Vitamin d soft capsule and manufacturing method thereof

Abstract

To provide a vitamin AD soft capsule having improved stability and bioavailability of a soft capsule preparation, and to provide a method for producing the same.SOLUTION: It has been found that the addition of CGKRK peptide as an anti-aging agent to a wall material based on gelatin has an anti-aging effect on gelatin superior to that of a single amino acid, and can greatly alleviate the problems of soft capsule disintegration, delayed dissolution and reduced dissolution with a lower addition amount, thereby improving the stability and bioavailability of a vitamin AD soft capsule formulation.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This invention claims priority to a Chinese patent application bearing application number 202410793315.X and entitled "Vitamin AD soft capsule and its manufacturing method" filed with the State Intellectual Property Office of the People's Republic of China on June 19, 2024, the entire contents of which are hereby incorporated by reference into and made a part of the present invention for all purposes. [Technical Field]

[0002] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to vitamin AD soft capsules and a method for producing the same. [Background technology]

[0003] The information disclosed in the Background section is intended solely to enhance understanding of the overall background of the present invention and should not necessarily be taken as an admission or in any way suggesting that the information constitutes prior art already known to those skilled in the art.

[0004] Vitamin AD supplements are used to prevent and treat vitamin A and D deficiency disorders, such as rickets and tetany accompanied by night blindness. Soft capsules are a common dosage form for vitamin AD formulations. Considering raw material and process costs, most commercially available vitamin AD soft capsules use gelatin as the base wall material. Gelatin is a hydrophilic polymer derived from collagen, found in connective tissues such as animal skin and bones. Its main component is a protein composed of multiple amino acids. Gelatin is prone to aging during long-term storage, especially under high temperature and humidity conditions. This is primarily due to the self-oxidation crosslinking of amino acids (mainly arginine and lysine) in the gelatin molecule and crosslinking with externally introduced low-molecular-weight aldehydes, which slows the disintegration of the gelatin wall material, reduces solubility, and further affects drug absorption in the body.

[0005] Several amino acids have been shown to improve gelatin aging. For example, the applicant's prior patent applications CN101711875A and CN101953815A disclose, respectively, the addition of 1.5-3% lysine to capsule shells containing 37-43% gelatin to solve the problem of extended disintegration time due to gelatin aging, and the use of a combination of fumaric acid and L-lysine as antioxidants to inhibit capsule shell aging, with a fumaric acid to L-lysine weight ratio of 1:10-1:30. He Yulian et al. (Improving the Disintegration Time of Black Wolfberry Extract Soft Capsules [J]. Food Industry, 2021(002):042.) studied the effects of adding glycine, L-cysteine, and arginine to the capsule shell and contents on the disintegration time of black wolfberry extract soft capsules. The order of effectiveness of the three amino acids in alleviating disintegration problems was L-cysteine ​​> glycine > arginine. However, the anti-aging level of the wall materials in the above prior art still needs to be further improved. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the present invention aims to provide vitamin AD soft capsules and a method for producing the same. Specifically, the present inventors have unexpectedly discovered through research that adding CGKRK peptide as an anti-aging agent to a gelatin-based wall material has a superior anti-gelatin aging effect compared to a single amino acid, and that even at lower addition amounts, it significantly alleviates the problems of soft capsule collapse, delayed dissolution, and reduced dissolution rate, and further improves the stability and bioavailability of vitamin AD soft capsule formulations. Based on these research results, the present invention has been completed.

[0007] In order to achieve the above technical objectives, the technical solutions provided by the present invention are as follows:

[0008] In a first aspect of the present invention, there is provided a use of a CGKRK peptide as an anti-aging agent in the manufacture of vitamin AD soft capsules.

[0009] Specifically, the use includes improving the anti-aging properties of the wall material of vitamin AD soft capsules, alleviating the problems of soft capsule collapse, delayed dissolution and reduced dissolution rate, thereby improving the stability and bioavailability of vitamin AD soft capsule formulations.

[0010] The raw material for the wall of the vitamin AD soft capsule may be gelatin.

[0011] In a second aspect of the present invention, there is provided a vitamin AD soft capsule comprising a wall material and a capsule content liquid, wherein the mass ratio of the raw material of the wall material to the capsule content liquid, in parts by weight, is 1:1 to 3, preferably 1:1 to 2, for example, 1:1.5.

