Internal and external dual-occupying solid wrappage as well as preparation method and application of internal and external dual-occupying solid wrappage

Abstract

The invention belongs to the technical field of liposomes, and provides an internal and external dual-occupying solid inclusion as well as a preparation method and application thereof. The internal and external dual-occupying solid inclusion provided by the invention has a core-shell structure, the core is an active matter, the shell is a double-layer phospholipid shell, the double-layer phospholipid shell comprises an outer shell and an inner shell, the outer shell contains an outer occupying agent, the inner shell contains an inner occupying agent, and the outer occupying agent and the inner occupying agent are respectively and independently selected from at least one of oligosaccharides with specific polymerization degree, viscosity and viscosity-average molecular weight. The internal and external dual-occupying solid inclusion with a special structure provided by the invention not only is high in preparation stability, but also improves the stability of an inner core active matter, and in addition, as the outer layer is a phospholipid layer, the solid inclusion has good biocompatibility and skin affinity, so that the problem of skin feeling is solved, the skin affinity is good, and the solid inclusion has a good application prospect. The oil-soluble sunscreen dry powder can be well applied to the field of cosmetic preparation, for example, the skin-friendly problem during application of the oil-soluble sunscreen dry powder and the functional skincare raw materials can be solved.

Description

Technical Field

[0001] The present invention relates to the technical field of liposomes, and more specifically to a solid inclusion material with both internal and external occupancy, and a preparation method and application thereof. Background Art

[0002] Powder raw materials are widely used in cosmetics, especially in sunscreen products, functional skin care products, and hair dyes. Traditional powder raw materials have many disadvantages in the use of cosmetics. For example, powder raw materials tend to gradually agglomerate and flocculate over time when dissolved and used, losing the original uniform dispersion advantage of powder; and when added to products, there is also a problem of residual particles, resulting in the product not being smooth when applied.

[0003] For this reason, many researchers have made many improvements in physical and chemical aspects to address the defects of cosmetic dry powder raw materials. For example, a Chinese patent (publication number CN115501136A) discloses a method of using plasma to treat powder to reduce the surface energy of the powder, thereby reducing the tendency of the powder to agglomerate or aggregate. However, this method has high process and equipment requirements, and requires strict control of high-precision processing parameters. There are problems such as uneven batch processing of powder (some particles may not be surface treated). Another example is a Chinese patent (publication number CN114042014A) discloses a method of using perfluoropolyether and fluorosilane to jointly modify the surface of the powder, so that the powder has hydrophobic and oleophobic properties and moderate oil absorption properties. Although the problem of powder sticking to the skin is solved, the biocompatibility of this type of inorganic powder with the skin is still far behind, and it lacks the ability to nourish the skin. In addition, there is also a method of using liposome technology to encapsulate solids. Although it can effectively solve the compatibility problem between powders and skin, and can also effectively avoid the fading and inactivation of active ingredients caused by leakage of contents, liposome liquid preparations will inevitably be oxidized or disintegrate due to changes in the solvent environment. Although some researchers use freeze-drying to prepare liposome liquids into solid preparations, the phenomenon of ice crystal growth piercing the phospholipid bilayer will occur during the freeze-drying process, ultimately destroying the integrity of the active ingredients and preparations.

[0004] Therefore, there is an urgent need to develop a liposome-based powder raw material with excellent skin affinity, biocompatibility, active ingredient stability, formulation stability, and dispersibility, which can be well used in the fields of cosmetics. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention proposes a solid inclusion with dual internal and external positions, and a preparation method and application thereof. The solid inclusion with dual internal and external positions provided by the present invention is a liposome with a core-shell structure, which has good biocompatibility and skin affinity, and has high preparation stability, thereby improving the stability of the active substance encapsulated inside (even if stored at a high temperature of 70°C for 12 hours, the retention rate of the active substance is still greater than 90%), and even after freeze-drying, the structure will not break, and it also has good dispersibility, and the particles will not agglomerate when placed for a long time (at least 15 days of stable placement). The solid inclusion with dual internal and external positions provided by the present invention can be further used to prepare cosmetics, which have the advantages of low stickiness, less residue, and good skin feel, such as preparing sunscreens.

[0006] Specifically, a solid inclusion with both inner and outer spacers, the solid inclusion with both inner and outer spacers having a core-shell structure, the core being an active substance, the shell being a double-layer phospholipid shell, the double-layer phospholipid shell comprising an outer shell and an inner shell, the outer shell containing an outer spacer, and the inner shell containing an inner spacer; the inner spacer is at least one of the oligosaccharides with a degree of polymerization ≤5, and / or the viscosity-average molecular weight of the inner spacer is 200-1000Da, and / or the viscosity of the inner spacer at 25°C is 5-100mPas, and / or the outer spacer is at least one of the oligosaccharides with a degree of polymerization ≤5, and / or the viscosity-average molecular weight of the outer spacer is 200-1000Da, and / or the viscosity of the outer spacer at 25°C is 5-100mPas, and the types of the inner spacer and the outer spacer are the same or different.

