermore, the aromatic substance R2 is selected from any one or more of cinnamon essential oil, sweet orange essential oil, peppermint essential oil, cinnamaldehyde, thymol or menthone.

[0015] The present invention also provides a method for preparing pH-responsive polymer nanomicelles, the specific steps of which are as follows:

[0016] S1. preparing pH responsive polymer;

[0017] S2, dissolving the pH responsive polymer prepared in step S1 and R2 in solvent F to obtain a mixture;

[0018] S3, mixing the mixture prepared in step S2 with solvent G, and stirring to obtain pH-responsive polymer nanomicelles.

[0019] Furthermore, in step S1, the preparation method of the pH responsive polymer is as follows:

[0020] S1-1, in solvent E, reacting the compound represented by formula I'-1 with substitution reagent A under nitrogen protection for a period of time with reflux and stirring to obtain the compound represented by formula I'-2;

[0021] S1-2, in solvent E, reacting the compound represented by formula I'-3 with substitution reagent B under nitrogen protection for a period of time with reflux and stirring to obtain a compound represented by formula I'-4;

[0022] S1-3, under nitrogen protection, mixing the compound shown in formula I'-2 obtained in step S1-1, the compound shown in formula I'-4 obtained in step S1-2 and solvent E, adding catalyst C and catalyst D, and performing polymerization reaction to obtain a pH responsive polymer shown in formula I'-5;

[0023] Among them, the structural formulas of Formula I'-1 to Formula I'-5 are as follows:

[0024]

[0025] Furthermore, in step S1-1, the molar ratio of the compound represented by formula I'-1 to the substitution reagent A is 1:(1-6), preferably 1:4.

[0026] Furthermore, in step S1-1, the substitution reagent A is selected from any one or more of N-bromosuccinimide (NBS), acrylate (AE), 2-methyl-2-bromopropionyl bromide, carbon tetrabromide (CBr4) or trimethylphenylammonium tribromide.

[0027] Furthermore, in step S1-2, the molar ratio of the compound represented by formula I'-3 to the substitution reagent B is 1:(1-3), preferably 1:1.

[0028] Furthermore, in step S1-2, the substitution reagent B is selected from any one or more of acetyl chloride, benzoyl chloride, methacryloyl chloride (MACl), chloroacetyl chloride (CAC) or trichloroacetyl chloride.

[0029] Furthermore, in steps S1-1 and S1-2, the stirring time is 6 to 12 hours, and the stirring temperature is room temperature.

[0030] Furthermore, in step S1-3, the compound represented by formula I'-2: the compound represented by formula I'-4: solvent E=1 g: 0.5-1.5 g: 5-15 mL.

[0031] Furthermore, in step S1-3, the molar ratio of the compound represented by formula I'-2 to the catalyst C is 1:(1-3), preferably 1:1;

[0032] The molar ratio of the compound represented by formula I'-2 to the catalyst D is 1:(1-3), preferably 1:1.

[0033] Furthermore, in step S1-3, the catalyst C is selected from any one or more of triethylenediamine (TEDA), pentamethyldiethylenetriamine (PMDETA), N-dimethylcyclohexylamine (DMCHA), dimethylethanolamine (DMEA) or N-benzyldimethylamine (BDMA).

[0034] Furthermore, in step S1-3, the catalyst D is selected from any one or more of aluminum chloride, boron trifluoride, tin tetrachloride, cuprous bromide or zinc chloride.

[0035] Furthermore, in step S1-3, the polymerization reaction time is selected from 12h, 24h, 36h, 48h, 60h or 72h.

[0036] Furthermore, in steps S1-1, S1-2 and S1-3, the solvent E is selected from any one or more of dichloromethane, petroleum ether, ethyl acetate, N,N-dimethylformamide, toluene, tetrahydrofuran, methanol, ethanol or acetonitrile.

[0037] Furthermore, in step S2, the molar ratio of the pH responsive polymer to R2 is 1:(1-5), preferably 1:2.

[0038] Furthermore, in step S2, the mass ratio of the pH responsive polymer to the solvent F is 1:(10-100).

[0039] Furthermore, in step S3, the mass ratio of the mixture to the solvent G is 1:(100-1000).