[0012] The wall material contains gelatin, a plasticizer, a CGKRK peptide, and water, and the capsule content liquid contains vitamin A, vitamin D, and an oily solvent.

[0013] In a third aspect of the present invention, Step S1: mixing and dissolving the remaining ingredients of the wall material, other than gelatin and CGKRK peptide, under heating to obtain a mixture; After gelatin is swelled in water, it is added to the mixture obtained in step S1, and then CGKRK peptide is added thereto, and the heating temperature of step S1 is maintained, and the mixture is uniformly mixed and melted to produce a gelatin solution, and after removing air bubbles in the gelatin solution, the gelatin solution is poured out, filtered, and used and reserved in step S2; Step S3: forming the gelatin solution obtained in step S2 into gelatin strips; Step S4: dissolving vitamins A and D in an oily solvent to prepare a capsule content liquid; and step S5 of encapsulating an effective amount of capsule content liquid together with the gelatin strip obtained in step S3 to obtain the vitamin AD soft capsule. [Effects of the Invention]

[0014] The beneficial technical effects of the one or more technical solutions above are as follows:

[0015] The above technical solution is the first to propose adding CGKRK peptide as an anti-aging agent to a gelatin-based wall material, which has a better anti-gelatin aging effect than a single amino acid, and can significantly alleviate the problems of soft capsule collapse, delayed dissolution, and reduced dissolution rate with a lower added amount, and can further improve the stability and bioavailability of vitamin AD soft capsule formulations.

[0016] Furthermore, the above vitamin AD soft capsule preparation is very suitable for industrial mass production because the manufacturing method is simple and easy to carry out and the raw materials are inexpensive and readily available, and therefore has high practical value. DETAILED DESCRIPTION OF THE INVENTION

[0017] It should be noted that the following detailed description is illustrative and is intended to further explain the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0018] It should be noted that the terminology used herein is for the purpose of describing particular embodiments and is not intended to limit the exemplary embodiments of the present application. As used herein, the singular forms "a," "an," "the," and "the" are intended to include the plural forms unless the context clearly dictates otherwise. It should also be understood that when the terms "comprise" and / or "comprises" are used herein, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0019] Unless otherwise defined herein, all technical and scientific terms used herein have the meaning commonly understood by those of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can also be used in the practice of the present invention, preferred methods and materials are those described herein. Furthermore, as used herein, the terms "a," "one," or "one" include plural or plural unless the context clearly dictates otherwise. Numerical ranges throughout the application include any subranges therein and any numerical value incremented by the smallest subunit of a given value therein. Unless expressly stated otherwise, numerical values ​​throughout the application represent approximate measurements or range limits of the scope of embodiments, including slight deviations from the given value, and values ​​that closely correspond to the stated value, and the exact value stated. Except for the working examples provided at the end of the detailed description, all numerical values ​​of parameters (e.g., quantities or conditions) in the application (including the appended claims) should be understood to be modified in all instances by the term "about," regardless of whether "about" actually precedes the numerical value. "About" means that the stated numerical value allows for slight imprecision (being reasonably close to the value, being approximately or reasonably close to the value, approximating the value). Where "about" does not imply imprecision in this general sense in the art, "about," as used herein, refers to at least the variation that can occur with common methods of measuring and using such parameters. For example, "about" may include variations of 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.5% or less.

[0020] As used herein, all percentages are by weight unless the context clearly dictates otherwise.

[0021] As used herein, "soft capsule" refers to a dosage form in which a certain amount of a drug, active ingredient, nutrient, herbal extract, etc., together with appropriate auxiliary materials, is enclosed in a soft wall material of a spherical, oval, or other shape.

[0022] As used herein, the term "gelatin" refers to a product obtained by partial hydrolysis of collagen found in animal hides, bones, tendons, and ligaments. In one embodiment, the gelatin has a kinematic viscosity of about 24-28 mPa·s when measured using a rotational viscometer known to those skilled in the art at a gelatin aqueous solution concentration of 66.7 g / L and a water bath temperature of 60°C.

[0023] As used herein, the term "propylene glycol" refers to a good solvent capable of dissolving many organic and inorganic substances and is widely used as a solvent in the chemical industry. In cosmetics, it is often used as a humectant or moisturizer to adjust the viscosity and moisture content of products. In the food industry, it reacts with fatty acids to form propylene glycol fatty acid esters, which are primarily used as food emulsifiers and are also excellent solvents for seasonings and pigments. It also acts as a stabilizer, coagulant, anti-caking agent, defoamer, emulsifier, water-retaining agent, and thickener.