[0007] The solid inclusion material with inner and outer double spacers provided by the present invention has an outer shell wrapped with a double layer of phospholipid layers, and each layer of the phospholipid shell contains a spacer (i.e., an inner and outer spacer), and oligosaccharides with a specific degree of polymerization, viscosity, and molecular weight are selected as the outer and inner spacers, so that the outer and inner spacers can occupy positions in the inner and outer layers of the phospholipid bimolecule, respectively, so that the shell layer of the solid inclusion material is not easy to break, the structure is more solid, and the stability of the solid inclusion material preparation is significantly improved. Even during the freeze-drying process, the molecules are affected by low-temperature crystallization, and the continuous state of the phospholipid molecular layer can be maintained under low-temperature freezing, and the phenomena of powder agglomeration, content leakage, and difficulty in re-dissolution are not easy to occur, thereby also improving the stability of the active substance.

[0008] Preferably, the outer space occupier is distributed in the outermost layer of the outer shell of the double-layer phospholipid shell, and the inner space occupier is distributed in the innermost layer of the inner shell of the double-layer phospholipid shell, and the innermost layer of the inner shell of the double-layer phospholipid shell is in contact with the core.

[0009] Preferably, the particle size of the inner and outer dual-occupying solid inclusions is 0.2-0.6 μm.

[0010] More preferably, the particle size of the inner and outer dual-occupying solid inclusions is 0.3-0.5 μm.

[0011] Preferably, the active ingredient is soluble in an alcohol solvent.

[0012] Preferably, the active ingredients include but are not limited to drugs and / or functional cosmetic additives.

[0013] Preferably, the drug includes but is not limited to at least one of paclitaxel, curcumin, resveratrol, azithromycin, voriconazole, minoxidil, and glabridin.

[0014] Preferably, the functional cosmetic additives include but are not limited to at least one of a sunscreen (such as benzophenone-3, bis-ethylhexyloxyphenol methoxyphenyl triazine), an epidermal keratin softener (such as salicylic acid), and a moisturizer (such as ceramide).

[0015] Preferably, the oligosaccharide with a degree of polymerization ≤ 5 includes, but is not limited to, at least one of trehalose, sucrose, lactose, oligofructose, raffinose, isomaltooligosaccharide, and soybean oligosaccharide.

[0016] The second aspect of the present invention provides a method for preparing an inner and outer dual-occupying solid inclusion.

[0017] A method for preparing a solid inclusion with both inner and outer occupancy, comprising the following steps:

[0018] (1) dissolving phospholipids in a solvent, and then adding active substances and liposome membrane regulators to obtain an oil phase;

[0019] (2) dissolving the internal spacer in water to obtain an internal aqueous phase; dissolving the external spacer in water to obtain an external aqueous phase;

[0020] (3) adding the inner water phase to the oil phase, and stopping adding the inner water phase when turbidity begins to appear, thereby obtaining an inner place-occupying lipid continuum;

[0021] (4) adding the inner site-occupying lipid continuum to the outer aqueous phase, hydrating and incubating, and then performing a whole particle treatment and freeze-drying to obtain the inner and outer dual-site-occupying solid inclusions.

[0022] The present invention divides the aqueous phase into two parts, namely, an inner aqueous phase and an outer aqueous phase, and performs two assemblies (i.e., the inner aqueous phase is added with an oil phase to realize the occupation of an inner placeholder in an inner shell to obtain an inner placeholder lipid continuum, and then the inner placeholder lipid continuum is added to the outer aqueous phase to realize the occupation of an outer placeholder in an outer shell). Since the inner and outer placeholders are respectively involved in the two assembly processes of the liposome, each layer of the phospholipid shell contains a placeholder (i.e., an inner and outer placeholder), so that the shell layer of the package is not easy to break, and the package stability is significantly improved.

[0023] Preferably, in step (1), the phospholipid is lecithin and / or hydrogenated lecithin.

[0024] Preferably, in step (1), after the phospholipid is dissolved in a solvent, it is dissolved in a water bath at 50-70° C. to obtain a phospholipid phase, and then the active substance and the liposome membrane regulator are added and dissolved in a water bath at 50-70° C. to obtain an oil phase.

[0025] Preferably, in step (1), the solvent is an alcohol solvent.

[0026] Further preferably, in step (1), the solvent includes but is not limited to at least one of ethanol, 1,3-propylene glycol, 1,2-hexanediol, isopropanol, isopentyl glycol, and tert-butanol.

[0027] Preferably, in step (1), the liposome membrane regulator is cholesterol.

[0028] Preferably, in step (1), in the oil phase, the ratio of the total weight of the solvent to the total weight of the phospholipids (including lecithin and hydrogenated lecithin) (when the solvent is an alcohol solvent, referred to as the alcohol-lipid ratio) is (8-1):1, and / or the ratio of the total weight of the active ingredients to the total weight of the phospholipids (including lecithin and hydrogenated lecithin) (referred to as the drug-lipid ratio) is 1:(1-10), wherein the total weight of the phospholipids is the sum of the weights of all types of phospholipids in the oil phase, and the total weight of the active ingredients is the sum of the weights of all types of active ingredients in the oil phase.

[0029] Preferably, in step (1), the ratio of the total weight of the internal spacer to the total weight of the phospholipids is (10-1):10, and the ratio of the total weight of the external spacer to the total weight of the phospholipids is (10-1):10, wherein the total weight of the internal spacer is the sum of the weights of all types of spacers in the inner aqueous phase, and the total weight of the external spacer is the sum of the weights of all types of spacers in the outer aqueous phase.

[0030] Preferably, in step (2), the inner placeholder is dissolved in water and dissolved in a water bath at 30-50°C to obtain an inner aqueous phase; and / or, in step (2), the outer placeholder is dissolved in water and dissolved in a water bath at 30-50°C to obtain an outer aqueous phase.

