Highly stable liposomes, their preparation and use

Abstract

Highly stable liposomes, their production method, and uses are provided. The liposome composition comprises 2 to 5 parts by weight of a liquid oil, 3 to 10 parts by weight of a solid oil, 5 to 30 parts by weight of a phospholipid, 3 to 10 parts by weight of gelatin, 1 to 7 parts by weight of an active ingredient, and 20 to 70 parts by weight of water, wherein the liquid oil is one or more of glyceryl caprylate, soybean oil, and sunflower seed oil, the solid oil is one or more of monoglycerin fatty acid ester, diglycerin fatty acid ester, citric acid ester, palm stearin, and beeswax, the phospholipid has a phosphatidylcholine content of 30 to 60 wt%, and the gelatin has a Bloom value of 200 to 300. The liposome composition does not contain an excipient or contains 20 to 70 parts by weight of an excipient. The liposomes herein do not contain cholesterol and are characterized by high temperature resistance and high stability.

Description

[Technical Field]

[0001] This application claims priority from a Chinese patent application filed on November 25, 2022, with application number 202211486759.6 and titled "Highly stable liposomes, their preparation method and use."

[0002] The present invention relates to the field of formulations and their applications, and in particular to liposome formulations and methods for their preparation. [Background technology]

[0003] Liposomes are tiny vesicles formed by encapsulating an active ingredient, such as a drug, within a lipidoid bilayer. Conventional liposomes are composed of phospholipids and cholesterol and include an internal vesicular structure with a lipid bilayer coating an aqueous phase. As a new generation drug delivery system, liposomes improve drug efficacy, reduce toxicity, and achieve long-circulation and targeting properties.

[0004] Liposome manufacturing methods are often divided into active and passive drug loading methods based on the drug loading principle. Active drug loading involves first preparing blank liposomes, then loading the drug through different ion or compound gradients between the aqueous phase inside and outside the liposomes. This method is often used for amphiphilic substances. Passive drug loading involves first dissolving the drug in the aqueous phase (water-soluble drugs) or organic phase (lipid-soluble drugs), and then preparing drug-containing liposomes according to the selected liposome manufacturing method.

[0005] Chinese Patent CN109463751B discloses a coenzyme Q10 liposomal health food and its manufacturing method, in which coenzyme Q10, lecithin, cholesterol, polysorbate-80, and VE acetate are dissolved in ethanol by heating and evaporated under reduced pressure to form a smooth film, which is then vacuum-dried, followed by the addition of polyvinylpyrrolidone and glycerin, and an aqueous medium is added to hydrate the film to obtain an emulsion. Ultrasonic emulsification then results in nanoscale coenzyme Q10 liposomes, with an encapsulation rate of 60% and a biological acceptability three times that of the raw material. Patent CN109463751B uses polysorbate and cholesterol as auxiliary materials, limiting its application in food and health foods. Furthermore, organic solvents are used in the production process, resulting in a low encapsulation rate of 60% and a low biological acceptability three times that of the active pharmaceutical ingredient.

[0006] Chinese Patent CN103989635B discloses a method for preparing nano-coenzyme Q10 liposomes from supercritical carbon dioxide, which involves adding phosphatidylcholine, cholesterol, and coenzyme Q10 to absolute ethanol, stirring to fully dissolve the mixture, and then adding the resulting solution to an ultrasonic vibrator. The resulting solution is then introduced into a supercritical reactor, a carbon dioxide cylinder is opened, and the carbon dioxide gas is cooled to a liquid state using a chiller. After being pressurized with a high-pressure pump, the solution is introduced into the reactor, the pressure and temperature are controlled, and the pressure is maintained for a certain period of time. The resulting solution is then rapidly injected into a phosphate buffer solution using a nozzle, allowing the solution to disperse and precipitate, resulting in a coenzyme Q10 nanoliposome suspension, which is then collected. The coenzyme Q10 liposomes have an encapsulation rate of 78%. The liposome technology of Patent CN103989635B can also be applied to cholesterol and ethanol. Taking excessive cholesterol is not beneficial to health, and the use of organic solvents in the production process is highly dangerous.

[0007] Russian Patent RU2605616C1 discloses a method for producing liposomes based on UBIQUINOL, which includes preparing a solution containing a mixture of phospholipids and sterols in a weight ratio of 1:0.1-2, a mixture of panthenol, phospholipids, and sterols in a weight ratio of 1:1-4, and a cosolvent in the form of a nonionic surfactant in ethanol; dispersing the resulting lipid fraction-containing solution in an aqueous medium containing a cryoprotectant to obtain a suspension of lipid vesicles containing panthenol; homogenizing the lipid vesicle suspension; and isolating panthenol-containing liposomes of 220 nm or less. Patent RU2605616C1 also uses polysorbate and ethanol. Polysorbate is harmful to people with enteritis and sensitive digestive tracts, and the production and use of ethanol also poses certain risks.

[0008] Chinese Patent CN105030679A discloses a highly stable salvia essential oil nanoliposome antibacterial agent and its manufacturing method. In this patent, salvia essential oil nanoliposomes are prepared from salvia essential oil, soybean lecithin, cholesterol, a surfactant, chitosan, and gelatin. In this method, salvia essential oil, soybean lecithin, and cholesterol are mixed with an organic solvent and dried under reduced pressure to form a smooth thin film. An aqueous medium and a surfactant are then added to dissolve the film, followed by ultrasonication to form an emulsion. This is then uniformly stirred with chitosan and gelatin solutions, respectively, and filtered through centrifugation and a microfiltration membrane to obtain nanometer-sized liposomes. Patent CN105030679A uses cholesterol and a surfactant as auxiliary materials, and organic solvents are used in the manufacturing process, limiting its application in the food and health food fields.

[0009] There remains a need in the art for highly stable liposomal formulations for the delivery of active ingredients. Summary of the Invention

[0010] In response to the deficiencies of the prior art, the present invention produces cholesterol-free liposomes by combining a phospholipid with a specific phosphatidylcholine content range (PC content of 30-60 wt%) with gelatin having a high Bloom value (200-300). The produced liposomes may have one or more of the following properties: high temperature resistance, high stability, high encapsulation rate, high retention rate, and biological acceptability.

[0011] In one aspect, the present invention provides a liposome composition comprising 2 to 5 parts by weight of liquid oil, 3 to 10 parts by weight of solid oil, 5 to 30 parts by weight of phospholipid, 3 to 10 parts by weight of gelatin, 1 to 7 parts by weight of an active ingredient, and 20 to 70 parts by weight of water.

[0012] In one embodiment, the liquid oil is one or more of caprylic / capric glycerin, soybean oil, and sunflower seed oil. In one embodiment, the solid oil is one or more of monoglycerin fatty acid esters, diglycerin fatty acid esters, citric acid esters, palm stearin, and beeswax. In one embodiment, the phospholipid has a phosphatidylcholine content of 30 to 60 wt%. In one embodiment, the gelatin has a Bloom value of 200 to 300. In one embodiment, the liposome composition does not contain an excipient. In one embodiment, the liposome composition contains 20 to 70 parts by weight of an excipient.