[0024] As used herein, the term "hexanediol" refers to an organic compound having multiple isomers and generally refers to 1,2-hexanediol, unless otherwise specified, which may be used as a base for local anesthetics and pharmaceutical auxiliary materials for the treatment of diseases such as dermatitis.

[0025] As used herein, the term "maltitol" refers to a compound with diverse uses and properties, including as an auxiliary material for inhaled drugs to enhance the stability, solubility, and inhalability of drugs, thereby improving drug delivery, as an auxiliary material for anesthetic drugs to help adjust the solubility and osmotic pressure of drugs, and as a sustained-release agent to control the release rate of drugs in the body, thereby extending the duration of drug action.

[0026] As used herein, the term "glycerin" is a plasticizer commonly used in soft capsule shells to improve the flexibility of the capsule shell.

[0027] As used herein, the term "sorbitol" refers to a sugar alcohol that is slowly metabolized by the human body. It is a polyhydric alcohol similar in structure to monosaccharides and is formed by the reduction of the aldehyde group of glucose. Its hygroscopic properties prevent food from drying out or cracking, keeping food fresh and soft. It is also used in the pharmaceutical industry as a binder, wetting agent, and excipient for tablets, capsules, and granules.

[0028] As used herein, the term "CGKRK peptide" refers to a polypeptide having the amino acid sequence of CGKRK, i.e., consisting of the five residues cysteine-glycine-lysine-arginine-lysine, in that order. Due to the presence of arginine and lysine, it carries a cationic charge under physiological conditions and is often used as a transmembrane peptide in the biomedical field.

[0029] As used herein, "amino acid" refers to amino acids including cysteine, glycine, lysine, arginine, etc. Amino acids are important organic molecules in living organisms that are involved in building cellular structures, regulating metabolic processes in living organisms, and transmitting signals. In the present invention, they are used as antioxidants.

[0030] As used herein, the term "prevention and / or treatment" refers to any measure suitable for treating vitamin A and D deficiency and related diseases, or to either the prophylactic treatment of a disease or the symptoms so described, or the recurrence of such a disease, including recurrence after treatment has ended, or the treatment of symptoms of a disease that has developed, or to proactively intervene to prevent, inhibit or reduce the occurrence of such a disease or symptom.

[0031] As used herein, the term "plasticizer" refers to a substance that can increase the plasticity of a polymeric material; plasticizers are typically liquids with high boiling points and low volatility, or solids with low melting points.

[0032] As used herein, the term "IU" is an abbreviation for International Unit, a unit commonly used in pharmaceuticals to express the content or potency of, among other things, vitamins, hormones, antibiotics, and antitoxin biologics.

[0033] In a specific exemplary embodiment of the present invention, there is provided the use of a CGKRK peptide as an anti-aging agent in the manufacture of vitamin AD soft capsules.

[0034] Specifically, the use includes improving the anti-aging properties of the wall material of vitamin AD soft capsules, alleviating the problems of soft capsule collapse, delayed dissolution and reduced dissolution rate, thereby improving the stability and bioavailability of vitamin AD soft capsule formulations.

[0035] The raw material for the wall of the vitamin AD soft capsule may be gelatin.

[0036] The mass fraction of the CGKRK peptide in vitamin AD soft capsules is 5 wt% or less. The inventors have found through research that the anti-aging effect of the wall material due to the addition of CGKRK peptide initially improves and then tends to decrease with increasing addition amount. When the CGKRK peptide is used in amounts of 2 wt% and 4 wt%, the relatively high CGKRK peptide addition caused rapid deterioration of the wall material, and the disintegration time in an accelerated test was longer than that of soft capsules containing no antioxidant. Therefore, the mass fraction of the CGKRK peptide in vitamin AD soft capsules is 1 wt% or less, or even 0.3 to 0.8 wt%, for example, 0.wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, or 0.8 wt%.

[0037] In one or more specific embodiments of the present invention, a vitamin AD soft capsule is provided, which comprises a wall material and a capsule content liquid, wherein the mass ratio of the wall material to the capsule content liquid, in parts by weight, is 1:1 to 3, preferably 1:1 to 2, for example, 1:1, 1:1.5, or 1:2, and particularly preferably 1:1.5.

[0038] The wall material contains gelatin, a plasticizer, a CGKRK peptide, and water, and the capsule content liquid contains vitamin A, vitamin D, and an oily solvent.

