A nanocapsule with high transparency, its preparation method and application

Abstract

This invention relates to a highly transparent nanocapsule, its preparation method, and its application. The method involves polymerizing a polyisocyanate compound with at least one hydrophilic diol compound and at least one hydrophobic diol compound to form an amphiphilic block copolymer with isocyanate end groups. The amphiphilic block copolymer and an active ingredient are dissolved in a water-soluble organic solvent, and deionized water or an organic solvent is added dropwise at a rate of 10 mL / min to 100 mL / min under mechanical stirring to achieve self-emulsification and form a uniformly dispersed dispersion. A polyamine compound is then added to the dispersion to initiate a cross-linking reaction, forming the nanocapsule. This invention systematically solves the contradiction between high active ingredient loading and high optical transparency in the field of nanocarriers through material design and process route.

Description

Technical Field

[0001] This invention belongs to the field of nanocarrier technology, specifically relating to a highly transparent nanocapsule, its preparation method, and its application. Background Technology

[0002] Nanocarrier technology plays an increasingly important role in cosmetics, personal care products, and drug delivery systems, enhancing the stability of active ingredients, delivery efficiency, and patient compliance. Among these, the appearance of the formulation, particularly uniform and transparent drug formulations, is crucial. For example, transparent and homogeneous topical and ophthalmic formulations convey a high-end visual impression and a lightweight, residue-free texture; highly transparent (clear) injectable formulations better ensure safety by eliminating visible foreign matter and reducing the risk of potential embolism; and for oral liquid formulations (such as suspensions and emulsions), transparency significantly improves palatability, especially for pediatric medications. Therefore, developing nanocarrier systems that maintain excellent optical transparency and colloidal stability under high active ingredient loads has become a major technological challenge and upgrade direction to meet the common needs of high-end applications in many fields, such as cosmetics and local / systemic drug delivery.

[0003] Achieving optical transparency in a dispersed system is highly dependent on the particle size and distribution of nanoparticles. Due to light scattering, when the dispersed phase particles are sufficiently small and highly uniform in size, the system can exhibit a transparent or translucent state. However, as the particle size increases or the distribution widens, especially when a certain proportion of larger particles are present in the system, the light scattering effect is significantly enhanced, leading to turbidity, whitening, or opacity. More importantly, the difficulty of maintaining transparency increases exponentially with the increase in the loading (concentration) of the active ingredient. High concentrations mean a dramatic increase in the number of particles per unit volume, further amplifying any adverse factors that cause scattering (such as large particle size or uneven distribution).

[0004] Existing mainstream nanotechnology (such as conventional nanoemulsions, liposomes, and polymer micelles) often faces numerous limitations in resolving this "high concentration-high transparency" contradiction. For example, insufficient control over particle size and distribution makes it difficult to accurately and stably obtain extremely small and narrowly distributed particles while ensuring high loading. Larger particle sizes or excessively wide distributions (i.e., high polydispersity) directly induce strong scattering, compromising transparency. Furthermore, obtaining small particle sizes and stability often requires the use of large amounts of surfactants and additives. This not only increases cost and formulation complexity but may also lead to potential skin irritation, stickiness, or compatibility issues, affecting product safety and skin feel. In addition, nanoparticles at high concentrations are more prone to aggregation and fusion, resulting in increased particle size or wider distribution, causing the initially transparent system to gradually become cloudy during storage or use. Some technologies (such as polymer micelles) may achieve good transparency, but their oil / drug loading capacity is often limited, making it difficult to meet the requirements of high active ingredient content; while systems that can carry high loading capacity (such as some crude emulsions or liposomes) often cannot achieve transparency.

[0005] In general, existing mainstream technologies generally struggle to achieve synergistic optimization to simultaneously realize high active ingredient loading, highly uniform (narrow particle size distribution) nanostructures, excellent optical transparency (especially at the required high concentrations), good biocompatibility, pleasant feel, and long-term physical and chemical stability. Therefore, existing technologies often require compromises between loading, transparency, stability, skin feel, or safety, failing to meet the market's growing demand for highly effective, high-sensory-quality, and highly safe transparent nanomaterials. Summary of the Invention

[0006] To address the technical problems existing in the prior art, this invention proposes a high-transparency nanocapsule, its preparation method, and its application, aiming to overcome the shortcomings of existing nanocarrier technologies in constructing high-load, high-transparency, and high-stability nano-dispersion systems. In particular, it solves key problems such as reliance on high-dose surfactants, uneven particle size distribution, significant increase in turbidity at high concentrations, and difficulty in balancing load capacity with transparency / stability.

[0007] In a first aspect, a nanocapsule with high transparency is provided, comprising the following steps:

[0008] A polyisocyanate compound is polymerized with at least one hydrophilic diol compound and at least one hydrophobic diol compound to form an amphiphilic block copolymer with isocyanate end groups.

[0009] The amphiphilic block copolymer and the active ingredient are dissolved in a water-soluble organic solvent, and deionized water or organic solvent is added dropwise at a mechanical stirring speed of 10 mL / min to 100 mL / min to carry out self-emulsification and form a uniformly dispersed dispersion.

[0010] Polyamine compounds are added to the dispersion to carry out a cross-linking reaction, forming nanocapsules.