[0040] Furthermore, in step S3, the stirring temperature is room temperature, and the stirring time is 6 to 24 hours.

[0041] Furthermore, in step S2 and step S3, the solvent F and the solvent G are selected from any one or more of deionized water, dichloromethane, petroleum ether, ethyl acetate, N,N-dimethylformamide, toluene, tetrahydrofuran, methanol, ethanol or acetonitrile.

[0042] In addition, the present invention also provides an application of a pH-responsive polymer nano-micelle, wherein the pH-responsive polymer nano-micelle is used for preparing a controlled-release flavor.

[0043] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0044] 1. The modifiable pH-responsive polymer with ultrasensitive switching performance provided by the present invention can be used for stable storage and precise controlled release after encapsulation of various active substances.

[0045] 2. The method for preparing pH-responsive polymer nano-micelles provided by the present invention prepares compact nano-scale micelles by a solvent volatilization method, providing a prerequisite for encapsulating active substances.

[0046] 3. The application of the pH-responsive polymer nano-micelles provided by the present invention in the flavor and fragrance industry is suitable for the application of various natural flavors or synthetic flavors, and is suitable for application in various fields such as daily cosmetics, cleaning products and indoor air fresheners.

[0047] 4. pH-responsive polymer nanomicelles based on polyethylene glycol units and diisopropylamino units form compact nanomicelles to protect fragrances during storage, thereby fundamentally solving the problem of poor fragrance stability. During use, due to the precise switching performance, when the pH is below the critical pH, the compact nanomicelles depolymerize to achieve the effect of controlling the release of fragrances. At the same time, they have excellent universality and can meet the precise release of different fragrances under different environmental conditions, and are suitable for a variety of fragrance products such as hydrophilic daily cosmetics, cleaning products, and indoor air fresheners.

[0048] 5. The present invention improves the stability and selectivity of amphiphilic block polymers, and also improves the high sensitivity and precise controlled release performance as nanomicelles. The polyethylene glycol unit improves the hydrophilicity and stability of the polymer, and the diisopropylamino unit realizes the switching performance of the polymer under different pH conditions. By regulating the polymerization time and thus regulating the degree of polymerization of the diisopropylamino unit, the structural requirements of various switching performances are met. At the same time, nanomicelles are formed by self-assembly, which improves the precise controlled release performance of the nanomicelles, realizes the depolymerization from tight and stable micelles into hydrophilic single chains, and can load a variety of natural or synthetic fragrances. The preparation method is simple and has a high yield, and is suitable for large-scale production. In general, this type of pH-responsive polymer nanomicelles shows significant advantages in terms of simplicity of synthesis, industrial applicability and enhanced user experience, indicating that switch-type responsive polymers have broad application prospects in the field of controlled release of fragrances. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1Schematic diagram of the technical route of pH-responsive polymer nanomicelles in the present invention, wherein the red dots in Formula I represent R2, the green dots in Formula I represent the compound shown in Formula I'-4, and the blue wavy lines in Formula I represent the compound shown in Formula I'-2;

[0050] Figure 2 Schematic diagram of the preparation process of pH-responsive polymer nanomicelles in the present invention;

[0051] Figure 3 Schematic diagram of the preparation process of CIN@PEG-PND NPs (compound shown in Formula I-1) in Example 1 of the present invention;

[0052] Figure 4 Schematic diagram of the preparation process of CIN EOs@PEG-PND NPs (compound shown in Formula I-2) in Example 2 of the present invention;

[0053] Figure 5 Schematic diagram of the preparation process of THY@PEG-PND NPs (compound shown in Formula I-3) in Example 3 of the present invention;

[0054] Figure 6 Thermogravimetric TGA graphs of the fragrance nanomicelles CIN@PEG-PND NPs (the compound shown in Formula I-1), CIN EOs@PEG-PND NPs (the compound shown in Formula I-2), and THY@PEG-PND NPs (the compound shown in Formula I-3);

[0055] Figure 7 TEM images of the fragrance nano-micelles CIN@PEG-PND NPs (compound shown in Formula I-1) in buffer solutions of different pH values ​​(pH=5, 6, 7);

[0056] Figure 8 DLS graphs of the particle size of the fragrance nanomicelles CIN@PEG-PND NPs (compound shown in Formula I-1) in buffer solutions of different pH values ​​(pH = 4, 5, 6, 7, 8, 9);

[0057] Fig. 9 The cinnamaldehyde release curve of the fragrance nanomicelles CIN@PEG-PND NPs (the compound shown in Formula I-1) in buffer solutions with different pH values ​​(pH=6, 8). DETAILED DESCRIPTION

[0058] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0059] The room temperature in the embodiments of the present invention is 25-28°C.