[0039] In one or more specific embodiments, the wall material comprises: 35 to 45 parts by weight of gelatin, 20 to 30 parts by weight of a plasticizer; 0.3 to 0.8 parts by weight of CGKRK peptide, and 20 to 40 parts by weight of water.

[0040] In one or more specific embodiments, the wall material comprises: 38 to 42 parts by weight of gelatin, 22 to 28 parts by weight of a plasticizer; 0.3 to 0.7 parts by weight of CGKRK peptide, and 30 to 40 parts by weight of water.

[0041] In one specific embodiment, the raw materials for the wall material are: 40 parts by weight of gelatin, 25 parts by weight of a plasticizer; 0.5 parts by weight of CGKRK peptide, and 30 to 40 parts by weight of water.

[0042] In one or more specific embodiments, the plasticizer comprises one or more of propylene glycol, glycerin, hexylene glycol, sorbitol, maltol, etc., preferably a combination of glycerin and sorbitol, provided that the mass ratio of glycerin to sorbitol is 2 to 6:1, preferably 3 to 5:1, e.g., 4:1. The combination of glycerin and sorbitol can further reduce the oxygen permeability of the gelatin wall material and reduce the degree of aging of the wall material.

[0043] In one or more specific embodiments, the raw material for the wall of the vitamin AD soft capsule further comprises 0.5 to 5 parts by weight, preferably 0.5 to 1 part by weight, and more preferably 2 parts by weight, of polyethylene glycol 1000 vitamin E succinate (TPGS1000, CAS number: 9002-96-4). Research conducted by the present invention has revealed that adding TPGS1000 to a CGKRK peptide system can improve the anti-aging properties of the wall and shorten the disintegration time.

[0044] In one or more specific embodiments, in the capsule content liquid, vitamin A is one or more selected from vitamin A1, vitamin A2, vitamin A palmitate, and vitamin A acetate, preferably vitamin A acetate, and vitamin D is vitamin D2 and / or vitamin D3.

[0045] In one or more specific embodiments, the active ingredients in the capsule liquid contain only vitamin A and vitamin D. In some embodiments, the capsule liquid contains the complex vitamin AD2 or AD3, The IU ratio of vitamin A to vitamin D may be 2 to 10:1, for example, 3:1 or 10:1.

[0046] In one or more specific embodiments, in the capsule content liquid, the oily solvent includes animal oil and vegetable oil, where the animal oil includes, but is not limited to, lard, mutton tallow, beef tallow, cod liver oil, etc., and the vegetable oil includes, but is not limited to, peanut oil, olive oil, soybean oil, castor oil, sunflower oil, etc. Preferably, the oily solvent is soybean oil.

[0047] In one or more specific embodiments, the content of vitamin A in the capsule content liquid is 1000 to 2000 IU per 0.1 to 0.5 g of the capsule content liquid. In some embodiments, the capsule content liquid (0.3 g) per tablet may contain 1500 IU of vitamin A and 500 IU of vitamin D.

[0048] In one or more specific embodiments of the present invention, Step S1: mixing and dissolving the remaining ingredients of the wall material, other than gelatin and CGKRK peptide, under heating to obtain a mixture; After gelatin is swelled in water, it is added to the mixture obtained in step S1, and then CGKRK peptide is added thereto, and the heating temperature of step S1 is maintained, and the mixture is uniformly mixed and melted to produce a gelatin solution, and after removing air bubbles in the gelatin solution, the gelatin solution is poured out, filtered, and used and reserved in step S2; Step S3: forming the gelatin solution obtained in step S2 into gelatin strips; Step S4: dissolving vitamins A and D in an oily solvent to prepare a capsule content liquid; and step S5 of encapsulating an effective amount of capsule content liquid together with the gelatin strip obtained in step S3 to obtain the vitamin AD soft capsule.

[0049] Apparently, in the present invention, there is no priority between steps S1 to S3 and step S4, and therefore the manufacturing method may be performed in the order of S1 to S5, or in the order of S4, S1 to S3, and S5, or step S4 may be performed simultaneously with steps S1 to S3, and then step S5 may be performed.

[0050] In one or more specific embodiments, in step S1, the heating temperature is 60 to 80°C, for example, 70°C; In one or more specific embodiments, in step S2, the filtration is carried out under conditions of 80 to 120 mesh, preferably 100 mesh.