[0011] In one embodiment, the step of polymerizing the polyisocyanate compound with the hydrophilic diol segment compound and the hydrophobic diol segment compound satisfies at least one of the following conditions:

[0012] (1) The polyisocyanate compound is an aromatic isocyanate, an aliphatic isocyanate or its dimer, including any one of toluene diisocyanate TDI, diphenylmethane diisocyanate MDI, hexamethylene diisocyanate HDI, HDI dimer, isophorone diisocyanate IPDI, dicyclohexylmethane-4,4'-diisocyanate HMDI, methylcyclohexane diisocyanate HTDI, and dimer acid diisocyanate DDI;

[0013] (2) The hydrophilic diol segment compound is selected from polyethylene glycol or its derivatives;

[0014] (3) The hydrophobic diol segment compound is selected from at least one of long-chain alkyl diols or their derivatives, fatty acid monoester diols or their derivatives, fatty amide diols or their derivatives, and dihydroxyalkyl fatty amines or their derivatives;

[0015] (4) The equivalent ratio of the polyisocyanate compound to the hydrophilic diol segment compound and the hydrophobic diol segment compound is 1:(0.1~0.9):(0.1~0.9).

[0016] Water-soluble organic solvents include any one of the following: alcohols (such as methanol, ethanol, propylene glycol, etc.), ketones (such as acetone, butanone), ethers (tetrahydrofuran), nitrogen-containing compounds (such as NMP, DMF, acetonitrile, etc.), or other special solvents (such as DMSO).

[0017] Organic solvents include any one of the following: hydrocarbons (such as aliphatic hydrocarbons, aromatic hydrocarbons, etc.), halogenated hydrocarbons (such as dichloromethane, chloroform, carbon tetrachloride, etc.), alcohols (such as methanol, ethanol, isopropanol, n-butanol, etc.), ketones (such as acetone, butanone, etc.), ethers (such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), esters (such as ethyl acetate, butyl acetate, etc.), or other complex solvents (such as glycol ethers, polar aprotic solvents, etc.).

[0018] In one embodiment, the hydrophobic diol segment compound is selected from any one or more of the following: glyceryl monostearate, glyceryl monolaurate, glyceryl monocaprylate, glyceryl monodecanoate, dihydroxyethyl lauramide, dihydroxyethyl stearamide, oleoyl diethanolamine, N,N-di(2-hydroxyethyl)stearamine, N,N-di(hydroxyethyl)laurylamine, di(hydroxyethyl)stearylglycinate, cocoyl(dihydroxyethyl)methylammonium chloride, dodecyl dihydroxyethyl betaine, octadecyl dihydroxyethyl betaine, and dodecyl dihydroxyethylamine oxide.

[0019] In one embodiment, the step of dissolving the amphiphilic block copolymer with the active ingredient satisfies at least one of the following conditions:

[0020] The mass ratio of the active ingredient to the amphiphilic block copolymer is 1:(2~50).

[0021] The active ingredient is selected from any one or more of essential oils, synthetic esters, sunscreens, antioxidants, vitamins or their derivatives, whitening agents, and antitumor drugs.

[0022] In one embodiment, during the formation of the amphiphilic block copolymer, a diol compound containing degradable bonds is added to participate in the polymerization reaction, thereby introducing degradable segments into the amphiphilic block copolymer. The degradable segments contain any one or more of disulfide bonds, ester bonds, acetal bonds, or thioacetal bonds.

[0023] In one embodiment, the diol compound containing a degradable bond is selected from one or more of dihydroxyethyl disulfide (HEDS), 2,2'-(propane-2,2-diylbis(thioalkyldiyl))diethanol (TKOH), polylactic acid glycol, polycaprolactone glycol, and polypropylene carbonate glycol.

[0024] In one embodiment, the polyamine compound is selected from one or more of ethylenediamine, diethylenetriamine, triethylenetetramine, lysine, cystine, cystine, and polyetheramine.

[0025] In a second aspect, a nanocapsule with high transparency is obtained by the above-described method for preparing a nanocapsule with high transparency.

[0026] In one embodiment, the nanocapsule satisfies at least one of the following conditions:

[0027] The nanocapsule comprises a core and a shell. The core contains an active ingredient, and the shell is made of polyurethane or polyurea material, which is formed by crosslinking an amphiphilic block copolymer with a polyamine compound.

[0028] The polydispersity index (PDI) of the nanocapsules is less than 0.1;

[0029] The average particle size of the nanocapsules is less than 120 nm.

[0030] In one embodiment, the nanocapsules are used in the preparation of cosmetics, personal care products, and drug delivery systems.

[0031] The present invention provides a high-transparency nanocapsule, its preparation method, and its application, which have the following significant advantages and beneficial effects:

[0032] (1) Using emulsifier-free and gentle mechanical stirring, there is no need for high-energy-consuming equipment (such as high-pressure homogenization, ultrasonic crushing, etc.), which significantly reduces energy consumption and production threshold, and makes it easier to scale up and industrialize production;

[0033] (2) The highly uniform nanoparticle size and ultra-narrow particle size distribution allow the nanocapsules obtained by the preparation method to be dispersed in water. Even at high concentrations of active ingredients, the resulting nanocapsule solution can exhibit a clear or highly translucent appearance.

[0034] (3) By adjusting the polymer structure and reaction process parameters, the size and particle size distribution of nanocapsules can be flexibly and stably controlled to meet the specific particle size requirements of different application scenarios.

[0035] In summary, this invention systematically resolves the inherent contradiction between "high active ingredient loading" and "high optical transparency" in the field of nanocarriers through material design and process route. Compared with existing technologies, it achieves: an emulsifier-free self-stabilizing system, precise chemical construction of narrow-distribution nanostructures, efficient encapsulation through gentle stirring, and stable optical transparency under high loading. This technical route overcomes the inherent defects of existing mainstream technologies (nanoemulsions, liposomes, polymer micelles, etc.) in terms of emulsifier dependence, distribution control, energy consumption, loading-transparency balance, and stability, providing a safer, more efficient, sensorily superior, and potentially intelligently responsive nanocarrier solution.