[0013] In one embodiment, the active ingredient is selected from the group consisting of a fat-soluble active ingredient, a water-soluble active ingredient, a heat-sensitive active ingredient, an insoluble particle, an acid-sensitive active ingredient, or a digestive enzyme-sensitive active ingredient. In one embodiment, the active ingredient is a fat-soluble or water-soluble heat-sensitive active ingredient. In one embodiment, the active ingredient is an insoluble particle.

[0014] In one embodiment, the active ingredient is one or more of coenzyme Q10, curcumin, xanthophylls, and astaxanthin.

[0015] In one embodiment, the liposome composition does not include one or more of the following components: cholesterol, ethanol, and polysorbate. In one embodiment, the excipient is one or more of colloid, maltodextrin, cyclodextrin, starch, sugar alcohol, syrup, and whey protein.

[0016] In one aspect, the method of the present invention for making liposomes described herein includes the step of combining a liquid oil, a solid oil, a phospholipid, gelatin, an active ingredient, and water to form a liposome solution.

[0017] In one embodiment, when a fat-soluble active ingredient is used, the method comprises: (1) uniformly mixing a fat-soluble active ingredient, a liquid oil and a solid oil to obtain component A1; (2) uniformly mixing phospholipids, gelatin, and water to obtain component B1; (3) mixing component A1 and component B1 to form a homogeneous liquid system.

[0018] In one embodiment, when a water-soluble active ingredient is used, the method comprises: (1) uniformly mixing a liquid oil and a solid oil to obtain component A2; (2) uniformly mixing a water-soluble active ingredient, phospholipid, gelatin, and water to obtain component B2; (3) mixing component A2 and component B2 to form a homogeneous liquid system.

[0019] In one aspect, a method for producing a liposomal dosage form according to the present invention comprises the steps of: sterilizing the liposome solution at high temperature to obtain sterilized liquid liposomes; Adding a colloid excipient to the liposome solution, dispersing it thoroughly, and sterilizing it at high temperature to obtain a liposome gel; or The method includes one or more steps of adding an excipient to the liposome solution, mixing, sterilizing at high temperature, and drying to obtain a liposome powder.

[0020] In one embodiment, the excipient is one or more of maltodextrin, cyclodextrin, starch, sugar alcohol, syrup, and whey protein.

[0021] In one embodiment, the liposome solution of the present invention is produced by the method for producing liposomes described herein.

[0022] In one aspect, a liposomal dosage form according to the present invention is prepared from the liposomal solution described herein. In one embodiment, the liposomal dosage form is a solution, gel, powder, tablet, soft capsule, or jelly.

[0023] In one aspect, the liposomal dosage form of the present invention is a liquid liposome, a liposomal gel, or a liposomal powder. In one embodiment, the liposomal dosage form is produced by the methods described herein.

[0024] In one aspect, the present invention provides the use of the liposomal dosage form described herein in a food or health food or in the manufacture of a drug.

[0025] The beneficial effects of the present invention are as follows:

[0026] 1. The liposomes described herein are cholesterol-free, resistant to high temperatures, and highly stable.

[0027] 2. The active ingredients described herein (e.g., coenzyme Q10, etc.) have high encapsulation rates, high retention rates, and high biological acceptability.

[0028] 3. The present invention uses food raw materials and auxiliary materials, and has the advantages of high safety, wide application range, industrialized production and cost saving.

[0029] 4. Compared with conventional technologies, the liposome product containing active ingredients (e.g., coenzyme Q10) of the present invention is highly stable, does not split, has small and uniform particle size, and after a 3-month accelerated stability test (40°C, 70% humidity), the encapsulation rate is 92% or more and the active ingredient retention rate is 93% or more. Its biological acceptability is significantly improved compared to the raw material. In addition, the auxiliary materials used in the formulation composition product are safe and do not use organic solvents.

[0030] 5. The powder of the present invention has high resolubility. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 is a control diagram showing the severity of precipitation or separation of Coenzyme Q10 liposome samples after high-temperature sterilization. [Figure 2] This shows a raw material containing 98% Coenzyme Q10. Under a microscope, the raw material exhibits an irregular crystalline structure. [Figure 3] 1 is a micrograph showing the redissolved liquid of composition 12 in Table 3. [Figure 4] The scanning electron microscope structure of the sample of composition 6 in Table 2 is shown. [Figure 5] 1 is a scanning electron microscope photograph showing Coenzyme Q10 liposome powder of Composition 12 in Table 3. [Figure 6] FIG. 1 is an external view of a Coenzyme Q10 liposome solution of Composition 6 in Table 2. [Figure 7] FIG. 1 is an external view of Coenzyme Q10 liposome powder, Composition 12, in Table 3. [Figure 8] FIG. 1 is an external view showing the solution of Coenzyme Q10 liposome powder of Composition 12 in Table 3 after reconstitution. DETAILED DESCRIPTION OF THE INVENTION

[0032] definition To facilitate understanding of the present invention, a number of terms are defined below. Terms defined herein have meanings that are commonly understood by those of ordinary skill in the art.

[0033] As used herein, a "liposome" is a microscopic vesicle formed by encapsulating an active ingredient, such as a drug, within a lipidoid bilayer. Conventional liposomes are composed of phospholipids and cholesterol and include an internal vesicular structure with a lipid bilayer coating an aqueous phase.

[0034] As used herein, "liposome composition" refers to materials for producing liposomes by conventional liposome manufacturing methods (eg, passive drug loading).

[0035] As used herein, "passive drug loading" refers to first dissolving a drug in an aqueous phase (for water-soluble drugs) or an organic phase (for lipid-soluble drugs), and then preparing drug-containing liposomes according to a selected liposome preparation method.

[0036] As used herein, "liquid oil" refers to an oil that is liquid at room temperature.

[0037] As used herein, "solid fat" refers to fat that is solid at room temperature.

[0038] As used herein, "bloom" is an important physical property of gelatin, also known as freezing ability. In China, the bloom value of gelatin is measured and used according to the method specified in GB6783-94.

[0039] As used herein, "active ingredient" has the same meaning as functional ingredient. The active ingredient is selected from the group consisting of a fat-soluble active ingredient, a water-soluble active ingredient, a heat-sensitive active ingredient, an insoluble particle, an acid-sensitive active ingredient, or a digestive enzyme-sensitive active ingredient, as long as it can be coated to form a liposome. The active ingredient may be fat-soluble, water-soluble, or insoluble particle. The insoluble particles may have a size of 1 μm to 10 mm, for example, 10 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 800 μm, 850 μm, 900 μm, 950 μm, 1 mm, 1.5 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, or 9 mm. The size can be calculated based on the longest dimension of the particle. The shape of the particles is not particularly limited and may be various regular or irregular shapes. Preferably, the active ingredient is heat-sensitive and can withstand heat treatment after being coated with liposomes. Preferably, the active ingredient is an acid-sensitive or digestive enzyme-sensitive active ingredient, and can withstand digestion by digestive fluids (e.g., gastric juices) after being coated with liposomes. Herein, the active ingredient may be coenzyme Q10 and / or curcumin. As used herein, "coenzyme Q10" is a fat-soluble antioxidant that can activate human cells and cellular energy nutrients, improve human immunity, strengthen antioxidant properties, delay aging, and enhance human vitality. It can prevent cell damage in the adjunctive treatment of heart and brain diseases, and has a high therapeutic effect on improving human immunity. Coenzyme Q10 is heat-sensitive, and conventional manufacturing processes, such as sterilization and spray drying, are prone to decomposition of coenzyme Q10 due to the influence of temperature. Furthermore, coenzyme Q10 liposomes typically use phospholipids as a membrane material. When administered orally, acids, alkalis, and enzymes in the digestive system can destroy the liposome structure, leading to leakage of coenzyme Q10. Therefore, the stability and biological acceptability of the Coenzyme Q10 liposome product are both low. In the examples herein, the liposome of the present invention is illustrated using Coenzyme Q10 as an example.To provide coenzyme Q10 liposomes having high stability and high biological acceptability.