[0051] In one or more specific embodiments, in step S2, the standing time must be 2 hours or more.

[0052] In step S5, the "effective amount" refers to the amount of active compounds (vitamins A and D), including the compounds of the present invention, that can induce the biological or medical response in a tissue system, animal, or human that is desired by a researcher, veterinarian, physician, or other medical professional, including the alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated. In the present invention, the compounds are particularly used for the prevention and / or treatment of vitamin A and D deficiency disorders, such as rickets and tetany accompanied by night blindness.

[0053] During the encapsulation process, the temperature of the capsule content liquid is controlled at 20-30°C, for example 25°C.

[0054] The present invention will be further described below with reference to examples. The present invention will be further described below with reference to examples, but the scope of the described examples is not intended to limit the scope of the present invention. Any modifications made to the present invention by those skilled in the art based on the examples of the present invention without creative effort are also within the scope of the present invention. Furthermore, in the examples of the present invention, all manufacturing materials are commercially available products well known to those skilled in the art, unless otherwise specified. Example

[0055] In Examples 1 to 11, vitamin AD soft capsules were produced with 0.3 g of fill per tablet and 0.2 g of wall material composition per tablet. The formulation of the wall material composition is shown in Table 1.

[0056] The specific steps for producing vitamin AD soft capsules are as follows: (1) Raw material blending: Each raw material and auxiliary material was accurately weighed according to the blending ratio, and semi-finished product inspection was carried out. (2) Mixing: The remaining ingredients of the formulation other than gelatin and the CGKRK peptide or amino acid were placed in a melting tank, heated to 70°C to melt, and mixed uniformly. (3) Dissolution: The formulated amount of gelatin was taken and an appropriate amount of water was added to it so that the gelatin absorbed the water and swelled. (4) Preparation of gelatin solution: Swollen gelatin was placed in a melting tank, and then CGKRK peptide (purchased from Shanghai Chu▲Thai Biotechnology Co., Ltd.) or amino acids (various amino acids were purchased from Shanghai Aladdin Co., Ltd.) were added in the appropriate amounts, and the mixture was stirred uniformly to melt. The temperature inside the tank was maintained at approximately 70°C, and then vacuum suction was applied until the gelatin solution was free of air bubbles. The gelatin solution was then poured out and filtered through a 100-mesh filter, and the filtrate was left to stand for at least 2 hours while still warm, and then set aside. (5) Preparation of gelatin strips: The molten gelatin liquid was cast onto a cooling drum using an automatic rotary capsule press (RGY6-20 soft capsule machine, Beijing Changzheng Tianmin High-Tech Co., Ltd.) to produce two frozen gelatin strips approximately 5 to 6 inches wide. (6) Preparation of the medicinal solution: Vitamin A acetate and vitamin D3 were dissolved in soybean oil, stirred evenly, and then set aside as the contents. The contents of vitamin A acetate and vitamin D3 were 1500 IU / 0.3g and 500 IU / 0.3g, respectively. (7) Encapsulation: The frozen gelatin strip was passed through rollers to form an appropriate strip configuration, and then the Vitamin AD capsule contents were placed in an automatic rotary capsule press, where the temperature of the capsule contents was controlled at approximately 25°C for encapsulation. (8) Setting, rinsing, and drying: After molding and setting the soft capsules, they were washed with 95% ethanol. After centrifugation drying to evaporate the ethanol, they were placed in the dryer of an automatic rotary capsule press and dried for 3 to 5 hours. (9) Capsule selection: Dried soft capsules were selected, and vitamin AD soft capsules that met the appearance requirements were selected.

[0057] [Table 1]

[0058] Content measurement The qualified vitamin AD soft capsules manufactured in each example were measured in accordance with the method for measuring vitamin AD soft capsule content in the Pharmacopoeia of the People's Republic of China (2020 edition).

[0059] Dissolution measurement A disintegration time test was conducted on the qualified vitamin AD soft capsules manufactured in each example. Specifically, the second method (paddle method) of the dissolution measurement method in the "Pharmacopoeia of the People's Republic of China (2020 edition)" was adopted. Vitamin AD soft capsules were sampled and measured at a speed of 50 rpm using 900 mL of purified water as the dissolution medium.