[0036] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not intended to limit this disclosure. Attached Figure Description

[0037] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0038] Figure 1 These are TEM images of the nanocapsules prepared in some embodiments of the present invention;

[0039] Figure 2These are images of the appearance of the nanocapsule solutions prepared in some embodiments of the present invention;

[0040] Figure 3 These are comparative images of the gels prepared in some application examples and comparative examples of the present invention;

[0041] Figure 4 This is a graph showing the inhibitory effect of nanocapsules prepared in some embodiments of the present invention on tumor cells. Detailed Implementation

[0042] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0043] Experimental methods not specified in the examples are generally performed under conventional conditions in the art or under conditions recommended by the manufacturer; the raw materials and reagents used, unless otherwise specified, are all commercially available from the conventional market.

[0044] Specifically, a highly transparent nanocapsule includes the following steps:

[0045] Step 1: Polymerize the polyisocyanate compound with hydrophilic diol segment compounds and hydrophobic diol segment compounds to form an amphiphilic block copolymer with isocyanate end groups;

[0046] In some specific embodiments, the polyisocyanate compound is an aromatic isocyanate, an aliphatic diisocyanate, or a dimer thereof. In some specific embodiments, the polyisocyanate compound is selected from any one of toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), hexamethylene diisocyanate (HDI), HDI dimer, isophorone diisocyanate (IPDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), methylcyclohexane diisocyanate (HTDI), and dimer acid diisocyanate (DDI).

[0047] In some specific embodiments, the hydrophilic diol segment compound is selected from polyethylene glycol or its derivatives.

[0048] In some specific embodiments, the hydrophobic diol segment compound is selected from at least one of long-chain alkyl diols or their derivatives, fatty acid monoester diols or their derivatives, fatty amide diols or their derivatives, and dihydroxyalkyl fatty amines or their derivatives; in some specific embodiments, the hydrophobic diol segment compound is selected from any one or more of dihydroxyethyl lauramide, dihydroxyethyl stearamide, oleoyl diethanolamine, glyceryl monostearate, glyceryl monolaurate, glyceryl monocaprylate, glyceryl monodecanoate, N,N-di(2-hydroxyethyl)stearamine, N,N-di(hydroxyethyl)laurylamine, di(hydroxyethyl)stearylglycinate, cocoyl(dihydroxyethyl)methylammonium chloride, dodecyl dihydroxyethyl betaine, octadecyl dihydroxyethyl betaine, and dodecyl dihydroxyethylamine oxide. Further, the hydrophobic diol segment compound is dihydroxyethyl lauramide.

[0049] In some specific embodiments, the equivalence ratio of the polyisocyanate compound, the hydrophilic diol segment compound, and the hydrophobic diol segment compound is 1:(0.1~0.9):(0.1~0.9). In one specific example, the equivalence ratio of the polyisocyanate compound to the hydrophilic diol segment compound and the hydrophobic diol segment compound may be, but is not limited to, 1:0.1:0.1, 1:0.1:0.5, 1:0.1:0.89, 1:0.89:0.1, 1:0.5:0.1, 1:0.49:0.5, 1:0.5:0.49, or any three of these values ​​satisfying the range of equivalence ratio 1:(0.1~0.9):(0.1~0.9).

[0050] In some specific embodiments, during the formation of the amphiphilic block copolymer, a diol compound containing degradable bonds is added to participate in the polymerization reaction, thereby introducing degradable segments into the amphiphilic block copolymer. The degradable segments contain any one or more of disulfide bonds, ester bonds, acetal bonds, or thioacetal bonds.

[0051] In some specific embodiments, the diol compound containing a degradable bond is selected from one or more of dihydroxyethyl disulfide (HEDS), 2,2'-(propane-2,2-diylbis(thioalkyldiyl))diethanol (TKOH), polylactic acid glycol, polycaprolactone glycol, and polypropylene carbonate glycol.

[0052] In some specific embodiments, the equivalence ratio of the polyisocyanate compound to the degradable diol compound is 1:(0.1~0.8). In one specific example, the equivalence ratio of the polyisocyanate compound to the hydrophilic diol segment compound, the hydrophobic diol segment compound, and the degradable diol compound can be 1:0.3:0.29:0.4, 1:0.5:0.3:0.1, 1:0.1:0.1:0.79, 1:0.1:0.1:0.1, but is not limited to, or a range consisting of any four of these values.

[0053] Step 2: Dissolve the amphiphilic block copolymer and the active ingredient, and perform self-emulsification at a mechanical stirring speed of 10 mL / min-100 mL / min to form a uniformly dispersed dispersion.

[0054] In some specific embodiments, the mass ratio of the active ingredient to the amphiphilic block copolymer is 1:(2~50). In one specific example, the mass ratio of the active ingredient to the amphiphilic block copolymer is 1:50, 1:40, 1:25, 1:15, 1:9, 1:7, 1:6, 1:2, or any combination of these values.

[0055] In some specific embodiments, the active ingredients are selected from any one or more of essential oils, plant oils, synthetic esters, sunscreens, antioxidants, vitamins or their derivatives, whitening agents, and antitumor drugs. Specifically, essential oils may be selected from lavender, chamomile, sandalwood, ylang-ylang, lemon, eucalyptus, bergamot, sweet orange, grapefruit, jasmine, rose, frankincense, tea tree, geranium, rosemary, eucalyptus, peppermint, ginger, basil, citronellol, etc. Synthetic esters may be selected from caprylic / capric triglycerides, ethylhexyl palmitate, isopropyl myristate, isopropyl palmitate, C12-15 alkanol benzoate, PEG esters (such as PEG-100 stearate), glyceryl stearate, dioctyl ether, isodecanyl neopentanoate, diisopropyl adipate, etc. Sunscreen agents can be selected from ethylhexyl methoxycinnamate, octocrylene, homosalate, ethylhexyl salicylate, butyl methoxydibenzoylmethane, benzophenone-3, terephthalimide dicamphor sulfonic acid, etc. Antioxidants can be selected from green tea extract, resveratrol, caffeine, superoxide dismutase, coenzyme Q10, ferulic acid, nicotinamide, astaxanthin, idebenone, etc. Vitamins or their derivatives can be selected from vitamin E, vitamin A, etc. Whitening agents can be selected from arbutin, kojic acid, phenylethyl resorcinol, butyl resorcinol, glycyrrhizin, nicotinamide, fruit acids, salicylic acid, retinol and its derivatives, etc. Antitumor drugs can be selected from curcumin, paclitaxel, cisplatin, oxaliplatin, irinotecan, doxorubicin, gemcitabine, sorafenib, etc.