[0060] The reagents and materials used in the embodiments of the present invention are as follows:

[0061] Dichloromethane, triethylamine, tetrahydrofuran, polyethylene glycol monomethyl ether (Me-PEG-OH), methacryloyl chloride (MACl), etc. were purchased from Shanghai Titan Technology Co., Ltd.; cinnamaldehyde, cinnamon essential oil, thymol, etc. were purchased from Shanghai Myrel Technology Co., Ltd.

[0062] The reagents and raw materials used in the present invention are commercially available or can be prepared according to literature methods. Unless otherwise specified, percentages and parts are calculated by weight.

[0063] In conjunction with the accompanying drawings, some embodiments of the present invention are described in detail below. In the absence of conflict, the following embodiments and features in the embodiments may be combined with each other.

[0064] Example 1

[0065] This embodiment provides a method for synthesizing CIN@PEG-PND NPs (compound shown in Formula I-1), and the specific steps are as follows:

[0066] (1) Synthesis of I'-2-1

[0067]

[0068] 5 g of polyethylene glycol monomethyl ether, 228 mg of 2-methyl-2-bromopropionyl bromide and 253 mg of triethylamine were added to a three-necked flask containing 20 mL of dichloromethane, and stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, suction filtration was performed, and the obtained white filter cake was vacuum dried for 3 hours to obtain a pure white solid as shown in Formula I'-2-1, with a yield of 80%.

[0069] I'-2-1 H NMR spectrum: 1 H NMR(400MHz,Chloroform-d)δ4.34(d,J=5.1Hz,2H),3.67(d,J=1.6Hz,486H),3.40 (d,J=1.4Hz,3H),1.97(d,J=1.4Hz,7H),1.66–0.96(m,121H),0.93–0.78(m,30H).

[0070] (2) Synthesis of I'-4-1

[0071]

[0072] 1.45 g of diisopropylaminoethanol, 8.32 g of methacryloyl chloride and 5 g of triethylamine were added to a three-necked flask containing 20 mL of tetrahydrofuran, and stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, the mixture was purified by silica gel column chromatography to obtain a colorless oil as shown in Formula I'-4-1, with a yield of 47%.

[0073] I'-4-1 H NMR spectrum: 1 H NMR(400MHz,Chloroform-d)δ6.14(s,1H),5.59(q,J=1.6Hz,1H),4.12(td,J=7.1,1.6Hz,2H),3. 06(td,J=6.6,1.6Hz,2H),2.73(td,J=7.1,1.5Hz,2H),1.98(s,3H),1.06(dd,J=6.7,1.6Hz,12H).

[0074] I'-4-1 C NMR spectrum: 13 C NMR (101MHz, Chloroform-d) δ136.51,125.29,77.38,65.53,49.41,20.79,18.42.

[0075] I'-4-1 high resolution mass spectrometry: HRMS (TOF-ES+): m / z: calculate for C 12 H 24 NO2: 214.1811[M+H] + ; found: 214.1807.

[0076] (3) Synthesis of I'-5-1

[0077]

[0078] 1 g of pure white solid as shown in formula I'-2-1 and 1 g of colorless oil as shown in formula I'-4-1 were added to a Shrek tube containing 10 mL of N,N-dimethylformamide, and then 35 mg of pentamethyldiethylenetriamine and 29 mg of cuprous bromide were added thereto. The mixture was refluxed and stirred for 36, 48 and 60 hours respectively under nitrogen protection. After the reaction was completed, the mixture was freeze-dried for 12 hours to obtain a white flocculent solid (compound I'-5-1) as shown in formula I'-5-1, with a yield of 31.7%.

[0079] I'-5-1 reaction 36h H NMR spectrum: 1H NMR(401MHz,Chloroform-d)δ3.82(s,83H),3.63(s,599H),3.37(s,3H),2.97(s,82H),2.61(s,81H).