[0040] Liposome Composition The present disclosure provides liposome compositions comprising liquid oil, solid oil, phospholipids, gelatin, an active ingredient, water, and a preferred excipient. The liposome compositions of the present disclosure may be free of one or more of the following components: sterol or cholesterol, ethanol, and organic solvents such as polysorbates. Alternatively, the liposome compositions may be manufactured without the use of one or more of the following components: sterol or cholesterol, ethanol, and organic solvents such as polysorbates. Consuming large amounts of sterol or cholesterol is not beneficial to health. The use of organic solvents in the manufacturing process is highly hazardous. Polysorbates are harmful to individuals with enteritis or sensitive digestive tracts. The liposome compositions described herein may be composed of liquid oil, solid oil, phospholipids, gelatin, an active ingredient, and water, or may be composed of liquid oil, solid oil, phospholipids, gelatin, an active ingredient, water, and an excipient.

[0041] In the liposome composition herein, the liquid oil is one or more of glyceryl caprylate, soybean oil, and sunflower seed oil. The liposome composition herein may contain 2 to 5 parts by weight of the liquid oil, for example, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, or 5 parts by weight of the liquid oil.

[0042] In the liposome composition of the present specification, the solid oil or fat is one or more of monoglycerin fatty acid esters, diglycerin fatty acid esters, citric acid esters, palm stearin, and beeswax. The liposome composition of the present specification may contain 3 to 10 parts by weight of the solid oil or fat, for example, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, or 9 parts by weight.

[0043] In the liposome composition of the present specification, the phospholipid is a phospholipid having a phosphatidylcholine content of 30 to 60 wt%, which may be 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, or 59 wt%. The liposome composition of the present specification may contain 5 to 30 parts by weight of phospholipid, for example, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13 parts by weight, 14 parts by weight, 15 parts by weight, 16 parts by weight, 17 parts by weight, 18 parts by weight, 19 parts by weight, 20 parts by weight, 21 parts by weight, 22 parts by weight, 23 parts by weight, 24 parts by weight, 25 parts by weight, 26 parts by weight, 27 parts by weight, 28 parts by weight, or 29 parts by weight of phospholipid.

[0044] In the liposome composition of the present specification, the gelatin has a Bloom value of 200 to 300. For example, the Bloom value of the gelatin is 210, 220, 230, 240, 250, 260, 270, 280, or 290. The liposome composition of the present specification may contain 3 to 10 parts by weight of gelatin, for example, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, or 9 parts by weight.

[0045] In the liposome composition of the present specification, the liposome composition may not contain an excipient, and may contain 20 to 70 parts by weight of an excipient, for example, 21 parts by weight, 22 parts by weight, 23 parts by weight, 24 parts by weight, 25 parts by weight, 26 parts by weight, 27 parts by weight, 28 parts by weight, 29 parts by weight, 30 parts by weight, 31 parts by weight, 32 parts by weight, 33 parts by weight, 34 parts by weight, 35 parts by weight, 36 parts by weight, 37 parts by weight, 38 parts by weight, 39 parts by weight, 40 parts by weight, 41 parts by weight, 42 parts by weight, 43 parts by weight, 44 parts by weight, 45 parts by weight, 46 parts by weight, 47 parts by weight, 48 parts by weight, 49 parts by weight, 50 parts by weight, 51 parts by weight, 52 parts by weight, 53 parts by weight, 54 parts by weight, 55 parts by weight, 56 parts by weight, 57 parts by weight, 58 parts by weight, 59 parts by weight, 60 parts by weight, 61 parts by weight, 62 parts by weight, 63 parts by weight, 64 parts by weight, 65 parts by weight, 66 parts by weight, 67 parts by weight, 68 parts by weight, 69 parts by weight, 70 parts by weight, 71 parts by weight, 72 parts by weight, 73 parts by weight, 74 parts by weight, 75 parts by weight, 76 parts by weight, 77 parts by weight, 78 parts by weight, 79 parts by weight, 80 parts by weight, 81 parts by weight, 82 parts by weight, 83 parts by weight, 84 parts by weight, 85 parts by weight, 86 parts by weight, 87 parts by weight, The composition may include 1 part, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 ​​parts, 49 parts, 50 parts, 51 parts, 52 parts, 53 parts, 54 parts, 55 parts, 56 parts, 57 parts, 58 parts, 59 parts, 60 parts, 61 parts, 62 parts, 63 parts, 64 parts, 65 parts, 66 parts, 67 parts, 68 parts, or 69 parts by weight of an excipient. The excipient may be one or more of colloid, maltodextrin, cyclodextrin, starch, sugar alcohol, syrup, and whey protein. For example, the excipient is maltodextrin and whey protein isolate.

[0046] The liposome composition of the present specification may contain 1 to 7 parts by weight, for example, 2, 3, 4, 5, or 6 parts by weight, of an active ingredient. The active ingredient may be fat-soluble or water-soluble. The active ingredient may be a thermosensitive active ingredient. For example, the active ingredient is coenzyme Q10.

[0047] In the liposome composition of the present specification, the liposome composition contains 20 parts by weight to 70 parts by weight of water, for example, 21 parts by weight, 22 parts by weight, 23 parts by weight, 24 parts by weight, 25 parts by weight, 26 parts by weight, 27 parts by weight, 28 parts by weight, 29 parts by weight, 30 parts by weight, 31 parts by weight, 32 parts by weight, 33 parts by weight, 34 parts by weight, 35 parts by weight, 36 parts by weight, 37 parts by weight, 38 parts by weight, 39 parts by weight, 40 parts by weight, 41 parts by weight, 42 parts by weight, 43 parts by weight, 44 parts by weight, 45 parts by weight, 46 parts by weight, 47 parts by weight, 48 parts by weight, 49 parts by weight, 50 parts by weight, 51 parts by weight, 52 parts by weight, 53 parts by weight, 54 parts by weight, 55 parts by weight, 56 parts by weight, 57 parts by weight, 58 parts by weight, 59 parts by weight, 60 parts by weight, 61 parts by weight, 62 parts by weight, 63 parts by weight, 64 parts by weight, 65 parts by weight, 66 parts by weight, 67 parts by weight, 68 parts by weight, or 69 parts by weight of water.