[0056] Step 3: Add a polyamine compound to the dispersion to carry out a cross-linking reaction and form nanocapsules.

[0057] In some specific embodiments, the polyamine compound is an aliphatic polyamine or a polyetheramine. In some specific embodiments, the polyamine compound is selected from one or more of ethylenediamine, diethylenetriamine, triethylenetetramine, lysine, cystine, cystine, and polyetheramine.

[0058] A highly transparent nanocapsule is obtained by the above-described method for preparing highly transparent nanocapsules. The highly transparent nanocapsules prepared by the above method are dispersed in water to obtain a nanocapsule solution with an optically transparent or highly translucent appearance.

[0059] In some specific embodiments, the nanocapsule includes a core and a shell, the core containing an active ingredient and its soluble oil, and the shell being made of polyurethane or polyurea material, which is formed by crosslinking an amphiphilic block copolymer with a polyamine compound; further, the polydispersity index of the nanocapsule is less than 0.1; and the average particle size of the nanocapsule is less than 120 nm.

[0060] In some specific embodiments, nanocapsules are used to prepare cosmetics, such as skincare (anti-aging / moisturizing), skincare (anti-acne / oil control), whitening, sun protection, foundation, and other cosmetics.

[0061] In some specific embodiments, nanocapsules are used to prepare personal care products, such as baby care products, nail polish, nail polish remover, men's aftershave products, etc.

[0062] In some specific embodiments, nanocapsules are used for drug delivery, such as anti-inflammatory topical drugs, anti-hair loss topical drugs, wound healing and damaged tissue repair topical drugs, and anti-tumor drugs.

[0063] To make the objectives and advantages of the present invention clearer, the nanocapsules and their effects of the present invention are further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and should not be used to limit the present invention. Unless otherwise specified, the following embodiments do not include components other than unavoidable impurities. Unless otherwise specified, the drugs and instruments used in the embodiments are conventional choices in the art. Experimental methods in the embodiments that do not specify specific conditions are implemented according to conventional conditions, such as those described in literature, books, or methods recommended by the manufacturer.

[0064] Example 1: Preparation of nanocapsules A1

[0065] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate, 14.86 g of polyethylene glycol 1000, and 4.18 g of dihydroxyethyl lauramide were added, and the mixture was heated to 80 °C and reacted for 2 hours. The reaction system was then cooled to room temperature, and 50 mL of tetrahydrofuran and 12 g of resveratrol were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at a rate of 50 mL / min, and finally, 0.20 g of a 10 wt% diethylenetriamine solution was added to induce cross-linking and form nanocapsules. The resulting nanocapsule solution was subjected to rotary evaporation at 50 °C to remove the organic solvent and some water.

[0066] Example 2: Preparation of nanocapsules A2

[0067] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate, 5.35 g of polyethylene glycol derivative YmerN180, 2.48 g of dihydroxyethyl lauramide, and 1.83 g of dihydroxyethyl disulfide were added, and the mixture was heated to 70 °C and reacted for 5 hours. The reaction system was then cooled to room temperature, and 50 mL of acetone and 9 g of retinol were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at a rate of 50 mL / min, followed by the addition of 0.20 g of a 10 wt% diethylenetriamine solution to cross-link and form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 30 °C to remove the organic solvent and some water.

[0068] Example 3: Preparation of nanocapsules A3

[0069] In a three-necked flask, 5.00 g of pre-dried HDI dimer, 1.48 g of polyethylene glycol derivative YmerN120, and 0.53 g of dihydroxyethyl stearamide were added. The mixture was then slowly heated to 80 °C for 2 hours with mechanical stirring at 300 rpm. The reaction mixture was then cooled to 10–15 °C, and 50 mL of THF and 0.28 g of curcumin were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at a rate of 10 mL / min, and finally, 8.18 g of a 10 wt% diethylenetriamine solution was added dropwise to crosslink and form nanocapsules. The resulting nanogel solution was subjected to rotary evaporation at 50 °C to remove the organic solvent and some water.

[0070] Example 4: Preparation of nanocapsules A4

[0071] In a three-necked flask, 5.00 g of pre-dried dicyclohexylmethane-4,4'-diisocyanate, 3.82 g of polyethylene glycol 2000, and 3.52 g of oleoyldiethanolamine were added. The mixture was then slowly heated to 50 °C for 12 hours with mechanical stirring at 300 rpm. The reaction system was then cooled to 10–15 °C, and 30 mL of anhydrous ethanol and 0.26 g of isopropyl myristate were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at 30 mL / min, followed by 5.57 g of a 10 wt% triethylenetetramine solution to crosslink and form nanocapsules. The resulting nanocapsule solution was subjected to rotary evaporation at 50 °C to remove the organic solvent and some water.

[0072] Example 5: Preparation of nanocapsules A5

[0073] In a three-necked flask, 5.00 g of pre-dried isophorone diisocyanate, 11.25 g of polyethylene glycol 5000, and 7.18 g of glyceryl monostearate were added. The mixture was then slowly heated to 85 °C for 1.5 hours with mechanical stirring at 250 rpm. The reaction mixture was then cooled to 5-10 °C, and 30 mL of anhydrous ethanol and 0.96 g of ethylhexyl methoxycinnamate were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at 80 mL / min, followed by 0.33 g of a 10 wt% lysine solution to cross-link and form nanocapsules. The resulting nanogel solution was then subjected to rotary evaporation at 40 °C to remove the organic solvent and some water.