[0031] Preferably, in step (4), the temperature of the hydration incubation is 40-50° C., and / or the time of the hydration incubation is 1-2 h.

[0032] Preferably, in step (4), the granulation process is carried out in a high-pressure homogenizer, and the pressure of the granulation process is 600-800 bar.

[0033] Preferably, in step (4), the freeze-drying step includes pre-freezing at -3-3°C for 0.5-1.5h, then pre-freezing at -25 to -15°C for 1-3h, then pre-freezing at -60 to -40°C for 0.5-1.5h, then drying at -50 to -40°C for 5-15h, and finally drying at 0 to 10°C for 5-15h to obtain the inner and outer double-occupying solid inclusions. The freeze-drying operation of the present invention is to use gradient pre-freezing treatment in the pre-freezing stage, followed by sublimation drying and analytical drying, and finally obtain the inner and outer double-occupying solid inclusions in the form of dry powder.

[0034] The third aspect of the present invention provides an application of a solid packaging material with both inner and outer space occupation.

[0035] Application of a solid inclusion material with both inner and outer space occupied in the preparation of cosmetics or loading of drugs.

[0036] A fourth aspect of the present invention provides a cosmetic.

[0037] A cosmetic, the components of which include the solid wrapping material occupying both inner and outer positions.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0039] The solid inclusion material of inner and outer double-occupying provided by the present invention has a core-shell structure, the core is an active substance, the shell is a double-layer phospholipid shell, the double-layer phospholipid shell includes an outer shell and an inner shell, the outer shell contains an outer placeholder, the inner shell contains an inner placeholder, and the outer and inner placeholders are independently selected from at least one of oligosaccharides with a specific degree of polymerization, viscosity and viscosity-average molecular weight. The solid inclusion material of inner and outer double-occupying with a special structure provided by the present invention not only has high preparation stability, but also improves the stability of the active substance in the inner core (even if stored at a high temperature of 70°C for 12h, the retention rate of the active substance is still greater than 90%), even after freeze-drying, the structure will not be broken, and it also has good dispersibility, and particles will not agglomerate when placed for a long time (at least 15 days of stable placement), in addition, because the outer layer is a phospholipid layer, it has good biocompatibility and skin affinity, thereby solving the skin feel problem, and can be well applied to the field of cosmetic preparation, with the advantages of low stickiness, less residue, and good skin feel, for example, it can solve the skin affinity problem when oil-soluble sunscreen dry powder and functional skin care raw materials are used. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Schematic diagram of the structure of the solid inclusions prepared in Comparative Example 3 and Example 3 of the present invention;

[0041] Figure 2 This is a transmission electron microscope image of the solid inclusion obtained in Example 3 of the present invention;

[0042] Figure 3 The graph is a graph showing the change in particle size and polydispersity index (PDI) of the solid inclusions obtained in Example 3 of the present invention and Comparative Examples 3 and 4 over time. DETAILED DESCRIPTION

[0043] In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the following embodiments are listed for illustration. It should be pointed out that the following embodiments do not limit the protection scope of the present invention.

[0044] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0045] The “parts” in the following examples and comparative examples are parts by weight.

[0046] The raw materials used in the embodiments and comparative examples of the present invention are:

[0047] Sucrose: The viscosity-average molecular weight is 342.3 Da, and the viscosity measured at 25°C is 6.30 mPa.s.

[0048] Lactose: The viscosity-average molecular weight is 342.3 Da, and the viscosity measured at 25°C is 6.00 mPa.s.

[0049] Trehalose: The viscosity average molecular weight is 342.3 Da, and the viscosity measured at 25°C is 5.95 mPa.s.

[0050] Inulin: The viscosity average molecular weight is 2 kDa, and the viscosity measured at 25°C is 8.20 mPa.s.

[0051] Example 1

[0052] A solid inclusion material with both inner and outer spacers has a core-shell structure, wherein the core is an active substance (benzophenone-3), the shell is a double-layer phospholipid shell, the double-layer phospholipid shell comprises an outer shell and an inner shell, the outer spacer is distributed in the outermost layer of the outer shell of the double-layer phospholipid shell, the inner spacer is distributed in the innermost layer of the inner shell of the double-layer phospholipid shell, and the innermost layer of the inner shell of the double-layer phospholipid shell contacts the core.

[0053] A sunscreen solid wrapping material with both inner and outer space occupied comprises the following steps:

[0054] (1) dissolving 8.8 parts of lecithin, 4 parts of hydrogenated lecithin and 20 parts of ethanol in a water bath at 60° C., stirring and mixing to obtain a phospholipid phase for standby use;

[0055] (2) Add 0.2 parts of cholesterol and 8 parts of benzophenone-3 (sunscreen) to the phospholipid phase, dissolve in a 60° C. water bath, and stir to mix well to obtain an oil phase for standby use;

[0056] (3) Dissolve 5 parts of sucrose and 35 parts of water in a 40°C water bath to obtain an inner aqueous phase for later use;

[0057] (4) Dissolve 4 parts of sucrose and 15 parts of water in a 40°C water bath to obtain an external aqueous phase for later use;

[0058] (5) The inner aqueous phase was slowly added to the oil phase while stirring at 800 rpm. During the addition process, the solution was observed to change from clear to turbid, and the addition was stopped. The system still maintained water-in-oil. Most of the solvent was removed by vacuum rotary evaporation of the solution in a 55°C water bath until no liquid dripped within 10 seconds, and the rotary evaporation was terminated to obtain an inner place-occupying lipid continuum.