[0080] I'-5-1 reacted for 48h: 1 H NMR(400MHz,Chloroform-d)δ3.83(s,141H),3.63(s,637H),3.37(s,3H),2.98(s,140H),2.62(s,140H).

[0081] I'-5-1 reaction 60h H NMR spectrum: 1 H NMR(401MHz,Chloroform-d)δ3.81(s,210H),3.63(s,653H),3.37(s,3H),2.97(s,204H),2.61(s,201H).

[0082] (4) Synthesis of I-1

[0083] See also Figure 3 , add 0.5 g of compound I'-5-1 and 0.5 g of cinnamaldehyde into a beaker containing 10 mL of tetrahydrofuran and mix and stir. After dissolution, add the mixture into 250 mL of deionized water and stir at room temperature for 6 hours. After the reaction is completed, freeze-dry for 12 hours to obtain a light yellow flocculent solid I-1 with a yield of 25%.

[0084] Example 2

[0085] This embodiment provides a method for synthesizing CIN EOs@PEG-PND NPs (compound shown in formula I-2), and the specific steps are as follows:

[0086] (1) Synthesis of I'-2-1

[0087]

[0088] 5 g of polyethylene glycol monomethyl ether, 228 mg of 2-methyl-2-bromopropionyl bromide and 253 mg of triethylamine were added to a three-necked flask containing 20 mL of dichloromethane, and stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, suction filtration was performed, and the obtained white filter cake was vacuum dried for 3 hours to obtain a pure white solid as shown in Formula I'-2-1, with a yield of 80%.

[0089] I'-2-1 H NMR spectrum: 1H NMR(400MHz,Chloroform-d)δ4.34(d,J=5.1Hz,2H),3.67(d,J=1.6Hz,486H),3.40 (d,J=1.4Hz,3H),1.97(d,J=1.4Hz,7H),1.66–0.96(m,121H),0.93–0.78(m,30H).

[0090] (2) Synthesis of I'-4-1

[0091]

[0092] 1.45 g of diisopropylaminoethanol, 8.32 g of methacryloyl chloride and 5 g of triethylamine were added to a three-necked flask containing 20 mL of tetrahydrofuran, and stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, the mixture was purified by silica gel column chromatography to obtain a colorless oil as shown in Formula I'-4-1, with a yield of 47%.

[0093] I'-4-1 H NMR spectrum: 1 H NMR(400MHz,Chloroform-d)δ6.14(s,1H),5.59(q,J=1.6Hz,1H),4.12(td,J=7.1,1.6Hz,2H),3. 06(td,J=6.6,1.6Hz,2H),2.73(td,J=7.1,1.5Hz,2H),1.98(s,3H),1.06(dd,J=6.7,1.6Hz,12H).

[0094] I'-4-1 C NMR spectrum: 13 C NMR (101MHz, Chloroform-d) δ136.51,125.29,77.38,65.53,49.41,20.79,18.42.

[0095] I'-4-1 high resolution mass spectrometry: HRMS (TOF-ES+): m / z: calculate for C 12 H 24 NO2: 214.1811[M+H] + ; found: 214.1807.

[0096] (3) Synthesis of I'-5-1

[0097]

[0098] 1 g of pure white solid as shown in formula I'-2-1 and 1 g of colorless oil as shown in formula I'-4-1 were added to a Shrek tube containing 10 mL of N,N-dimethylformamide, and then 35 mg of pentamethyldiethylenetriamine and 29 mg of cuprous bromide were added thereto. The mixture was refluxed and stirred for 36, 48 and 60 hours respectively under nitrogen protection. After the reaction was completed, the mixture was freeze-dried for 12 hours to obtain a white flocculent solid (compound I'-5-1) as shown in formula I'-5-1, with a yield of 31.7%.

[0099] I'-5-1 reaction 36h H NMR spectrum: 1 H NMR(401MHz,Chloroform-d)δ3.82(s,83H),3.63(s,599H),3.37(s,3H),2.97(s,82H),2.61(s,81H).

[0100] I'-5-1 reacted for 48h: 1 H NMR(400MHz,Chloroform-d)δ3.83(s,141H),3.63(s,637H),3.37(s,3H),2.98(s,140H),2.62(s,140H).