[0074] Example 6: Preparation of nanocapsules A6

[0075] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate, 26.46 g of polyethylene glycol 1000, and 0.81 g of glyceryl monolaurate were added. The mixture was then slowly heated to 85 °C for 2 hours with mechanical stirring at 300 rpm. The reaction system was then cooled to 15-20 °C, and 50 mL of THF and 3.59 g of oxidized resveratrol were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at 100 mL / min, followed by 0.45 g of 10 wt% cystine solution to crosslink and form nanocapsules. The resulting nanogel solution was then subjected to rotary evaporation at 40 °C to remove the organic solvent and some water.

[0076] Example 7: Preparation of nanocapsules A7

[0077] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate (HDI), 17.83 g of Ymer N90, and 0.65 g of glyceryl monocaprylate were added. The mixture was then slowly heated to 60 °C for 8 hours with mechanical stirring at 300 rpm. The reaction mixture was then cooled to room temperature, and 40 mL of acetone and 2.93 g of retinyl propionate were added and stirred until completely dissolved. 500 mL of deionized water was then added dropwise at 50 mL / min, followed by 28.57 g of a 10 wt% cysteine ​​solution, which cross-linked to form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 40 °C to remove the organic solvent and some water.

[0078] Example 8: Preparation of nanocapsules A8

[0079] In a three-necked flask, 5.00 g of pre-dried methylcyclohexane diisocyanate, 14.76 g of polyethylene glycol 1000, and 3.70 g of glyceryl monodecanoate were added. The mixture was then slowly heated to 60 °C and reacted for 10 hours with mechanical stirring at 300 rpm. The reaction system was then cooled to room temperature, and 50 mL of tetrahydrofuran and 3.91 g of butylresorcinol were added and stirred until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at a rate of 40 mL / min, followed by the addition of 0.89 g of a 10 wt% polyetheramine solution to crosslink and form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 35 °C to remove the organic solvent and some water.

[0080] Example 9: Preparation of nanocapsules A9

[0081] In a three-necked flask, 5.00 g of pre-dried toluene diisocyanate, 14.35 g of polyethylene glycol 1000, and 4.86 g of dodecyl dihydroxyethyl betaine were added. The mixture was then slowly heated to 60 °C for 5 hours with mechanical stirring at 300 rpm. The reaction mixture was then cooled to 15-20 °C, and 60 mL of anhydrous ethanol and 0.48 g of butylresorcinol were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at 40 mL / min, followed by the addition of 0.20 g of a 10 wt% diethylenetriamine solution to crosslink and form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 35 °C to remove the organic solvent and some water.

[0082] Example 10: Preparation of nanocapsules A10

[0083] In a three-necked flask, 5.00 g of pre-dried diphenylmethane diisocyanate, 9.99 g of polyethylene glycol 1000, and 4.21 g of octadecyl dihydroxyethyl betaine were added. The mixture was then slowly heated to 60 °C for 5 hours with mechanical stirring at 300 rpm. The reaction mixture was then cooled to room temperature, and 50 mL of acetone and 0.95 g of butylresorcinol were added and stirred until completely dissolved. 500 mL of deionized water was then added dropwise at a rate of 40 mL / min, followed by the addition of 0.14 g of a 10 wt% diethylenetriamine solution to crosslink and form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 35 °C to remove the organic solvent and some water.

[0084] Example 11: Preparation of nanocapsules A11

[0085] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate, 14.86 g of polyethylene glycol 1000, and 3.05 g of dodecyl dihydroxyethylamine oxide were added. The mixture was then slowly heated to 50 °C and reacted for 12 hours with mechanical stirring at 300 rpm. The reaction system was then cooled to 5-10 °C, and 60 mL of anhydrous ethanol and 11.5 g of butylresorcinol were added and stirred until completely dissolved. Then, 500 mL of deionized water was added dropwise at 40 mL / min, followed by the addition of 0.20 g of a 10 wt% diethylenetriamine solution to cross-link and form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 35 °C to remove the organic solvent and some water.

[0086] Example 12: Preparation of nanocapsules A12

[0087] In a three-necked flask, 5.00 g of pre-dried dimer diisocyanate, 13.57 g of polyethylene glycol 1000, 2.91 g of N,N-di(2-hydroxyethyl)stearamine, and 0.61 g of 2,2'-(propane-2,2-diylbis(thionyl))diethanol were added. The mixture was then slowly heated to 70 °C for 3 hours with mechanical stirring at 300 rpm. The reaction mixture was then cooled to 5-10 °C, and 3.12 g of irinotecan was added with stirring until complete decomposition. Subsequently, 500 mL of deionized water was added dropwise at 10 mL / min, followed by the addition of 1.63 g of a 10 wt% ethylenediamine solution to cross-link and form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 50 °C to remove the organic solvent and some water.

[0088] Example 13: Preparation of nanocapsules A13

[0089] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate, 2.97 g of polyethylene glycol 1000, 0.85 g of N,N-di(hydroxyethyl)laurylamine, and 23.48 g of polylactic acid glycol were added. The mixture was then slowly heated to 85 °C for 3 hours with mechanical stirring at 400 rpm. The reaction system was then cooled to room temperature, and 50 mL of tetrahydrofuran and 1.359 g of curcumin were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at 30 mL / min, followed by 0.18 g of a 10 wt% ethylenediamine solution to cross-link and form nanocapsules. The resulting nanocapsule solution was subjected to rotary evaporation at 50 °C to remove the organic solvent and some water.