[0059] (6) The inner site-occupying lipid continuum is slowly added to the outer aqueous phase while stirring at 800 rpm, and the mixture is hydrated and incubated in a 45°C water bath for 1-2 h, and then added to a high-pressure homogenizer and granulated at 700 bar to obtain an inner and outer dual site-occupying liposome liquid;

[0060] (7) freeze-drying the internal and external dual-occupying liposome liquid, specifically, pre-freezing at 0°C for 1 h, -20°C for 2 h, and -50°C for 1 h, followed by a first drying at -45°C for 10 h and a second drying at 5°C for 10 h, to obtain an internal and external dual-occupying sunscreen solid inclusion in the form of a dry powder.

[0061] Example 2

[0062] A solid inclusion material with both inner and outer spacers has a core-shell structure, wherein the core is an active substance (bis-ethylhexyloxyphenol methoxyphenyl triazine), the shell is a double-layer phospholipid shell, the double-layer phospholipid shell comprises an outer shell and an inner shell, the outer spacer is distributed in the outermost layer of the outer shell of the double-layer phospholipid shell, the inner spacer is distributed in the innermost layer of the inner shell of the double-layer phospholipid shell, and the innermost layer of the inner shell of the double-layer phospholipid shell contacts the core.

[0063] A sunscreen solid wrapping material with both inner and outer space occupied comprises the following steps:

[0064] (1) dissolving 15 parts of lecithin, 5 parts of 1,2-hexanediol, 10 parts of ethanol and 10 parts of tert-butyl alcohol in a water bath at 60° C., stirring and mixing to obtain a phospholipid phase for standby use;

[0065] (2) adding 0.1 parts of cholesterol and 10 parts of bis-ethylhexyloxyphenol methoxyphenyl triazine (sunscreen) to the phospholipid phase, dissolving them in a 60° C. water bath, stirring and mixing to obtain an oil phase for standby use;

[0066] (3) Dissolve 7 parts of sucrose and 15.9 parts of water in a 40°C water bath to obtain an inner aqueous phase for later use;

[0067] (4) Dissolve 7 parts of lactose and 20 parts of water in a 40°C water bath to obtain an external aqueous phase for later use;

[0068] (5) The inner aqueous phase was slowly added to the oil phase while stirring at 800 rpm; the addition was stopped when the solution began to become turbid from being clear during the addition process, and the system remained in the water-in-oil state. Most of the solvent was removed by vacuum rotary evaporation of the solution in a 55° C. water bath until no more liquid dripped within 10 s, and the rotary evaporation was terminated to obtain an inner place-occupying lipid continuum;

[0069] (6) The inner site-occupying lipid continuum is slowly added to the outer aqueous phase while stirring at 800 rpm, and the mixture is hydrated and incubated in a 45°C water bath for 1-2 h, and then added to a high-pressure homogenizer and granulated at 700 bar to obtain an inner and outer dual site-occupying liposome liquid;

[0070] (7) freeze-drying the inner and outer dual-occupying liposome liquid, specifically, pre-freezing at 0°C for 1 h, -20°C for 2 h, and -50°C for 1 h in a gradient pre-freezing process, followed by a first drying at -45°C for 10 h and a second drying at 5°C for 10 h, to obtain an inner and outer dual-occupying solid inclusion in the form of a dry powder.

[0071] Example 3

[0072] A solid inclusion material with both inner and outer spacers has a core-shell structure, wherein the core is an active substance (glabridin), the shell is a double-layer phospholipid shell, the double-layer phospholipid shell comprises an outer shell and an inner shell, the outer spacer is distributed in the outermost layer of the outer shell of the double-layer phospholipid shell, the inner spacer is distributed in the innermost layer of the inner shell of the double-layer phospholipid shell, and the innermost layer of the inner shell of the double-layer phospholipid shell contacts the core.

[0073] A skin care solid wrapping material with both inner and outer space occupying parts comprises the following steps:

[0074] (1) dissolving 13 parts of lecithin, 3.6 parts of 1,3-propylene glycol and 24 parts of tert-butyl alcohol in a water bath at 60° C., stirring and mixing to obtain a phospholipid phase for standby use;

[0075] (2) Add 0.4 parts of cholesterol and 5 parts of glabridin (functional cosmetic additive) to the phospholipid phase, dissolve in a 60°C water bath, stir and mix evenly to obtain an oil phase for standby use;

[0076] (3) Dissolve 4 parts of trehalose and 20 parts of water in a 40°C water bath to obtain an inner aqueous phase for later use;

[0077] (4) Dissolve 5 parts of trehalose and 25 parts of water in a 40°C water bath to obtain an external aqueous phase for later use;

[0078] (5) The inner aqueous phase was slowly added to the oil phase while stirring at 800 rpm. The addition was stopped when the solution began to become turbid from clear. The system remained in the oil-in-water state. Most of the solvent was removed by vacuum rotary evaporation of the solution in a 55°C water bath until no more liquid dripped within 10 s, and the rotary evaporation was terminated to obtain an inner place-occupying lipid continuum.