[0048] Liposome manufacturing method The present invention provides a method for producing liposomes. The method may be a passive drug loading method. The method of the present invention may include a step of mixing a liquid oil, a solid oil, a phospholipid, gelatin, an active ingredient, and water to form a liposome solution. In one embodiment, when a fat-soluble active ingredient is used, the method includes the steps of (1) uniformly mixing the fat-soluble active ingredient, liquid oil, and solid oil to form Component A1, (2) uniformly mixing the phospholipid, gelatin, and water to form Component B1, and (3) mixing Component A1 and Component B1 to form a homogeneous liquid system. In one embodiment, when a water-soluble active ingredient is used, the method includes the steps of (1) uniformly mixing the liquid oil and solid oil to form Component A2, (2) uniformly mixing the water-soluble active ingredient, phospholipid, gelatin, and water to form Component B2, and (3) mixing Component A2 and Component B2 to form a homogeneous liquid system.

[0049] For example, the method of the present invention comprises: (1) Sufficiently dissolving and uniformly mixing coenzyme Q10, glyceryl caprylate, glyceryl monostearate, and glyceryl distearate to obtain component A; (2) A step of dissolving phospholipids and gelatin in water sufficiently and mixing them uniformly to obtain component B; (3) Adding A to B and stirring to mix and form a homogenous system, followed by homogenization (e.g., twice under 600 bar).

[0050] Furthermore, the method for producing a liposome dosage form according to the present invention includes the method for producing the liposome described above, and sterilizing the liposome solution at high temperature to obtain sterilized liquid liposomes; Adding a colloid excipient to the liposome solution, dispersing it thoroughly, and sterilizing it at high temperature to obtain a liposome gel; or The method includes one or more steps of adding an excipient to the liposome solution, mixing, sterilizing at high temperature, and drying to obtain a liposome powder, where the excipient may be one or more of maltodextrin, cyclodextrin, starch, sugar alcohol, syrup, and whey protein.

[0051] For example, a method for producing a liposomal dosage form includes: (1) Sufficiently dissolving and uniformly mixing coenzyme Q10, glycerin caprylate, glyceryl monostearate, and glycerin distearate to obtain component A; (2) thoroughly dissolving phospholipids and gelatin in water and mixing them uniformly to obtain component B; (3) Adding A to B and stirring to mix to form a homogeneous system, followed by homogenization (e.g., twice under 600 bar).

[0052] The homogenized solution in (3) may be directly sterilized at high temperature (e.g., 80°C to 100°C for 10 to 30 minutes) to produce a liposome solution. Alternatively, 20 to 70 parts of an excipient, preferably a colloid, may be added to the homogenized solution in (3), and the mixture may be thoroughly dispersed using methods such as high shear, colloid milling, or high-pressure homogenization, followed by sterilization at high temperature (e.g., 80°C to 100°C for 10 to 30 minutes) to produce a coenzyme Q10 liposome gel. Alternatively, 20 to 70 parts of an excipient, preferably maltodextrin, cyclodextrin, starch, sugar alcohol, syrup, or whey protein, may be added to the homogenized solution in (3), and the mixture may be thoroughly and uniformly mixed. The mixture may then be sterilized at high temperature (e.g., 80°C to 100°C for 10 to 30 minutes), and finally, the water may be removed by methods such as spray drying or freeze drying to produce a coenzyme Q10 liposome powder.

[0053] Liposomes and their dosage forms The liposomes herein may be the liposome liquid prepared above directly, or may be a specific dosage form formed after adding an excipient to the liposome liquid. The liposome dosage form may be a solution, gel, powder, tablet, soft capsule, or jelly. The liposome liquid may be sterilized (e.g., high-temperature sterilization) or may not be sterilized. Preferably, the liposome liquid may be sterilized at high temperature. Preferably, the liposome dosage form herein is a liquid liposome, liposome gel, or liposome powder prepared by the method described herein. For example, 20 to 70 parts of an excipient may be added to the coenzyme Q10 liposomes of the present specification, followed by spray drying to produce a coenzyme Q10 liposome powder, in which the coenzyme Q10 liposome content in the powder is in the range of 0.8% to 18%. Compared to liquid formulations, the powder is more stable, has advantageous storage properties, and has a wider range of applications. It may be directly used as a milk powder, or may be applied to health foods such as tablets, granules, soft capsules, and jellies.

[0054] application The liposome formulations described herein can be used in the manufacture of food or health foods, or drugs. For example, the active ingredient is coenzyme Q10. Coenzyme Q10 can prevent cell damage in the auxiliary treatment of heart disease, brain disease, etc., and has a strong therapeutic effect on improving the human immune system. Its specific functions are as follows:

[0055] 1. Improvement and prevention of heart disease: The heart is a high-energy consuming organ and has the highest coenzyme Q10 content of any organ in the human body. When the human body is deficient in coenzyme Q10, the heart is the first to be affected. Coenzyme Q10 can improve myocardial function and improve cardiovascular disease.

[0056] 2. Protecting brain nerve cells: Besides the heart, the brain is the most active organ in the human body with high energy demands. Coenzyme Q10 can provide brain cells with sufficient oxygen and energy, maintaining healthy and active brain and nerve cells.

[0057] 3. Antioxidation and reduction of cell apoptosis: Coenzyme Q10 has antioxidant properties, can scavenge free radicals, prevent cell damage, reduce cell apoptosis, and protect cells. Skin aging and increased wrinkles are also related to Q10 content. Coenzyme Q10 can increase the concentration of hyaluronic acid in the skin and improve skin moisture content, which is highly effective in improving dull skin tone and reducing wrinkles.

[0058] 4. Strengthening the body's immune system: Coenzyme Q10 has the ability to scavenge free radicals, and its antioxidant capacity is 50 times that of vitamin E. Coenzyme Q10 can enhance the immune system and play an important role in improving the body's immune system, anti-inflammatory, anti-tumor, etc. At the same time, it can also alleviate the discomfort caused by radiation therapy and chemotherapy for cancer patients.

[0059] 5. In the auxiliary treatment of other diseases, coenzyme Q10 has an auxiliary therapeutic effect on headache, emphysema, facial nerve palsy, periodontitis, alopecia areata, chronic obstructive pulmonary disease, bronchitis, asthma, etc. Clinically, muscle malnutrition and kidney disease have also been observed to be associated with coenzyme Q10 deficiency.

[0060] Hereinafter, the embodiments of the present application will be described in detail with reference to examples. Those skilled in the art will understand that the following examples are for illustrative purposes only and should not be construed as limiting the scope of the present application. Unless specific conditions are specified in the examples, the examples are carried out according to general conditions or conditions suggested by the manufacturer. Unless the manufacturer is specified, the reagents or equipment used are all ordinary products that are commercially available. Unless otherwise specified, all amounts listed are expressed in parts by weight based on the total weight. The present application should not be construed as being limited to the specific examples. [Example]

[0061] material Ingredients include coenzyme Q10, gelatin, phospholipids, caprylic / capric acid glycerin.

[0062] The equipment includes a homogenizer, high-performance liquid chromatography, a spray dryer, a particle size analyzer, a pH meter, a water bath, an instability coefficient measuring instrument, and a thermostatic vibrometer. All of the above materials are common materials and can be purchased commercially.