[0090] Example 14: Preparation of nanocapsules A14

[0091] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate, 2.97 g of polyethylene glycol 1000, 1.15 g of bis(hydroxyethyl)stearyl glycinate, and 1.48 g of polycaprolactone diol were added. The mixture was then slowly heated to 75 °C with mechanical stirring at 400 rpm for 3 hours. The reaction mixture was then cooled to room temperature, and 100 mL of butanone and 1.18 g of citronellol were added and stirred until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at 40 mL / min, followed by 12.51 g of a 10 wt% ethylenediamine solution to crosslink and form nanocapsules. The resulting nanogel solution was then subjected to rotary evaporation at 40 °C to remove the organic solvent and some water.

[0092] Example 15: Preparation of nanocapsules A15

[0093] In a three-necked flask, 5.00 g of pre-dried hexamethylene diisocyanate, 8.92 g of polyethylene glycol 1000, 3.50 g of cocoyl (dihydroxyethyl) methyl ammonium chloride, and 23.78 g of polypropylene carbonate glycol were added. The mixture was then slowly heated to 90 °C for 1 hour with mechanical stirring at 150 rpm. The reaction mixture was then cooled to 0–5 °C, and 80 mL of anhydrous ethanol and 7.02 g of ylang-ylang were added, stirring until completely dissolved. Subsequently, 500 mL of deionized water was added dropwise at 20 mL / min, followed by 0.18 g of a 10 wt% ethylenediamine solution to cross-link and form nanocapsules. The resulting nanocapsule solution was then subjected to rotary evaporation at 30 °C to remove the organic solvent and some water.

[0094] Comparative Example 1: This comparative example provides a nanocapsule, the preparation method of which includes the following steps:

[0095] 0.88 g of Tween 20 was dissolved in 68.2 g of deionized water and stirred until homogeneous to obtain the aqueous phase. In another container, 1 g of retinol was dissolved in 1.5 g of caprylic / capric triglyceride, 1.5 g of Span 20 was mixed, and finally 5.3 g of hexamethylene diisocyanate was added and mixed to obtain the oil phase. The oil phase was poured into the aqueous phase and immediately homogenized and emulsified at 12,000 rpm for 5 minutes using a high-speed homogenizer to obtain an emulsion. The emulsion was transferred to a beaker, and 21.5 g of DETA aqueous solution (8 wt%) was added dropwise under mechanical stirring at 600 rpm. The mixture was stirred and crosslinked for 3 hours to obtain a retinol nanocapsule dispersion.

[0096] Comparative Example 2: This comparative example provides another nanocapsule, the preparation method of which includes the following steps:

[0097] 0.78 g of Tween 20 was dissolved in 72 g of deionized water and stirred at room temperature to obtain an aqueous phase. In another container, 0.25 g of Span 80 was dissolved in 15 mL of tetrahydrofuran and stirred until dissolved. Then, 0.56 g of irinotecan was added, followed by 1.5 g of hexamethylene diisocyanate, and the mixture was stirred to obtain a clear oil phase. The oil phase was added dropwise to the aqueous phase under continuous stirring at 1000 rpm. After the addition was complete, 6.05 g of DETA (10 wt%) aqueous solution was added to initiate a crosslinking reaction for 3 hours to obtain irinotecan nanocapsules. The obtained nanocapsule solution was subjected to rotary evaporation at 40 °C to remove the organic solvent and some water.

[0098] Comparative Example 3: The only difference from Example 2 is that self-emulsification was carried out by adding deionized water or organic solvent dropwise at 5 mL / min under mechanical stirring.

[0099] Comparative Example 4: The only difference from Example 2 is that self-emulsification was carried out by adding deionized water or organic solvent dropwise at 120 mL / min under mechanical stirring.

[0100] Test Example 1: Characterization of the microstructure and particle size distribution of nanocapsules

[0101] Hydrated particle size (DLS) and polydispersity index (PDI) tests: The nanocapsule aqueous dispersions prepared in Examples 1-15 and Comparative Examples 1-4 were diluted with deionized water to a suitable concentration and tested using a dynamic light scattering particle size analyzer at 25°C. Each sample was tested in parallel at least three times, and the results were averaged. The average particle size and polydispersity index data are shown in Table 1.

[0102] Transmission electron microscopy (TEM) observation: The nanocapsules prepared in Examples 1-15 were diluted with deionized water to appropriate concentrations and dropped onto copper grids covered with carbon support films. After drying, the samples were negatively stained with 2% phosphotungstic acid solution. The microstructure of the nanocapsules was observed and imaged using a transmission electron microscope. Microstructure images of the nanocapsules prepared in Examples 2, 8, and 15 are shown below. Figure 1 (a) Figure 1 (b) Figure 1 As shown in (c).

[0103] Test Example 2: Transparency Test

[0104] The nanocapsule aqueous dispersions prepared in Examples 1-15 and Comparative Examples 1-4 were precisely diluted with deionized water to a concentration of 0.05 wt% of active ingredient, and then mixed thoroughly to serve as test samples. Morphological images of the test samples from Examples 2, Comparative Examples 1 and 2 were captured using a camera. Figure 2 As shown, from left to right, the samples from Example 2, Comparative Example 1, and Comparative Example 2 are their appearances. Using deionized water as a blank reference, the absorbance (Abs) of each diluted sample dispersion was measured at a wavelength of 600 nm using a UV-Vis spectrophotometer. According to the Lambert-Beer law, the transmittance T (%) of the sample at 600 nm was calculated: T (%) = 10 -Abs × 100%. Record the transmittance value of each nanocapsule sample dilution at 600 nm. The higher the transmittance value, the better the transparency of the nanocapsule dispersion. The transmittance data are shown in Table 1 after processing.