[0079] (6) The inner site-occupying lipid continuum is slowly added to the outer aqueous phase while stirring at 800 rpm, and the mixture is hydrated and incubated in a 45°C water bath for 1-2 h, and then added to a high-pressure homogenizer and granulated at 700 bar to obtain an inner and outer dual site-occupying liposome liquid;

[0080] (7) freeze-drying the internal and external dual-site-occupying liposome liquid, specifically, pre-freezing at 0°C for 1 h, -20°C for 2 h, and -50°C for 1 h in a gradient pre-freezing process, followed by a first drying at -45°C for 10 h and a second drying at 5°C for 10 h, to obtain an internal and external dual-site-occupying glabridin solid-encapsulated dry powder preparation.

[0081] Example 4

[0082] A solid inclusion material with both inner and outer spacers has a core-shell structure, wherein the core is an active substance (salicylic acid), the shell is a double-layer phospholipid shell, the double-layer phospholipid shell comprises an outer shell and an inner shell, the outer spacer is distributed in the outermost layer of the outer shell of the double-layer phospholipid shell, the inner spacer is distributed in the innermost layer of the inner shell of the double-layer phospholipid shell, and the innermost layer of the inner shell of the double-layer phospholipid shell contacts the core.

[0083] A skin care solid wrapping material with both inner and outer space occupying parts comprises the following steps:

[0084] (1) Dissolve 7.5 parts of lecithin, 4.5 parts of 1,3-butanediol, 10 parts of isopropanol and 10 parts of tert-butanol in a 60° C. water bath, stir and mix to obtain a phospholipid phase for standby use;

[0085] (2) Add 0.05 parts of cholesterol and 5 parts of salicylic acid (functional cosmetic additive) to the phospholipid phase, dissolve in a 60°C water bath, stir and mix evenly to obtain an oil phase for standby use;

[0086] (3) Dissolve 5.7 parts of trehalose, 1.25 parts of sodium hydroxide and 25 parts of water in a 40°C water bath to obtain an inner aqueous phase for later use;

[0087] (4) Dissolve 6 parts of sucrose and 25 parts of water in a 40°C water bath to obtain an external aqueous phase for later use;

[0088] (5) The inner aqueous phase was slowly added to the oil phase while stirring at 800 rpm. The addition was stopped when the solution began to become turbid from clear. The system remained in the oil-in-water state. Most of the solvent was removed by vacuum rotary evaporation of the solution in a 55°C water bath until no more liquid dripped within 10 s, and the rotary evaporation was terminated to obtain an inner place-occupying lipid continuum.

[0089] (6) The inner site-occupying lipid continuum is slowly added to the outer aqueous phase while stirring at 800 rpm, and the mixture is hydrated and incubated in a 45°C water bath for 1-2 h, and then added to a high-pressure homogenizer and granulated at 700 bar to obtain an inner and outer dual site-occupying liposome liquid;

[0090] (7) freeze-drying the internal and external dual-occupying liposome liquid, specifically, pre-freezing at 0°C for 1 h, -20°C for 2 h, and -50°C for 1 h, followed by a first drying at -45°C for 10 h and a second drying at 5°C for 10 h, to obtain a salicylic acid solid-encapsulated dry powder preparation with internal and external dual-occupying sites.

[0091] Comparative Example 1

[0092] A sunscreen solid package, which differs from Example 1 in that the sucrose in the inner water phase and the outer water phase are replaced with inulin of equal weight, respectively. The specific preparation method is as follows:

[0093] (1) dissolving 8.8 parts of lecithin, 4 parts of hydrogenated lecithin and 20 parts of ethanol in a water bath at 60° C., stirring and mixing to obtain a phospholipid phase for standby use;

[0094] (2) Add 0.2 parts of cholesterol and 8 parts of benzophenone-3 into the phospholipid phase, dissolve in a 60°C water bath, stir and mix evenly to obtain an oil phase for later use;

[0095] (3) Dissolve 5 parts of inulin and 35 parts of water in a 40°C water bath to obtain an inner aqueous phase for later use;

[0096] (4) Dissolve 4 parts of inulin and 15 parts of water in a 40°C water bath to obtain an external aqueous phase for later use;

[0097] (5) The inner aqueous phase was slowly added to the oil phase while stirring at 800 rpm; the addition was stopped when the solution began to become turbid from being clear during the addition process, and the system remained in the water-in-oil state. Most of the solvent was removed by vacuum rotary evaporation of the solution in a 55° C. water bath until no more liquid dripped within 10 s, and the rotary evaporation was terminated to obtain a lipid continuum;

[0098] (6) The lipid continuum is slowly added to the external aqueous phase while stirring at 800 rpm, and the mixture is hydrated and incubated in a 45° C. water bath for 1-2 h, and then added to a high-pressure homogenizer and granulated at 700 bar to obtain an inulin-occupied liposome liquid;

[0099] (7) The liposome liquid occupied by inulin is freeze-dried, specifically, it is pre-frozen at 0°C for 1 h, -20°C for 2 h, and -50°C for 1 h in a gradient pre-freezing process, followed by a first drying at -45°C for 10 h and a second drying at 5°C for 10 h to obtain a solid inclusion in the form of a dry powder.