[0101] I'-5-1 reaction 60h H NMR spectrum: 1 H NMR(401MHz,Chloroform-d)δ3.81(s,210H),3.63(s,653H),3.37(s,3H),2.97(s,204H),2.61(s,201H).

[0102] (4) Synthesis of I-2

[0103] See also Figure 4 , add 0.5g of compound I'-5-1 and 0.5g of cinnamon essential oil into a beaker containing 10mL of tetrahydrofuran and mix and stir. After dissolution, add the mixture into 250mL of deionized water and stir at room temperature for 6 hours. After the reaction is completed, freeze-dry for 12 hours to obtain a light yellow flocculent solid I-2 with a yield of 25%.

[0104] Example 3

[0105] This embodiment provides a method for synthesizing THY@PEG-PND NPs (compound shown in formula I-3), and the specific steps are as follows:

[0106] (1) Synthesis of I'-2-1

[0107]

[0108] 5 g of polyethylene glycol monomethyl ether, 228 mg of 2-methyl-2-bromopropionyl bromide and 253 mg of triethylamine were added to a three-necked flask containing 20 mL of dichloromethane, and stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, suction filtration was performed, and the obtained white filter cake was vacuum dried for 3 hours to obtain a pure white solid as shown in Formula I'-2-1, with a yield of 80%.

[0109] I'-2-1 H NMR spectrum: 1 H NMR(400MHz,Chloroform-d)δ4.34(d,J=5.1Hz,2H),3.67(d,J=1.6Hz,486H),3.40 (d,J=1.4Hz,3H),1.97(d,J=1.4Hz,7H),1.66–0.96(m,121H),0.93–0.78(m,30H).

[0110] (2) Synthesis of I'-4-1

[0111]

[0112] 1.45 g of diisopropylaminoethanol, 8.32 g of methacryloyl chloride and 5 g of triethylamine were added to a three-necked flask containing 20 mL of tetrahydrofuran, and stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, the mixture was purified by silica gel column chromatography to obtain a colorless oil as shown in Formula I'-4-1, with a yield of 47%.

[0113] I'-4-1 H NMR spectrum: 1 H NMR(400MHz,Chloroform-d)δ6.14(s,1H),5.59(q,J=1.6Hz,1H),4.12(td,J=7.1,1.6Hz,2H),3. 06(td,J=6.6,1.6Hz,2H),2.73(td,J=7.1,1.5Hz,2H),1.98(s,3H),1.06(dd,J=6.7,1.6Hz,12H).

[0114] I'-4-1 C NMR spectrum: 13 C NMR (101MHz, Chloroform-d) δ136.51,125.29,77.38,65.53,49.41,20.79,18.42.

[0115] I'-4-1 high resolution mass spectrometry: HRMS (TOF-ES+): m / z: calculate for C 12 H 24 NO2: 214.1811[M+H]+ ; found: 214.1807.

[0116] (3) Synthesis of I'-5-1

[0117]

[0118] 1 g of pure white solid as shown in formula I'-2-1 and 1 g of colorless oil as shown in formula I'-4-1 were added to a Shrek tube containing 10 mL of N,N-dimethylformamide, and then 35 mg of pentamethyldiethylenetriamine and 29 mg of cuprous bromide were added thereto. The mixture was refluxed and stirred for 36, 48 and 60 hours respectively under nitrogen protection. After the reaction was completed, the mixture was freeze-dried for 12 hours to obtain a white flocculent solid (compound I'-5-1) as shown in formula I'-5-1, with a yield of 31.7%.

[0119] I'-5-1 reaction 36h H NMR spectrum: 1 H NMR(401MHz,Chloroform-d)δ3.82(s,83H),3.63(s,599H),3.37(s,3H),2.97(s,82H),2.61(s,81H).

[0120] I'-5-1 reacted for 48h: 1 H NMR(400MHz,Chloroform-d)δ3.83(s,141H),3.63(s,637H),3.37(s,3H),2.98(s,140H),2.62(s,140H).

[0121] I'-5-1 reaction 60h H NMR spectrum: 1 H NMR(401MHz,Chloroform-d)δ3.81(s,210H),3.63(s,653H),3.37(s,3H),2.97(s,204H),2.61(s,201H).