[0063] The manufacturing method is (1) Sufficiently dissolving and uniformly mixing the prescribed amounts of coenzyme Q10, glycerin caprylcaprate, glyceryl monostearate, and glyceryl distearate to obtain component A; (2) A step of dissolving the prescribed amounts of phospholipids and gelatin in water and mixing them uniformly to obtain component B; (3) Add A to B and stir to form a homogeneous mixture, then homogenize twice at 600 bar; (4) sterilizing the homogenized solution at high temperature (80°C to 100°C, 10 minutes to 30 minutes) to produce a liposome solution; or (5) Add 20 to 70 parts of excipients to the homogenized solution in (3), mix the excipients thoroughly and uniformly, and then sterilize at high temperature (80 to 100°C for 10 to 30 minutes). Finally, remove water by spray drying, freeze drying, or other methods to obtain coenzyme Q10 liposome powder.

[0064] Measurement method Appearance stability evaluation For the visual stability evaluation, the coenzyme Q10 liposome samples (samples obtained after step 3) were sterilized at 90°C for 30 minutes, and then the severity of precipitation or separation was observed. The degree of precipitation or separation increased from right to left, as shown in Figure 1. Figure 1 is a comparison diagram showing the severity of precipitation or separation of the coenzyme Q10 liposome samples after high-temperature sterilization.

[0065] The evaluation indicators are as follows (from left to right in Figure 1):

[0066] +++: After sterilization, clear separation or precipitation is observed on the liquid surface. ++: After sterilization, very clear precipitation or separation was observed on the liquid surface. +: After sterilization, a small amount of precipitation or separation was observed on the liquid surface. -: No precipitation or separation is observed on the liquid surface after sterilization.

[0067] Regarding microscopic observation, The sample to be detected was placed on a glass slide, flattened evenly, and covered with a cover glass to prepare a temporary slide.

[0068] The microscope used was a semi-transmitting polarizing microscope VPV-900. The specific operation was as follows: adjust the brightness, fix the temporary slide on the stage, first align the low-magnification objective lens with the light passage hole, and adjust the coarse focus knob until the field of view was clear. If the field of view was not clear, further adjustment was made using the fine focus knob, or switch to the high-magnification objective lens for observation.

[0069] In the field of view, a bright spot, i.e., a crystalline structure, was observed in the center of the sample.

[0070] Regarding scanning observation using an electron microscope, The specific procedure for scanning with an electron microscope is as follows: A small amount of powder was scooped up with a toothpick and evenly distributed on the conductive adhesive. The excess powder was then blown off with a dust can, after which the metal spraying process was performed. The sample was gold (platinum) sprayed using a Quorum SC7620 sputtering deposition system, with the current during metal spraying controlled at 5 mA to 7 mA and the metal spraying time set to 60 s.

[0071] After the sample processing was completed, the morphology of the samples was observed using a Zeiss Sigma 300 scanning electron microscope, and the morphology of the samples was recorded using secondary electron images, and electron microscope scanning diagrams of the samples were obtained.

[0072] Regarding particle size and stability tests, The prepared coenzyme Q10 liposome samples were sterilized at 90°C for 30 minutes, and then the particle size and stability were measured.

[0073] Particle size measurements were performed using a Mastersizer 3000 laser particle size analyzer. The specific procedure was as follows: The liposome particle size measurement system was run, washed three times, and then the sample to be measured was added. Once the light blocking level reached the system's preset value, measurement began. Each sample was measured three times, and the average value was used as the particle size of the coenzyme Q10 liposomes. If Dx(50), D[3,2], and D[4,3] were all close, this indicated that the sample had a uniform particle size distribution.

[0074] The stability test was performed using an instability index meter, with the following specific procedures: The system rotation speed was set to 4000 rpm, and the time was set to 2 hours. The sample was added and the system was then run. The sample stability was determined based on the instability index; the smaller the instability index, the higher the stability. For coenzyme Q10 liposome samples, when the instability index was greater than 0.2, separation and precipitation occurred.

[0075] Regarding detection of content, For the measurement by high-performance liquid chromatography (Pharmacopoeia General Rule 0512), the chromatography conditions and system applicability test were performed using octadecylsilane as the chromatographic column packing, methanol-absolute ethanol (1:1) as the mobile phase, the column temperature was 35°C, and the detection wavelength was 275 nm. Appropriate amounts of coenzyme Q10 control and coenzyme Q9 control were dissolved and diluted with absolute ethanol to prepare a mixed solution containing approximately 0.2 mg of each per mL. 20 μL of the mixed solution was injected into the liquid chromatograph. The resolution between the coenzyme Q9 and coenzyme Q10 peaks was greater than 4, and the theoretical plate number, calculated based on the coenzyme Q10 peak, was required to be greater than 3,000. For the measurement method, 20 mg of the prepared sample was precisely weighed, added to approximately 40 mL of absolute ethanol, and dissolved by shaking in a 50°C water bath. After cooling, the mixture was transferred to a 100 mL volumetric flask, diluted to the graduated mark with absolute ethanol, and shaken until uniform. As the test solution, 20 μL of the above mixture was precisely weighed and injected into a liquid chromatograph. The chromatogram was recorded. An appropriate amount of coenzyme Q10 control was also weighed and analyzed in the same manner. The coenzyme Q10 content was calculated using the external standard method based on peak area, and recorded as W1. A standard curve of coenzyme Q10 versus peak area was prepared, and W1 was calculated by substituting the peak area measured by high-performance liquid chromatography into the standard curve.

[0076] Regarding retention rate, Coenzyme Q10 liposome samples were sterilized at 90°C for 30 minutes, and then subjected to a 3-month accelerated stability test at 40°C and 75% humidity. The coenzyme Q10 content was determined at 0 and 3 months using the "content detection" method. The retention rate of coenzyme Q10 liposomes was calculated according to the following formula:

[0077] Retention rate = measured actual content of Coenzyme Q10 (W1) / detection value at 0 months (W0)*100%.

[0078] Regarding inclusion rate detection, The coenzyme Q10 liposome samples were sterilized at 90°C for 30 minutes, and then subjected to an accelerated stability test at 40°C and 75% humidity for 3 months, and the encapsulation rate was detected using the "content detection" method.

[0079] For free coenzyme Q10, 0.2 g of the sample after the accelerated test was weighed, 2 mL of n-hexane was added, and the mixture was extracted by vortex shaking. The mixture was then centrifuged at 10,000 rpm for 10 minutes, and the upper layer of n-hexane was removed. The free coenzyme Q10 in the liposomes was measured using the detection method in 8.3.3.

[0080] Regarding the total content of coenzyme Q10, the total content of coenzyme Q10 in coenzyme Q10 liposomes was directly detected using the detection method of "content detection."

[0081] Encapsulation rate = (1 - free coenzyme Q10 / total coenzyme Q10 content) * 100% Regarding resolubility tests, To prepare a formula, add 1g of Coenzyme Q10 liposome powder (5% Coenzyme Q10 content) to 200mL of warm water and stir for 30 seconds to completely disperse the powder. If there is no clumping or precipitation, it indicates high resolubility. The shorter the time required to dissolve the powder to the required state, the higher the resolubility.