[0100] Comparative Example 2

[0101] A sunscreen solid wrapping material, which is different from Example 1 in that the time of adding the spacer sucrose is changed, and the specific preparation method is as follows:

[0102] (1) dissolving 8.8 parts of lecithin, 4 parts of hydrogenated lecithin and 20 parts of ethanol in a water bath at 60° C., stirring and mixing to obtain a phospholipid phase for standby use;

[0103] (2) Add 0.2 parts of cholesterol and 8 parts of benzophenone-3 (sunscreen) to the phospholipid phase, dissolve in a 60° C. water bath, and stir to mix well to obtain an oil phase for standby use;

[0104] (3) 35 parts of water were kept warm in a water bath at 40°C as the internal water phase for later use;

[0105] (4) 15 parts of water are kept warm in a water bath at 40°C as the external aqueous phase for later use;

[0106] (5) The inner aqueous phase was slowly added to the oil phase while stirring at 800 rpm; the addition was stopped when the solution began to become turbid from being clear during the addition process, and the system remained in the water-in-oil state. Most of the solvent was removed by vacuum rotary evaporation of the solution in a 55° C. water bath until no more liquid dripped within 10 s, and the rotary evaporation was terminated to obtain a non-space-occupying lipid continuum;

[0107] (6) Slowly adding the non-space-occupying lipid continuum to the external aqueous phase while stirring at 800 rpm, hydrating and incubating in a 45° C. water bath for 1-2 h, then adding the mixture to a high-pressure homogenizer and performing a granulation process at 700 bar to obtain a non-space-occupying liposome liquid;

[0108] (7) 9 parts of sucrose were slowly added to the non-space-occupying liposome liquid while stirring at 800 rpm. After the liquid was evenly dissolved, it was freeze-dried. Specifically, it was pre-frozen at 0°C for 1 h, -20°C for 2 h, and -50°C for 1 h in a gradient pre-freezing process, followed by a first drying at -45°C for 10 h and a second drying at 5°C for 10 h to obtain a non-space-occupying solid inclusion in the form of a dry powder.

[0109] Comparative Example 3

[0110] A skin care solid encapsulation, which is different from Example 3 in that no spacer trehalose is added to the inner water phase and the outer water phase. The specific preparation method is as follows:

[0111] (1) dissolving 13 parts of lecithin, 3.6 parts of 1,3-propylene glycol and 24 parts of tert-butyl alcohol in a water bath at 60° C., stirring and mixing to obtain a phospholipid phase for standby use;

[0112] (2) adding 0.4 parts of cholesterol and 5 parts of glabridin to the phospholipid phase, dissolving them in a 60° C. water bath, stirring and mixing to obtain an oil phase for later use;

[0113] (3) Dissolve 4 parts of trehalose and 20 parts of water in a 40°C water bath to obtain an inner aqueous phase for later use;

[0114] (4) Dissolve 5 parts of trehalose and 25 parts of water in a 40°C water bath to obtain an external aqueous phase for later use;

[0115] (5) The inner aqueous phase was slowly added to the oil phase while stirring at 800 rpm; the addition was stopped when the solution began to become turbid from being clear during the addition process, and the system remained in the water-in-oil state. Most of the solvent was removed by vacuum rotary evaporation of the solution in a 55° C. water bath until no more liquid dripped within 10 s, and the rotary evaporation was terminated to obtain a non-space-occupying lipid continuum;

[0116] (6) Slowly adding the non-space-occupying lipid continuum to the external aqueous phase while stirring at 800 rpm, hydrating and incubating in a 45° C. water bath for 1-2 h, then adding the mixture to a high-pressure homogenizer and performing a granulation process at 700 bar to obtain a non-space-occupying liposome liquid;

[0117] (7) freeze-drying the non-site-occupying liposome liquid, specifically, pre-freezing at -50°C for 4 hours, followed by a first drying at -45°C for 10 hours, and a second drying at 5°C for 10 hours, to obtain a non-site-occupying solid inclusion in the form of a dry powder.

[0118] Comparative Example 4

[0119] A skin care solid encapsulation, which is different from Example 3 in that only one water phase is provided, and the oil phase and the water phase are mixed only once. The specific preparation method is as follows:

[0120] (1) dissolving 13 parts of lecithin, 3.6 parts of 1,3-propylene glycol and 24 parts of tert-butyl alcohol in a water bath at 60° C., stirring and mixing to obtain a phospholipid phase for standby use;

[0121] (2) adding 0.4 parts of cholesterol and 5 parts of glabridin to the phospholipid phase, dissolving them in a 60° C. water bath, stirring and mixing to obtain an oil phase for later use;

[0122] (3) Dissolve 9 parts of trehalose and 45 parts of water in a 40°C water bath to obtain an aqueous phase for later use;

[0123] (4) slowly adding the aqueous phase to the oil phase while stirring at 800 rpm, incubating in a 45° C. water bath for 1-2 h to obtain pre-liposomes, adding the pre-liposomes to a high-pressure homogenizer, and performing a particle size treatment at 700 bar to obtain a non-space-occupying liposome liquid;

[0124] (5) freeze-drying the non-site-occupying liposome liquid, specifically, pre-freezing at 0°C for 1 h, -20°C for 2 h, and -50°C for 1 h in a gradient pre-freezing process, followed by a first drying at -45°C for 10 h and a second drying at 5°C for 10 h, to obtain a non-site-occupying glabridin solid-encapsulated dry powder preparation.

[0125] Product effect testing

[0126] 1. Structure and morphology of solid inclusions

[0127] The structural schematic diagrams of the solid inclusions obtained in Comparative Example 3 and Example 3 are respectively as follows: Figure 1 (A) and Figure 1 (B) is shown, wherein the encapsulated solid is the active substance. As can be seen from the figure, the shell structure of Comparative Example 3 does not contain a spacer, while the inner and outer shell structures of the solid encapsulation prepared in Example 3 of the present invention contain inner and outer spacers, respectively, thereby greatly improving the overall stability of the solid encapsulation and the stability of the active substance encapsulated in the core. The structures of the solid encapsulations prepared in Examples 1, 2, and 4 are similar to those in Example 3.