[0105] Test Example 3: Determination of Drug Loading Capacity in Nanocapsules

[0106] Accurately measure equal volumes of the drug-loaded nanocapsule dispersions prepared in Examples 1-15 and the drug-loaded nanocapsule aqueous dispersions in Comparative Examples 1-4, and place them in centrifuge tubes. Add sufficient anhydrous ethanol. Place the mixture in an ice-water bath and sonicate it at 300W for 1 hour using an ultrasonic cell disruptor to ensure complete rupture of the nanocapsules and full release and dissolution of the drug. Centrifuge the sonicated mixture at 5000 rpm for 30 min at low temperature to precipitate capsule fragments and other insoluble substances. Collect the supernatant and filter it through a 0.22 μm microporous membrane to obtain a clear drug ethanol solution. Use a UV-Vis spectrophotometer to test the drug content. The drug loading data are shown in Table 1.

[0107] Table 1

[0108] Nanocapsules Average particle size / nm Polydispersion Index (PDI) transmittance / % Drug content / wt% A1 64.99 0.044 50.21 9.1 A2 81.48 0.091 71.03 8.6 A3 89.11 0.053 47.32 1.44 A4 74.94 0.082 63.07 0.2 A5 69.12 0.059 55.87 1.3 A6 64.38 0.014 51.16 4.2 A7 69.86 0.043 47.32 9.8 A8 69.52 0.061 74.68 8.1 A9 70.25 0.103 53.64 0.18 A10 82.52 0.071 60.78 9.2 A11 76.14 0.056 59.42 7.4 A12 77.95 0.085 53.18 5.1 A13 93.62 0.093 53.64 0.12 A14 79.00 0.074 50.58 0.21 A15 85.83 0.053 46.83 6.2 Comparative Example 1 191.33 0.294 7.39 0.85 Comparative Example 2 96.65 0.244 21.94 1.32 Comparative Example 3 230.46 0.090 7.86 8.59 Comparative Example 4 176.14 0.215 8.12 8.26

[0109] As shown in Table 1, the average particle size of the nanocapsules prepared in Examples 1-15 was controlled within the range of 60-120 nm, and the dispersion uniformity was high (PDI < 0.1). When tested at the same dilution with a drug loading of 0.05 wt%, their transmittance was significantly higher than that of Comparative Examples 1-4, demonstrating a significant advantage in optical transparency. Optical transparency is highly dependent on particle size and dispersion. According to Rayleigh scattering law, scattering intensity is proportional to the sixth power of particle size. The average particle size of the nanocapsules prepared in Examples 1-15 (approximately 80 nm) was much smaller than that of the nanocapsules in Comparative Examples 1-4 (approximately 200 nm), resulting in a sharp drop in scattering intensity. The polydispersity index (PDI) of the nanocapsules prepared in Examples 1-15 was significantly lower than that of Comparative Examples 1-4, with PDI < 0.1, indicating highly uniform particle size. This minimized incoherent stray light caused by multi-scale particles, improving visual clarity. Compared with Comparative Examples 1-4, the drug loading of the nanocapsules prepared in Examples 1-15 was significantly improved under the same mass ratio of active ingredient to amphiphilic block copolymer. For example, in Example 2 and Comparative Example 1, where the active ingredient was retinol, the drug loading of the nanocapsules prepared in Example 2 (8.6 wt%) was significantly higher than that in Comparative Example 1 (0.85 wt%). Similarly, in Example 7, where the active ingredient was retinol, the drug loading of the nanocapsules prepared in Example 7 (9.8 wt%) was also significantly higher than that in Comparative Example 1 (0.85 wt%). In Example 12 and Comparative Example 2, where the active ingredient was irinotecan, the drug loading of the nanocapsules prepared in Example 12 (5.1 wt%) was significantly higher than that in Comparative Example 2 (1.32 wt%). In summary, the key to the successful preparation method of the nanocapsules in this application lies in using monomers with similar reactivity to construct a well-defined, self-emulsifying amphiphilic block polymer, which spontaneously forms an initial template with a stable interface and uniform size during emulsification. Simultaneously, during the mixing process of water and water-soluble organic solvents, the oil phase is "torn apart" under the force of water-oil diffusion, achieving efficient nano-sizing and obtaining fine and monodisperse nanodroplets. These droplets ultimately solidify to obtain transparent nanocapsules with high drug loading, moderate particle size, and extremely narrow distribution. Meanwhile, in Comparative Examples 3 and 4, the excessively fast or slow droplet acceleration during emulsification affects the oil-water diffusion process, resulting in excessively large or unevenly distributed final particle sizes.

[0110] Application Example 1: Preparation and Evaluation of Soothing Gel Containing Transparent Nanocapsules

[0111] 1. Formulation composition (weight percentage, w / w%):

[0112] Gel matrix:

[0113] Phase A (Carbomer U20: 0.8%; Deionized water: 83.4%)

[0114] Phase B (Active ingredients and functional additives: Glycerin: 4.0%, Panthenol: 1.0%).

[0115] Other (phenoxyethanol and ethylhexylglycerin: 0.8%, triethanolamine: 1% to adjust pH to 7.5 ± 0.5, A2 dispersion: 10.0%).

[0116] 2. Preparation process

[0117] Disperse U20 evenly in most of the deionized water and homogenize for 3 min. Heat to 85 °C, add glycerol and panthenol, keep warm and stir for 30 min, cool to 45 °C, add phenoxyethanol and ethylhexylglycerin, and stir until homogeneous. Add triethanolamine solution dropwise until the system is clear, viscous and the pH reaches 7.5 ± 0.5. Add A2 dispersion and stir until homogeneous to obtain a clear or translucent soothing gel.

[0118] Comparative Example 1: The difference from Application Example 1 is that A2 dispersion is removed from the formulation and replaced with an equal amount of deionized water.