[0060] Accelerated Testing The vitamin AD soft capsules produced in each example were packaged in a polyester / aluminum / polyethylene composite pharmaceutical film and subjected to accelerated testing at 40°C and 75% relative humidity. Samples were collected after 3 or 6 months to measure the content and determine disintegration time. Since the degree of aging of the soft capsule wall material is positively correlated with disintegration time, the degree of aging was evaluated using the disintegration time of the soft capsule as an evaluation index.

[0061] The test results are shown in Tables 2 and 3.

[0062] [Table 2]

[0063] [Table 3]

[0064] Results analysis When comparing Vitamin AD soft capsules (Example 11) manufactured without adding any antioxidants with Vitamin AD soft capsules (Examples 2 to 10) manufactured with the addition of various amino acids (cysteine, glycine, lysine, and arginine) and CGKRK peptides, which have been reported to be effective, as antioxidants, the results of the disintegration time and content of the soft capsules obtained in the accelerated test were very different. The disintegration time of vitamin AD soft capsules manufactured without adding any antioxidants increased from 5.6 min to 32.6 min in a 3-month accelerated test, and further increased to 39.5 min in a 6-month accelerated test. This indicates that the soft capsule wall had deteriorated significantly, and the vitamin A and D content in the soft capsules had also decreased significantly.

[0065] In Examples 7 to 10, vitamin AD soft capsules prepared by adding 2 wt% of cysteine, glycine, lysine, or arginine to the wall material showed shorter disintegration times, although to different degrees, compared to soft capsules containing no antioxidants, in 3-month and 6-month disintegration time experiments. This indicates that these amino acids play a role in preventing the wall material from aging. The vitamin A and D contents in the soft capsules also increased.

[0066] In Examples 2 to 4, the disintegration time of the corresponding vitamin AD soft capsules prepared by adding 0.3 to 0.8 wt% CGKRK peptide was approximately 6 min at 0 months, increased to 7.9 to 9.2 min after 3 months of accelerated disintegration, and further increased to 8.8 to 11.3 min after 6 months. This indicates a more pronounced anti-aging effect compared to soft capsules containing no antioxidants but added amino acids. Furthermore, the amount of CGKRK peptide added, which has a significant anti-aging effect, was significantly lower than the amount of amino acids added. This further demonstrates that CGKRK peptide has an unexpected effect on the anti-aging of gelatin-based wall materials. This is because CGKRK peptides simultaneously contain active groups such as free thiol, amino, and guanidino, providing more complex antioxidant or anti-crosslinking pathways, which gives them a stronger ability to competitively capture reactive oxygen species within the wall material system or to competitively bind with external aldehyde molecules, thereby avoiding damage to the gelatin matrix structure in the wall material and exhibiting better anti-aging effects than single amino acids.

[0067] Furthermore, the effect of the amount of CGKRK peptide added on the wall material was investigated. A comparison of Examples 2 to 4 revealed that after 6 months of accelerated testing, the disintegration time of soft capsules containing 0.5 wt% CGKRK peptide was extended by 46.7% compared to 0 months, the disintegration time of soft capsules containing 0.3 wt% CGKRK peptide was extended by 65.1% compared to 0 months, and the disintegration time of soft capsules containing 0.8 wt% CGKRK peptide was extended by 71.2% compared to 0 months. This indicates, to some extent, that the anti-aging effect of the wall material due to the addition of CGKRK peptide initially improves and then declines with increasing addition amount. The inventors further increased the amount of CGKRK peptide used to 2 wt% and 4 wt% (Examples 5 and 6). They found that the addition of relatively large amounts of CGKRK peptide caused rapid deterioration of the wall material, resulting in a longer disintegration time in the accelerated testing than soft capsules containing no antioxidants. This is thought to be because, under the high temperature and humidity conditions of the accelerated test, lysine, arginine, and cysteine ​​residues in the excess CGKRK peptide cross-linked with the gelatin groups, accelerating the aging of the gelatin in the wall material.

[0068] The inventors of the present invention found that when 2 wt% of TPGS-PEG1000 was added to a system containing 0.5 wt% CGKRK peptide, the addition of TPGS-PEG1000 slightly shortened the disintegration time at 0, 3, and 6 months. This is thought to be related to the synergistic effect of the PEG chains and vitamin E contained in TPGS-PEG1000 with the CGKRK peptide, enhancing the anti-aging effect of the wall material.

[0069] It should be noted that the above examples are for illustrating the technical solutions of the present invention, but are not intended to limit the same. Although the present invention has been described in detail with reference to the examples shown, those skilled in the art can make modifications or equivalent substitutions to the technical solutions of the present invention as needed without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. Use of CGKRK peptide as an anti-aging agent in the manufacture of vitamin AD soft capsules.