[0122] (4) Synthesis of I-3

[0123] See also Figure 3 , add 0.5 g of compound I'-5-1 and 0.5 g of thymol into a beaker containing 10 mL of tetrahydrofuran and mix and stir. After dissolution, add the mixture into 250 mL of deionized water and stir at room temperature for 6 hours. After the reaction is completed, freeze-dry for 12 hours to obtain a yellow flocculent solid I-3 with a yield of 25%.

[0124] Table 1 is the gel permeation chromatography GPC and molecular weight table of each component of the precursor compound PEG-PND (compound shown in formula I'-5-1) prepared in Example 1, Example 2 and Example 3 at different polymerization reaction times (36h, 48h, 60h). It can be seen from the table that with the increase of reaction time, the degree of polymerization of diisopropylamino increases continuously, and the relative molecular weight of pH responsive polymer increases continuously, meeting the structural requirements of pH responsive polymers with different degrees of polymerization, which indicates that the polymer nano-micelles have excellent selectivity and structural controllability.

[0125] Table 1 Gel permeation chromatography (GPC) of the precursor compound PEG-PND at different polymerization reaction times and molecular weights of each component (36h, 48h, 60h)

[0126]

[0127] Figure 6 The thermogravimetric TGA graphs of CIN@PEG-PND NPs (compound shown in Formula I-1) prepared in Example 1, CINEOs@PEG-PND NPs (compound shown in Formula I-2) prepared in Example 2, and THY@PEG-PND NPs (compound shown in Formula I-3) prepared in Example 3. As can be seen from the figure, the polymer nano-micelles improve the thermal stability of cinnamaldehyde (CIN), cinnamon essential oil (CINEOs) and thymol (THY), and also show stable loading performance, which indicates the excellent universality and fragrance loading capacity of the polymer nano-micelles.

[0128] Figure 7 The TEM images of CIN@PEG-PND NPs (compound shown in Formula I-1) prepared in Example 1 in different pH buffer solutions (pH = 5, 6, 7) are shown in the figure. As can be seen from the figure, the structural morphology of the polymer nanomicelles under different pH conditions, due to the protonation behavior of diisopropylamino groups, as the pH value decreases, CIN@PEG-PND NPs depolymerize from tight micelles to single-chain states, achieving controlled release of the fragrance, which indicates the excellent pH-responsive switch performance of CIN@PEG-PND NPs.

[0129] Figure 8 The DLS graphs of the particle size of CIN@PEG-PND NPs (compound shown in Formula I-1) prepared in Example 1 in different pH buffer solutions (pH = 4, 5, 6, 7, 8, 9) are shown in the figure. As can be seen from the figure, the switching behavior of the nanomicelles in the aqueous solution is controlled by changing the pH value of the solution environment. The particle size of the polymer nanomicelles increases after depolymerization into single chains, and then decreases due to increased hydrophilicity, which indicates the excellent controlled release performance of CIN@PEG-PND NPs.

[0130] Fig. 9 The cinnamaldehyde release curves of CIN@PEG-PND NPs (compound shown in Formula I-1) prepared in Example 1 in different pH buffer solutions (pH=6, 8) are shown in the figure. It can be seen from the figure that under conditions below the critical pH value, the protonation behavior of the polymer nano-micelles leads to the rapid release of cinnamaldehyde after micelle depolymerization, with a release rate of up to 89%, while under alkaline conditions, the release rate of cinnamaldehyde is extremely low due to the micelle state, which indicates the excellent fragrance release performance of CIN@PEG-PND NPs.

[0131] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A pH-responsive polymer nanomicelle, characterized in that: The pH-responsive polymer nano-micelles are prepared from a pH-responsive polymer and a fragrance substance R2. Wherein, the aromatic substance R2 is selected from any one or more of hydrocarbons, alcohols, esters, ketones or ethers; The structure of the pH responsive polymer is shown in Formula I'-5: In formula I'-5, R1 is selected from any one or more of chemical groups such as alkyl, phenyl, alkoxy, amino, amide or nitro. The n is 20 to 200, The x is 30-100.

2. A pH-responsive polymer nanomicelle according to claim 1, characterized in that: The aromatic substance R2 is selected from any one or more of cinnamon essential oil, sweet orange essential oil, peppermint essential oil, cinnamaldehyde, thymol or menthone.