[0082] Regarding in vitro digestion experiments, The infogest in vitro digestion method was used to simulate oral and gastrointestinal digestion and absorption, and the bioavailability of coenzyme Q10 liposomes was evaluated. The coenzyme Q10 liposome samples were sterilized at 90°C for 30 minutes, and then a sample equivalent to 50 mg of coenzyme Q10 was weighed out and 5 g of purified water was added to prepare the test fluids. Simulated saliva (SSF), gastric fluid (SGF), and intestinal fluid (SIF) were prepared, and the corresponding enzymes, i.e., oral mucosal protein, pepsin, pancreatin, pancreatic lipase, and cholate, were added. The pH of the saliva was adjusted to 6.8, the pH of the gastric fluid to 3.0, and the pH of the intestinal fluid to 7.0. The samples were then incubated at 37.2°C for 1 hour for preparation. The liquid to be measured was added to 4 mL of simulated saliva, and the pH was adjusted to 6.8 to simulate the oral digestive environment. The mixture was then incubated at 37°C for 10 minutes to complete oral digestion. After the digestion in the simulated saliva was completed, 8 mL of simulated gastric fluid was added to the digestive fluid, and the pH was adjusted to 3.0 to simulate the gastric digestive environment. The temperature was kept at 37°C for 1 hour to complete the gastric digestion simulation. After the digestion in the simulated stomach was completed, 16 mL of simulated intestinal fluid was added to the digestive fluid, and the pH was adjusted to 7.0 to simulate the intestinal digestive environment. The incubation time was 2 hours, and the pH was dynamically adjusted to maintain the pH at 7.0 during this period, thereby completing the digestion in the simulated intestine. Finally, the reaction was terminated in an ice bath, and the mixture was centrifuged at 14,000 rpm for 30 minutes to obtain the supernatant, i.e., the micellar layer. The content before digestion is the actual content of coenzyme Q10 before the in vitro digestion experiment, and the contents of coenzyme Q10 before digestion and in the micelle layer were both detected according to the method of "content detection."

[0083] Table 1. Digestive fluid prescription [Table 1] calculation formula Biological acceptability = Coenzyme Q10 content in the micelle layer / Coenzyme Q10 content before digestion * 100% Example 1: Consideration of the effect of gelatin bloom Samples were prepared according to the formula (parts by weight) in Table 2, and the particle size, instability index, visual stability, encapsulation rate, and retention rate of the Coenzyme Q10 liposome samples were evaluated using gelatin with different bloom strengths. The results show that when Coenzyme Q10 liposomes were prepared using gelatin with a bloom strength of 200 or less, the resulting liposome products were unstable, exhibiting layered precipitation after standing, large and non-uniform particle sizes, and a significant decrease in retention rate and encapsulation rate after a three-month accelerated stability test. Coenzyme Q10 liposomes prepared using gelatin with a bloom strength of 200 or more were stable, exhibiting small and uniform particle sizes, and no significant change in retention rate and encapsulation rate after a three-month accelerated stability test (see Figure 6). Figure 4 shows the scanning electron microscope (SEM) structure of a sample of Composition 6. The scanning electron microscope (SEM) structure of the Coenzyme Q10 liposome liquid revealed many circular liposome structures within the SEM field, the particle sizes of which were consistent with those detected by particle size measurement. Figure 6 shows the Coenzyme Q10 liposome solution of Composition 6. The Coenzyme Q10 liposome solution was a homogeneous yellow liquid. Therefore, not all gelatins can improve the stability of liposomes, but gelatins with high bloom can significantly improve the stability of liposomes.

[0084] Table 2 Liposomes prepared with gelatins of different bloom sizes [Table 2] According to the formulation of each ingredient in Table 2, 30 parts of maltodextrin and 20 parts of isolated whey protein were added, and the air intake temperature was set to 100°C, the air outlet temperature was set to 55°C, and the moisture was removed by spray drying to prepare powders (Compositions 1 to 6 were used to obtain Compositions 7 to 12, respectively) (see Figure 7). The resolubility of each powder was measured, and the results are shown in Table 3. As can be seen from the results, liposome powders made with gelatin having a bloom value of 200 or more had higher resolubility than liposome powders made with gelatin having a bloom value of less than 200 (see Figure 8).

[0085] Microscopic observation of the reconstituted liquid of Composition 12 revealed that the liposomes prepared with coenzyme Q10 exhibited a regular spherical crystalline structure (Figure 3), compared to the irregular crystalline structure of the raw coenzyme Q10 shown in Figure 2 (Figure 2). Figure 5 is a scanning electron micrograph further showing the coenzyme Q10 liposome powder of Composition 12. The scanning electron micrograph of the coenzyme Q10 liposome powder after preparation revealed that the wall material adhered to the liposome surface, resulting in an irregular particle structure.

[0086] 7 is an external view of the Coenzyme Q10 liposome powder of Composition 12. After the Coenzyme Q10 liposomes were made into a powder and then covered with a packaging material, the color lightened to become a pale yellow particulate powder.

[0087] 8 is an external view showing the solution after reconstitution of the Coenzyme Q10 liposome powder in Composition 12. After dissolving the Coenzyme Q10 liposome powder in water, a homogeneous yellow solution was obtained.

[0088] Table 3. Effect of Bloom Value of Gelatin on Redissolution of Powder [Table 3] Example 2: Study of the effect of different PC contents on phospholipids Coenzyme Q10 liposome samples were prepared according to the formulations in Table 4 (parts by weight), and different PCs were used for the phospholipids to evaluate the particle size, instability coefficient, appearance stability, encapsulation rate, and retention rate of the Coenzyme Q10 liposome samples.

[0089] The results show that coenzyme Q10 liposomes prepared with phospholipids containing low amounts of PC exhibited large particle sizes and uneven particle distribution. After sterilization at high temperatures, the particle sizes increased, significant stratification and precipitation occurred, the instability coefficient was high, and the retention and encapsulation rates were low after a three-month accelerated stability test. Coenzyme Q10 liposomes prepared with phospholipids containing high amounts of PC exhibited small particle sizes and uniform particle distribution, no stratification or precipitation after standing, a low instability coefficient, and high retention and encapsulation rates after a three-month accelerated stability test. It was found that phospholipids containing 80% PC were not stable. Therefore, coenzyme Q10 liposomes prepared with phospholipids containing an appropriate amount of PC (30 wt% to 60 wt%) exhibited higher stability.

[0090] Table 4. Coenzyme Q10 liposomes prepared with phospholipids containing different amounts of PC [Table 4] According to the formulation of each ingredient in Table 4, 30 parts of maltodextrin and 20 parts of isolated whey protein were added, and the air intake temperature was set to 100°C, the air outlet temperature was set to 55°C, and the moisture was removed by spray drying to produce powders (Compositions 13 to 17 were used to obtain Compositions 18 to 22, respectively). The resolubility of each powder was measured, and the results are shown in Table 5. As can be seen from the results, the resolubility of liposome powders produced with phospholipids having an appropriate PC content (30 wt% to 60 wt%) was high.

[0091] Table 5. Effect of phospholipids with different PC contents on the resolubility of powders. [Table 5] Example 3: Consideration of the effect of the amount of coenzyme Q10 added to liposomes Coenzyme Q10 liposome samples were prepared according to the formulations (in parts by weight) in Table 6, and the content of coenzyme Q10 was adjusted. The particle size, instability index, appearance stability, encapsulation rate, and retention rate of the coenzyme Q10 liposome samples were evaluated.