[0128] Take the solid inclusion powder prepared in Example 3, dissolve it with deionized water, drip an appropriate amount on the copper mesh and let it stand for 30 minutes, and absorb the excess liquid with filter paper. Then drip a phosphotungstic acid solution with a solute mass concentration of 2% on the copper mesh to dye the sample for 10 minutes, absorb the excess liquid with filter paper, and observe the morphology of the solid inclusion with a transmission electron microscope after drying at room temperature. The results are as follows Figure 2As shown, it can be seen that the liposomes are spherical in shape, the phospholipid membrane does not break even after freeze-drying under the protection of the inner and outer double layers of the space-occupying agent, the particle size remains uniform, the particles are dispersed with each other without agglomeration, and the particle size is about 0.3-0.5 μm.

[0129] 2. Dispersibility of solid inclusions

[0130] (1) Test method

[0131] A certain amount of the solid inclusions prepared in Example 3, Comparative Example 3, and Comparative Example 4 were respectively taken, dissolved in deionized water, and stored at room temperature. The particle size and polydispersity index (PDI) of the solid inclusions in water were measured regularly using a nanoparticle size analyzer to evaluate whether the inclusion particles were agglomerated or ruptured and precipitated.

[0132] (2) Test results

[0133] The results are as follows Figure 3 As shown, the particle size and dispersibility of the solid inclusions in Example 3 in aqueous solution do not change over time, indicating that the dispersibility is good and the particles do not agglomerate at least within 15 days. This is because during the assembly of liposomes, the placeholders in the inner aqueous phase gradually deposit and participate in the formation of the inner membrane of the liposomes during the vacuum rotary evaporation process, protecting the inner membrane from being pierced by the fine crystals of the inclusions produced by freeze drying; on the other hand, during the gradient pre-freezing of the placeholders in the outer aqueous phase, the liposome external solution is first frozen at 0°C for 1h, the intermolecular motion is reduced, and the shape of the liposome membrane is basically fixed; then frozen at -20°C for 2h, at this suitable transition temperature and duration, the inner and outer placeholders can fully fill the gaps in the phospholipid bilayer, the crystals grow slowly and fully within 2h, and the solution gradually tends to a glassy state; finally, freezing at -50°C for 1h allows the inclusion solution to completely transform from a glassy state to a crystalline state for drying. Since the solid coatings of Comparative Example 3 did not adopt a gradient pre-freezing process, and Comparative Example 4 only had one outer shell containing a spacer (not double inner and outer spacers), the solid coatings of both may have leaked after freeze-drying, resulting in sticking or precipitation when they were re-dissolved, causing the particle size and PDI of both to increase significantly over time.

[0134] 3. Stability of active ingredients

[0135] (1) Test method: Weigh 5 g of the solid inclusion powder and benzophenone-3 raw material powder obtained in Example 1, Comparative Example 1, and Comparative Example 2, respectively, and then place them in a 25 mL stoppered colorimetric tube, add 1.0 mL of tetrahydrofuran, then add 20 mL of methanol, vortex oscillate for 2 min, and then ultrasonically extract for 30 min, cool to room temperature, dilute to scale with methanol, shake well, filter with a 0.45 μm filter membrane, and use them as test solutions. Measure the initial absorbance values ​​of the four groups of test solutions at a wavelength of 335 nm. Then, expose the four groups of test solutions and place them in a constant temperature water bath at 70°C at the same time. Measure the absorbance values ​​at a wavelength of 335 nm again after 1 h, 6 h, and 12 h, and calculate the retention rate according to the following formula (1). The results are shown in Table 1.

[0136] Retention rate = A t / A 初始 ×100% Formula (1)

[0137] Among them, A t A refers to the absorbance value at the test time t; 初始 It refers to the absorbance value of the test solution before the test.

[0138] (2) Test results

[0139] Table 1 Retention rate of the solid inclusions and pure benzophenone-3 powder of Example 1, Comparative Example 1 and Comparative Example 2 under high temperature (70°C) storage

[0140]

[0141] As shown in Table 1, the retention rate of benzophenone-3 in the solid inclusions prepared in Example 1, Comparative Example 1 and Comparative Example 2 is high, indicating that the storage stability at high temperature (70° C.) is excellent and less susceptible to oxidation and degradation than the benzophenone-3 raw material powder, which is due to the protection of the lecithin shell. The retention rate of the active substance in the solid inclusions of Example 1 after storage at 70° C. for 12 hours is still higher than 90%, reaching 94.4%. This is mainly due to the fact that sucrose with suitable viscosity and viscosity-average molecular weight is selected as a placeholder in Example 1, which can be evenly occupied in the inner and outer shells of the phospholipid bimolecule during the liposome assembly process, thereby making the liposome structure more solid, and the stability of the solid inclusions after freeze-drying is also significantly improved compared with Comparative Examples 1 and 2.

[0142] 4. Skin feel characteristics

[0143] (1) Test method

[0144] The solid inclusions prepared in Example 1, Comparative Example 1 and Comparative Example 2 were respectively configured into sunscreens 1-3 according to the formulas in Table 3 below. According to T / GDCA 003-2020 General Rules for Sensory Evaluation of Cosmetics, some skin feel properties of the two sunscreens were scored with a score of 0-15 points (scoring criteria as shown in Table 2), and the scoring results are shown in Table 4.