3. A method for preparing pH-responsive polymer nanomicelles according to claim 1 or 2, characterized in that: The specific steps are as follows: S1. preparing pH responsive polymer; S2, dissolving the pH responsive polymer prepared in step S1 and R2 in solvent F to obtain a mixture; S3, mixing the mixture prepared in step S2 with solvent G, and stirring to obtain pH-responsive polymer nanomicelles.

4. The method for preparing a pH-responsive polymer nanomicelle according to claim 3, characterized in that: In step S1, the preparation method of the pH responsive polymer is as follows: S1-1, in solvent E, reacting the compound represented by formula I'-1 with substitution reagent A under nitrogen protection for a period of time with reflux and stirring to obtain the compound represented by formula I'-2; S1-2, in solvent E, reacting the compound represented by formula I'-3 with substitution reagent B under nitrogen protection for a period of time with reflux and stirring to obtain a compound represented by formula I'-4; S1-3, under nitrogen protection, mixing the compound shown in formula I'-2 obtained in step S1-1, the compound shown in formula I'-4 obtained in step S1-2 and solvent E, adding catalyst C and catalyst D, and performing polymerization reaction to obtain a pH responsive polymer shown in formula I'-5; Among them, the structural formulas of Formula I'-1 to Formula I'-5 are as follows:

5. The method for preparing a pH-responsive polymer nanomicelle according to claim 4, characterized in that: In step S1-1, the molar ratio of the compound represented by formula I'-1 to the substitution reagent A is 1:(1-6), In step S1-2, the molar ratio of the compound represented by formula I'-3 to the substitution reagent B is 1:(1-3), In step S1-3, the compound represented by formula I'-2: the compound represented by formula I'-4: solvent E=1 g: 0.5-1.5 g: 5-15 mL; In step S1-3, the molar ratio of the compound represented by formula I'-2 to catalyst C is 1:(1-3), and the molar ratio of the compound represented by formula I'-2 to catalyst D is 1:(1-3), In step S1-3, the polymerization reaction time is selected from 12h, 24h, 36h, 48h, 60h or 72h.

6. The method for preparing a pH-responsive polymer nanomicelle according to claim 4, characterized in that: In step S1-1, the substitution reagent A is selected from any one or more of N-bromosuccinimide, acrylate, 2-methyl-2-bromopropionyl bromide, carbon tetrabromide or trimethylphenylammonium tribromide; In step S1-2, the substitution reagent B is selected from any one or more of acetyl chloride, benzoyl chloride, methacryloyl chloride, chloroacetyl chloride or trichloroacetyl chloride; In step S1-3, the catalyst C is selected from any one or more of triethylenediamine, pentamethyldiethylenetriamine, N-dimethylcyclohexylamine, dimethylethanolamine or N-benzyldimethylamine; In step S1-3, the catalyst D is selected from any one or more of aluminum chloride, boron trifluoride, tin tetrachloride, cuprous bromide or zinc chloride; In steps S1-1, S1-2 and S1-3, the solvent E is selected from any one or more of dichloromethane, petroleum ether, ethyl acetate, N,N-dimethylformamide, toluene, tetrahydrofuran, methanol, ethanol or acetonitrile.

7. The method for preparing a pH-responsive polymer nanomicelle according to claim 3, characterized in that: In step S2, the molar ratio of the pH responsive polymer to R2 is 1:(1-5), The mass ratio of the pH responsive polymer to the solvent F is 1:(10-100).

8. The method for preparing a pH-responsive polymer nanomicelle according to claim 3, characterized in that: In step S3, the mass ratio of the mixture to the solvent G is 1:(100-1000).

9. The method for preparing a pH-responsive polymer nanomicelle according to claim 3, characterized in that: In step S2 and step S3, the solvent F and the solvent G are selected from any one or more of deionized water, dichloromethane, petroleum ether, ethyl acetate, N,N-dimethylformamide, toluene, tetrahydrofuran, methanol, ethanol or acetonitrile.

10. A use of the pH responsive polymer nanomicelles as claimed in claim 1 or 2, characterized in that: The pH responsive polymer nano micelles are used for preparing controlled-release flavors.

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