[0092] As can be seen from the results, when the amount of coenzyme Q10 was 1 to 7 parts by weight, the coenzyme Q10 liposomes produced had small, uniform particle size, excellent stability, and high retention and encapsulation rates after a 3-month accelerated stability test.When the amount of coenzyme Q10 exceeded this range, the coenzyme Q10 liposomes produced had an uneven particle size distribution, low stability, and reduced retention and encapsulation rates.

[0093] Table 6. Effect of the ratio of coenzyme Q10 to liposomes [Table 6] Example 4: Consideration of the effect of the amount of phospholipid added to coenzyme Q10 liposomes Coenzyme Q10 liposome samples were prepared according to the formulations (in parts by weight) in Table 7, and the phospholipid content was adjusted. The particle size, instability index, appearance stability, encapsulation rate, and retention rate of the coenzyme Q10 liposome samples were evaluated.

[0094] As can be seen from the results, when the phospholipid content is 5 to 30 parts by weight, the produced coenzyme Q10 liposomes have small particle size, uniformity, high stability, high retention rate and encapsulation rate; when the phospholipid content exceeds a certain ratio, they are prone to precipitation, causing solution separation.

[0095] Table 7. Effect of different ratios of phospholipids on coenzyme Q10 liposomes [Table 7] Example 5: Consideration of the effect of the amount of gelatin added to coenzyme Q10 liposomes Coenzyme Q10 liposomes were prepared according to the formulations (in parts by weight) in Table 8, and the gelatin content was adjusted. The particle size, instability index, appearance stability, encapsulation rate, and retention rate of the coenzyme Q10 liposome samples were evaluated.

[0096] As can be seen from the results, when the gelatin content was 3 to 10 parts by weight, the coenzyme Q10 liposomes produced had small particle sizes, uniform particle size, excellent stability, and high retention and encapsulation rates after a 3-month accelerated stability test. When the gelatin content exceeded this range, the coenzyme Q10 liposomes produced had non-uniform particle size distribution, poor stability, and reduced retention and encapsulation rates after a 3-month accelerated stability test.

[0097] Table 8. Effect of different gelatin ratios on coenzyme Q10 liposomes [Table 8] Example 6 In vitro digestion experiments The in vitro digestion experiment was performed as described above. The experimental composition and results are shown in Table 9. As can be seen from the results, the bioacceptability of Coenzyme Q10 liposomes in the in vitro digestion experiment was significantly improved compared to the raw material. By improving gelatin bloom and controlling the PC content and phospholipid ratio, the bioacceptability of Coenzyme Q10 liposomes can be improved to a certain extent.

[0098] Table 9. In vitro digestion experiment results [Table 9] Example 7 Liposomes of other active ingredients Curcumin is a diketone compound that has pharmacological effects such as anti-inflammatory, antioxidant, antibacterial, antitumor, blood lipid lowering, and improving bile function. However, it is insoluble in water, has low solubility in fats and oils, and is rapidly metabolized in the body, limiting its use in everyday products. The liposome composition and manufacturing method in this patent are also applied to curcumin.

[0099] Curcumin liposome samples were prepared according to the formulations (in parts by weight) in Table 10, and the particle size, instability index, and appearance stability of the curcumin liposome samples were evaluated.

[0100] As can be seen from the results, the composition can improve the stability of curcumin liposomes, reducing the particle size and instability coefficient, and showing stable appearance without separation after sterilization at high temperature.

[0101] Table 10. Liposome stability considerations for other active ingredients [Table 10]

[0102] According to the formulation of each component in Table 10, 30 parts of maltodextrin and 20 parts of whey protein isolate were added, and the air intake temperature was set to 150°C, the air outlet temperature was set to 70°C, and the moisture was removed by spray drying to prepare powders (compositions 45 to 48 were used to obtain compositions 49 to 52, respectively). The resolubility of each powder was measured, and the results are shown in Table 11. As can be seen from the results, curcumin liposomes had high resolubility after preparing powders using the formulation of the composition in the patent.

[0103] Table 11. Consideration of resolubility of curcumin liposome powder [Table 11]

[0104] Carotenoids are the main source of vitamin A in the body and are fat-soluble components with strong antioxidant properties, as well as immunoregulatory, eye protection, anti-cancer, and anti-aging effects, but are easily oxidized and unstable to light and heat, limiting their application. Xanthophyll and astaxanthin belong to carotenoids and are widely used in general foods and health foods. The formulation of the composition in this patent can effectively improve the stability of xanthophyll and astaxanthin liposomes.

[0105] Xanthophyll and astaxanthin liposome samples were prepared according to the formulations in Table 12 (parts by weight), and the particle size, instability index, and appearance stability of the xanthophyll and astaxanthin liposome samples were evaluated.

[0106] As can be seen from the results, the composition can improve the stability of xanthophyll and astaxanthin liposomes, reducing the particle size and instability coefficient, and showing stable and non-separated appearance after sterilization at high temperature.

[0107] Table 12. Stability considerations of xanthophyll and astaxanthin liposomes [Table 12]

[0108] According to the formulation of each component in Table 12, 30 parts of maltodextrin and 20 parts of whey protein isolate were added, and the air intake temperature was set to 120°C, the air outlet temperature was set to 60°C, and the moisture was removed by spray drying to prepare powders (compositions 53 to 56 were used to obtain compositions 57 to 60, respectively). The resolubility of each powder was measured, and the results are shown in Table 13. As can be seen from the results, xanthophyll and astaxanthin liposomes had high resolubility after preparing powders according to the formulation of the patented composition.

[0109] Table 13. Consideration of resolubility of xanthophyll and astaxanthin liposome powders [Table 13] Omega-3 is an unsaturated fatty acid commonly found in deep-sea fish and some plants, and is highly beneficial to human health, with excellent effects on diabetes, cardiovascular disease, inflammation, dementia, depression, Alzheimer's disease, dry eye conditions, neurodevelopment and health, etc. The main types of Omega-3 include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Algae oil and fish oil are rich in Omega-3 such as DHA, but unsaturated fatty acids are easily oxidized, causing the effects to be lost. The formulation of the composition in this patent can effectively improve the stability of algae oil and fish oil liposomes.

[0110] Algal oil and fish oil liposome samples were prepared according to the formulations in Table 14 (parts by weight), and the particle size, instability index, appearance stability, encapsulation rate, and retention rate of the DHA algal oil liposome samples were evaluated.

[0111] As can be seen from the results, the composition can improve the stability of algal oil and fish oil liposomes, reducing the particle size and instability coefficient, and showing a stable appearance without separation after sterilization at high temperature.

[0112] Table 14. Consideration of the stability of algal oil and fish oil liposomes [Table 14]

[0113] According to the formulation of each ingredient in Table 14, 30 parts of maltodextrin and 20 parts of whey protein isolate were added, and the air intake temperature was set to 150°C, the air outlet temperature was set to 70°C, and the moisture was removed by spray drying to produce powders (compositions 61 to 64 were used to obtain compositions 65 to 68, respectively). The resolubility of each powder was measured, and the results are shown in Table 15. As can be seen from the results, the algae oil and fish oil liposomes had high resolubility after producing powders using the formulation of the composition in the patent.