[0145] Table 2 Common skin feel characteristics scale of creams and skin care products in "T / GDCA 003-2020 General Rules for Sensory Evaluation of Cosmetics"

[0146]

[0147] Table 3 Formula composition of sunscreen 1-3

[0148]

[0149]

[0150] Note: "Solid inclusions" in Table 3 represent one of the solid inclusion powders prepared in Example 1, Comparative Example 1 and Comparative Example 2, i.e., Sunscreen 1 contains 10.00 wt% of the solid inclusions of Example 1, Sunscreen 2 contains 10.00 wt% of the solid inclusions of Comparative Example 1, and Sunscreen 3 contains 10.00 wt% of the solid inclusions of Comparative Example 2.

[0151] (2) Test results

[0152] Table 4 Skin feel characteristics scoring results of sunscreens 1-3

[0153] Skin feel properties Example 1 Comparative Example 1 Comparative Example 2 Ease of application 12 12 12 Water 9 6 8 Skin stickiness (instant) 10 15 15 Amount of residue (immediate) 5 15 13

[0154] From the evaluation results of skin feel properties in Table 4, it can be seen that the sunscreen prepared by the solid inclusions of Example 1 of the present invention has low stickiness, less residue and good skin feel.

[0155] When comparative example 1 uses inulin with a molecular weight greater than 1000Da as a spacer, the stickiness when applied to sunscreen is greatly improved compared to example 1, and the paste residue after application is also more obvious, indicating that the selection of an inappropriate spacer cannot prevent the inclusion from rupturing during the freeze-drying process. The process used in the solid inclusions of comparative example 2 is to add the spacer after high-pressure homogenization, and the inner spacer is not deposited and assembled on the inner shell of the liposome by vacuum rotary evaporation, and the outer spacer is not assembled on the outer shell of the liposome, but is free in the external aqueous solution. When applied to sunscreen, it is also very sticky, and there are also more residues after application, and the residues are mainly benzophenone-3, indicating that the spacer is not assembled into the phospholipid bilayer, resulting in the rupture and leakage of the liposome during freeze-drying.

Claims

1. A solid inclusion, characterized in that: The inner and outer dual-spaced solid inclusion has a core-shell structure, wherein the core is an active substance, and the shell is a double-layer phospholipid shell, wherein the double-layer phospholipid shell comprises an outer shell and an inner shell, wherein the outer shell contains an outer spacer, and the inner shell contains an inner spacer; the inner spacer is at least one of the oligosaccharides with a degree of polymerization ≤5, and / or the viscosity-average molecular weight of the inner spacer is 200-1000Da, and / or the viscosity of the inner spacer at 25°C is 5-100mPas, and / or the outer spacer is at least one of the oligosaccharides with a degree of polymerization ≤5, and / or the viscosity-average molecular weight of the outer spacer is 200-1000Da, and / or the viscosity of the outer spacer at 25°C is 5-100mPas, and the inner spacer and the outer spacer are of the same or different types.

2. The solid inclusion according to claim 1, characterized in that: The active substances include drugs and / or functional cosmetic additives.

3. The solid inclusion according to claim 1, characterized in that: The oligosaccharide with a degree of polymerization of ≤5 includes at least one of trehalose, sucrose, lactose, oligofructose, raffinose, isomaltooligosaccharide and soybean oligosaccharide.

4. The method for preparing the solid inclusion according to any one of claims 1 to 3, characterized in that: The steps include: (1) dissolving phospholipids in a solvent, and then adding active substances and liposome membrane regulators to obtain an oil phase; (2) dissolving the internal spacer in water to obtain an internal aqueous phase; dissolving the external spacer in water to obtain an external aqueous phase; (3) adding the inner water phase to the oil phase, and stopping adding the inner water phase when turbidity begins to appear, thereby obtaining an inner place-occupying lipid continuum; (4) adding the inner site-occupying lipid continuum to the outer aqueous phase, hydrating and incubating, and then performing a whole particle treatment and freeze-drying to obtain the inner and outer dual-site-occupying solid inclusions.

5. The preparation method according to claim 4, characterized in that: In step (1), the solvent is an alcohol solvent.

6. The preparation method according to claim 4, characterized in that: In step (1), the phospholipids include lecithin and / or hydrogenated lecithin.

7. The preparation method according to claim 5 or 6, characterized in that: In step (1), in the oil phase, the ratio of the total weight of the solvent to the total weight of the phospholipids is (8-1):1, and / or the ratio of the total weight of the active ingredients to the total weight of the phospholipids is 1:(1-10), wherein the total weight of the phospholipids is the sum of the weights of all types of phospholipids in the oil phase, and the total weight of the active ingredients is the sum of the weights of all types of active ingredients in the oil phase.

8. The preparation method according to claim 4, characterized in that: In step (4), the freeze-drying step includes pre-freezing at -3 to 3°C for 0.5 to 1.5 hours, then pre-freezing at -25 to -15°C for 1 to 3 hours, then pre-freezing at -60 to -40°C for 0.5 to 1.5 hours, then drying at -50 to -40°C for 5 to 15 hours, and finally drying at 0 to 10°C for 5 to 15 hours to obtain the solid inclusions with both inner and outer occupancy.

9. Use of the solid inclusion material according to any one of claims 1 to 3 in the preparation of cosmetics or loading of drugs.

10. A cosmetic, characterized in that: The cosmetic component comprises the solid inclusion material according to any one of claims 1 to 3.

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