[0119] 3. Evaluation Method:

[0120] Appearance and transparency: Figure 3 The images show the gels prepared in the examples and comparative examples. Figure (3) on the left shows the gel from Example 1, and Figure (3) on the right shows the gel from Comparative Example 1. Equal volumes of emulsion from Example 1 and Comparative Example 1 were added to cuvettes, with water as 100% reference. The transmittance was scanned using a UV-Vis spectrophotometer in the wavelength range of 400-700 nm. As shown in Table 2, the transmittance in Example 1 was significantly greater than that in Comparative Example 1.

[0121] Table 2

[0122] lotion transmittance / % Application Example 1 63.2 Application Comparative Example 1 25.1

[0123] Stability test:

[0124] Room temperature / long-term stability: Equal volumes of emulsions from Application Example 1 and Application Comparative Example 1 were stored at room temperature (25 °C) for 3 to 6 months. pH and active ingredient content were measured periodically. As shown in Table 3, the pH and active ingredient content stability of Application Example 1 were higher than those of Application Comparative Example 1.

[0125] Table 3

[0126]

[0127] Application Example 2: Inhibitory Effect of Irinotecan-Loaded Nanocapsules on Tumor A549 Cells

[0128] Human lung cancer A549 cells in logarithmic growth phase were seeded at a density of 5 × 10³ cells per well in 96-well plates and cultured at 37 °C in a 5% CO2 incubator for 24 hours. Fresh culture medium containing different concentrations of irinotecan nanocapsules (0, 10, 20, 40, and 80 μM based on the preparation method in Example 13) was added. After 24 hours, the old culture medium was removed and fresh culture medium solution containing 5 μg / mL CCK8 was added. One hour later, the absorbance at 450 nm was measured using a microplate reader, and cell viability was calculated using the following formula: Viability (%) = (A 样品 -A 空白 ) / (A 对照 -A 空白 ), where A 样品 The absorbance of the pores of irinotecan nanocapsules, A 空白 The absorbance of the well containing only culture medium, A 对照 The absorbance is for wells containing cells but without added drugs. Results are as follows: Figure 4 As shown, irinotecan-loaded nanocapsules can significantly inhibit the proliferation of A549 cells, and the inhibitory effect is concentration-dependent.

[0129] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0130] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for preparing nanocapsules with high transparency, characterized in that, Includes the following steps: A polyisocyanate compound is polymerized with at least one hydrophilic diol segment compound and at least one hydrophobic diol segment compound to form an amphiphilic block copolymer with isocyanate end groups. The amphiphilic block copolymer and the active ingredient were dissolved in a water-soluble organic solvent, and deionized water was added dropwise at a rate of 10 mL / min-100 mL / min under mechanical stirring to form a uniformly dispersed dispersion. Polyamine compounds are added to the dispersion to carry out a cross-linking reaction, forming nanocapsules; The polyisocyanate compound includes any one of toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), hexamethylene diisocyanate (HDI), HDI dimer, isophorone diisocyanate (IPDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), methylcyclohexane diisocyanate (HTDI), and dimer acid diisocyanate (DDI). The hydrophilic diol segment compound is selected from polyethylene glycol or its derivatives, and the polyethylene glycol derivative is selected from any one of YmerN180, Ymer N120, and Ymer N90; The hydrophobic diol segment compound is selected from any one or more of the following: glyceryl monostearate, glyceryl monolaurate, glyceryl monocaprylate, glyceryl monodecanoate, dihydroxyethyl lauramide, dihydroxyethyl stearamide, oleoyl diethanolamine, N,N-di(2-hydroxyethyl)stearamine, N,N-di(hydroxyethyl)laurylamine, di(hydroxyethyl)stearylglycinate, cocoyl(dihydroxyethyl)methylammonium chloride, dodecyl dihydroxyethyl betaine, octadecyl dihydroxyethyl betaine, and dodecyl dihydroxyethylamine oxide. The polyamine compound is selected from one or more of ethylenediamine, diethylenetriamine, triethylenetetramine, lysine, cystine, and polyetheramine; The equivalent ratio of the polyisocyanate compound to the hydrophilic diol segment compound and the hydrophobic diol segment compound is 1:(0.1~0.9):(0.1~0.9). The mass ratio of the active ingredient to the amphiphilic block copolymer is 1:(2~50). The polydispersity index (PDI) of the nanocapsules is less than 0.1; The average particle size of the nanocapsules is less than 120 nm.

2. The method for preparing highly transparent nanocapsules according to claim 1, characterized in that, The active ingredient is selected from any one or more of sunscreens, antioxidants, and whitening agents.

3. The method for preparing highly transparent nanocapsules according to claim 1, characterized in that, The active ingredient is an essential oil.

4. The method for preparing highly transparent nanocapsules according to claim 1, characterized in that, In the process of forming amphiphilic block copolymers, a diol compound containing degradable bonds is added to participate in the polymerization reaction, thereby introducing degradable segments into the amphiphilic block copolymer. The degradable segments contain any one or more of disulfide bonds, ester bonds, acetal bonds, or thioacetal bonds.

5. The method for preparing highly transparent nanocapsules according to claim 4, characterized in that, The diol compound containing a degradable bond is selected from one or more of 2,2'-(propane-2,2-diylbis(thionyl))diethanol, dihydroxyethyl disulfide, polylactic acid glycol, polycaprolactone diol, and polypropylene carbonate diol.

6. The method for preparing highly transparent nanocapsules according to claim 1, characterized in that, The active ingredient is an anti-tumor drug.

7. A nanocapsule with high transparency, characterized in that, It is obtained by the preparation method according to any one of claims 1-6.

8. The application of a nanocapsule in the preparation of cosmetics and personal care products, characterized in that, The nanocapsule is a highly transparent nanocapsule prepared by the preparation method described in any one of claims 1 to 5.

9. The application of a nanocapsule in a drug delivery system, characterized in that, The nanocapsules are highly transparent nanocapsules prepared by the preparation method described in claim 6.

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