[0114] Table 15. Consideration of resolubility of algal oil and fish oil liposome powder [Table 15]

[0115] Fat-soluble vitamins, including vitamin A, vitamin D, vitamin E, and vitamin K, are hydrophobic compounds that are easily soluble in lipids and organic solvents and are absorbed together with lipids. The formulation of the composition in this patent can effectively improve the stability of fat-soluble liposomes, such as VA (vitamin A) and VK (vitamin K) liposomes.

[0116] VA and VK liposome samples were prepared according to the formulations (parts by weight) in Table 16, and the particle size, instability coefficient, appearance stability, and encapsulation rate of the VA and VK liposome samples were evaluated.

[0117] As can be seen from the results, the composition can improve the stability of VA and VK liposomes, reducing the particle size and instability coefficient, and showing stable appearance without separation after sterilization at high temperature.

[0118] Table 16. Consideration of stability of VA and VK liposomes [Table 16]

[0119] According to the formulation amounts of each ingredient in Table 16, 30 parts of maltodextrin and 20 parts of whey protein isolate were added, and the air intake temperature was set to 160°C, the air outlet temperature was set to 75°C, and the moisture was removed by spray drying to produce powders (compositions 69 to 72 were used to obtain compositions 73 to 76, respectively). The resolubility of each powder was measured, and the results are shown in Table 17. As can be seen from the results, VA and VK liposomes had high resolubility after producing powders using the composition formulation in the patent.

[0120] Table 17. Consideration of resolubility of algae oil liposome powder [Table 17]

[0121] Water-soluble vitamins are vitamins that are soluble in water but not in non-polar organic solvents, including B vitamins and vitamin C. Polyphenols are naturally occurring phenols that contain a large amount of phenolic structural units and are characterized by including epigallocatechin gallate (EGCG), epigallocatechin gallate, etc. VC and EGCG are relatively unstable, and the formulation of the composition in this patent can effectively improve the stability of VC and EGCG liposomes.

[0122] VC and EGCG liposome samples were prepared according to the formulations (parts by weight) in Table 18, and the particle size, instability index, appearance stability, encapsulation rate, and retention rate of the VC and EGCG liposome samples were evaluated.

[0123] As can be seen from the results, the composition can improve the stability of VC and EGCG liposomes, reducing the particle size and instability coefficient, and showing that the appearance after high-temperature sterilization is stable and does not separate.

[0124] Table 18. Considerations of liposome stability of other active ingredients [Table 18]

[0125] According to the formulation amounts of each ingredient in Table 18, 30 parts of maltodextrin and 20 parts of isolated whey protein were added, and the air intake temperature was set to 140°C, the air outlet temperature was set to 60°C, and the moisture was removed by spray drying to produce powders (compositions 77 to 80 were used to produce compositions 81 to 84, respectively). The resolubility of each powder was measured, and the results are shown in Table 19. As can be seen from the results, VC and EGCG liposomes had high resolubility after producing powders using the composition formulation in the patent.

[0126] Table 19. Consideration of resolubility of VC and EGCG liposome powder [Table 19]

[0127] While the present invention has been described with reference to illustrative embodiments, those skilled in the art will recognize that various other modifications, omissions, and / or additions may be made, and that elements of the described embodiments may be substituted with substantially equivalent elements, without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, the specification is not intended to limit the invention to the particular embodiments disclosed for carrying out the invention, but rather, the invention is intended to cover all embodiments falling within the scope of the appended claims.

Claims

1. A liposome composition comprising 2 to 5 parts by weight of liquid oil, 3 to 10 parts by weight of solid oil, 5 to 30 parts by weight of phospholipid, 3 to 10 parts by weight of gelatin, 1 to 7 parts by weight of an active ingredient, and 20 to 70 parts by weight of water.

2. the liquid oil is one or more of glyceryl caprylate, soybean oil, sunflower seed oil; and / or The solid fat or oil is one or more of monoglycerin fatty acid ester, diglycerin fatty acid ester, citric acid ester, palm stearin, beeswax, and / or The phospholipid is a phospholipid having a phosphatidylcholine content of 30 to 60 wt %; and / or the gelatin has a Bloom value of 200 to 300, and / or 2. The liposome composition according to claim 1, wherein the liposome composition contains no excipient or 20 to 70 parts by weight of an excipient.

3. 3. The liposome composition according to claim 1, wherein the active ingredient is selected from the group consisting of a fat-soluble active ingredient, a water-soluble active ingredient, a heat-sensitive active ingredient, an insoluble particle, an acid-sensitive active ingredient, or a digestive enzyme-sensitive active ingredient.

4. The liposome composition of claim 3, wherein the active ingredient is one or more of coenzyme Q10, curcumin, xanthophyll, astaxanthin, algae oil, fish oil, vitamins, and polyphenols.

5. The liposome composition of claim 1 , which is free of one or more of the following components: cholesterol, ethanol, and polysorbate.

6. 3. The liposome composition of claim 2, wherein the excipient is one or more of a colloid, maltodextrin, cyclodextrin, starch, sugar alcohol, syrup, and whey protein.

7. 5. The liposome composition of claim 4, wherein the vitamin is selected from vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, and vitamin K, and the polyphenol is selected from epigallocatechin gallate (EGCG) and epigallocatechin gallate.

8. A method for producing liposomes using the liposome composition according to any one of claims 1 to 7, comprising the step of mixing liquid oil, solid oil, phospholipid, gelatin, an active ingredient and water to form a liposome solution.

9. The active ingredient is a fat-soluble active ingredient or a water-soluble active ingredient, When a fat-soluble active ingredient is used, the method comprises: (1) uniformly mixing a fat-soluble active ingredient, a liquid oil and a solid oil to prepare component A1; (2) uniformly mixing phospholipids, gelatin, and water to obtain component B1; (3) mixing component A1 and component B1 to form a homogeneous liquid system; When a water-soluble active ingredient is used, the method comprises: (1) uniformly mixing a liquid oil and a solid oil to obtain component A2; (2) uniformly mixing a water-soluble active ingredient, a phospholipid, gelatin, and water to obtain component B2; (3) mixing components A2 and B2 to form a homogeneous liquid system.

10. The method of claim 8, and sterilizing the liposome solution at high temperature to obtain sterilized liquid liposomes; Adding a colloid excipient to the liposome solution, dispersing it thoroughly, and sterilizing it at high temperature to obtain a liposome gel; or adding an excipient to the liposome solution, mixing the mixture, sterilizing the mixture at high temperature, and drying the mixture to obtain a liposome powder; A method for producing a liposomal dosage form, wherein the excipient is one or more of maltodextrin, cyclodextrin, starch, sugar alcohol, syrup, and whey protein.

11. A liposome solution produced by the method according to claim 8.

12. A liposome dosage form prepared from the liposome solution of claim 11, which is a solution, gel, powder, tablet, soft capsule or jelly.

13. A liposomal dosage form, which is a liquid liposome, a liposomal gel, or a liposomal powder, produced by the method of claim 10.

14. 13. Use of the liposomal dosage form according to claim 12 in food or health food or in the manufacture of a drug.

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