2. The raw material of the wall material of the vitamin AD soft capsule contains gelatin, The use according to claim 1, further characterized in that the mass fraction of the CGKRK peptide in the vitamin AD soft capsule is 5 wt% or less, preferably 1 wt% or less, more preferably 0.3-0.8 wt%.

3. The capsules contain a wall material and a capsule content liquid, and the mass ratio of the wall material raw material to the capsule content liquid is 1:1 to 3, preferably 1:1 to 2, in parts by weight; The vitamin AD soft capsule is characterized in that the raw materials of the wall material include gelatin, a plasticizer, a CGKRK peptide, and water, and the capsule content liquid includes vitamin A, vitamin D, and an oily solvent.

4. The raw materials for the wall material are: 35 to 45 parts by weight of gelatin; 20 to 30 parts by weight of plasticizer 0.3 to 0.8 parts by weight of CGKRK peptide; 4. The vitamin AD soft capsule according to claim 3, further comprising 20 to 40 parts by weight of water.

5. The raw materials for the wall material are: 38 to 42 parts by weight of gelatin; 22 to 28 parts by weight of a plasticizer; 0.3 to 0.7 parts by weight of CGKRK peptide; 4. The vitamin AD soft capsule according to claim 3, further comprising 30 to 40 parts by weight of water.

6. the plasticizer comprises one or more of propylene glycol, glycerin, hexylene glycol, sorbitol, and maltol, and is preferably a combination of glycerin and sorbitol, with the glycerin to sorbitol mass ratio being 2 to 6:1, preferably 3 to 5:1; Furthermore, the raw material of the wall material of the vitamin AD soft capsule further contains 0.5 to 5 parts by weight, preferably 0.5 to 1 part by weight, of polyethylene glycol 1000 vitamin E succinate. Vitamin AD soft capsule according to any one of claims 3 to 5.

7. In the capsule content liquid, vitamin A is one or more selected from vitamin A1, vitamin A2, vitamin A palmitate, and vitamin A acetate, and is preferably vitamin A acetate, and vitamin D is vitamin D2 and / or vitamin D3, Furthermore, the active ingredients in the capsule content liquid contain only vitamin A and vitamin D, and the capsule content liquid also contains complex vitamin AD2 or AD3, The IU ratio of vitamin A to vitamin D is 2-10:1, In the capsule content liquid, the oily solvent includes animal oil and vegetable oil, the animal oil includes lard, mutton tallow, beef tallow, and cod liver oil, and the vegetable oil includes peanut oil, olive oil, soybean oil, castor oil, and sunflower oil, and preferably the oily solvent is soybean oil; The vitamin AD soft capsule according to claim 3, wherein the content of vitamin A in the capsule content liquid is 1000 to 2000 IU per 0.1 to 0.5 g of the capsule content liquid.

8. Step S1: mixing and dissolving the remaining ingredients of the wall material, other than gelatin and CGKRK peptide, under heating to obtain a mixture; After gelatin is swelled in water, it is added to the mixture obtained in step S1, then CGKRK peptide is added thereto, and the heating temperature of step S1 is maintained, and the mixture is uniformly mixed and melted to produce a gelatin solution, and after removing air bubbles in the gelatin solution, the gelatin solution is poured out, filtered, and used and reserved in step S2; Step S3: forming the gelatin solution obtained in step S2 into gelatin strips; Step S4: dissolving vitamins A and D in an oily solvent to prepare a capsule content liquid; The method for producing vitamin AD soft capsules according to any one of claims 3 to 7, further comprising: a step S5 of encapsulating an effective amount of capsule content liquid together with the gelatin strip obtained in step S3 to obtain the vitamin AD soft capsules.

9. The method according to claim 8, wherein there is no priority between steps S1 to S3 and step S4, and therefore the manufacturing method is performed in the order of S1 to S5, or in the order of S4, S1 to S3, and S5, or step S4 is performed simultaneously with steps S1 to S3, and then step S5 is performed.

10. In step S1, the heating temperature is 60 to 80°C, In step S2, the filtration is performed using a mesh size of 80 to 120, and the standing time is 2 hours or more.

9. The method of claim 8, wherein in step S5, the temperature of the capsule content liquid is controlled to 20-30°C during the encapsulation process.

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