CN113576944B

CN113576944B - Freeze-dried ball, preparation method thereof and skin care product

Info

Publication number: CN113576944B
Application number: CN202110906352.3A
Authority: CN
Inventors: 莫美玲
Original assignee: Zhongshan Zhongyan Cosmetic Co ltd
Current assignee: Zhongshan Zhongyan Cosmetic Co ltd
Priority date: 2021-08-09
Filing date: 2021-08-09
Publication date: 2023-07-07
Anticipated expiration: 2041-08-09
Also published as: CN113576944A

Abstract

The invention relates to the technical field of skin care products, in particular to a freeze-dried ball, a preparation method thereof and a skin care product. The freeze-dried ball comprises the following components in percentage by mass: 2-10% of small molecular excipient, 0.1-1% of high molecular excipient, 0.01-5% of physiologically acceptable skin care active ingredient, pH regulator and water; the pH regulator is at least one of ascorbic acid, ascorbyl glucoside, lactobionic acid and mandelic acid, and maintains the pH value of the freeze-dried stock solution to be less than 3. The freeze-dried balls can avoid microbial contamination. The invention also provides a preparation method of the freeze-dried ball and a skin care product comprising the freeze-dried ball.

Description

Freeze-dried ball, preparation method thereof and skin care product

Technical Field

The invention relates to the technical field of skin care products, in particular to a freeze-dried ball, a preparation method thereof and a skin care product.

Background

In the field of skin care products, consumers have a high prospect on the appearance of freeze-dried products. The common penicillin bottle package can not meet the pursuit of consumers for beautiful appearance. Therefore, a package of a freeze-dried product using a blister as a substitute for a penicillin bottle has been widely used, however, the freeze-dried product manufactured using the blister is usually achieved by ex-situ freeze-drying, i.e. freeze-drying with a mold first and then transferring the blister. However, since no preservative is added to the formulation of the lyophilized product, the raw solution prior to lyophilization must be sterilized (typically by filtration) in order to prevent contamination of the product by microorganisms. At the same time, the freeze-dried production plant needs to maintain a sterile environment. Even so, there is still a high risk of microbial contamination of the lyophilized product, especially ex situ lyophilized products, because of the need for filling or transfer.

Disclosure of Invention

Based on the above, the invention provides a freeze-dried ball without microbial contamination, a preparation method thereof and a skin care product.

In one aspect of the invention, a freeze-dried ball is provided, which comprises the following components in percentage by mass:

2-10% of small molecular excipient, 0.1-1% of high molecular excipient, 0.01-5% of physiologically acceptable skin care active ingredient, pH regulator and water;

the pH regulator is at least one of ascorbic acid, ascorbyl glucoside, lactobionic acid and mandelic acid, and the pH value of the freeze-dried stock solution is maintained to be less than 3.

Optionally, the lyophilized pellet as described above, wherein the small molecule excipient is at least one of mannitol, sorbitol, sucrose, and trehalose;

the polymer excipient is at least one of pullulan, dextran, chitosan, sodium hyaluronate, polyvinylpyrrolidone, polyethylene glycol and hydroxypropyl methylcellulose.

Optionally, the lyophilized pellet as described above wherein the physiologically acceptable skin care active ingredient is at least one of niacinamide, carnosine, tranexamic acid, glutathione, tea polyphenols, and tannins.

In one aspect of the present invention, there is also provided a method for preparing the above-mentioned lyophilized pellet, comprising the steps of:

dissolving the small molecular excipient, the high molecular excipient, the physiologically acceptable skin care active ingredient and the pH regulator in water, injecting the obtained solution into a mold for freeze shaping, demolding and freeze-drying.

Optionally, according to the preparation method of the freeze-dried balls, the solution is subjected to filtration sterilization, and the pore diameter of a filter element used for filtration sterilization is 0.2-0.5 μm.

Optionally, according to the preparation method of the freeze-dried balls, the temperature of the solution injected into the mold for freeze-shaping is-20 ℃ to-30 ℃.

Optionally, according to the preparation method of the freeze-dried balls, the freeze-drying temperature is between-25 ℃ and 30 ℃ and the time is between 15h and 25h.

Optionally, the preparation method of the freeze-dried balls further comprises the step of packaging the freeze-dried product in a non-oxidizing atmosphere with a humidity of less than 10% at 35-45 ℃.

In still another aspect of the present invention, there is further provided a skin care product comprising the above-described lyophilized pellet.

Optionally, the skin care product as described above is a liquid skin care product or a solid skin care product, wherein the liquid skin care product comprises at least one of an emulsion, a water agent, an oil agent and a spray, and the solid skin care product comprises at least one of a cream, a film agent and a gel agent.

According to the invention, the micromolecular excipient and the macromolecule excipient are used cooperatively, so that the macromolecule excipient has better redissolution property on the basis of ensuring the molding. The pH regulator is further combined, so that the growth of microorganisms can be inhibited on the basis of not affecting the basic efficacy of the freeze-dried balls, and the risk of pollution of the freeze-dried balls in the ex-situ preparation process is effectively reduced.

Detailed Description

Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.

Accordingly, it is intended that the present invention cover such modifications and variations as fall within the scope of the appended claims and their equivalents. Other objects, features and aspects of the present invention will be disclosed in or be apparent from the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not intended as limiting the broader aspects of the present invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

Except where shown or otherwise indicated in the operating examples, all numbers expressing quantities of ingredients, physical and chemical properties, and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about". For example, therefore, unless indicated to the contrary, the numerical parameters set forth in the foregoing specification and attached claims are approximations that can be varied appropriately by those skilled in the art utilizing the teachings disclosed herein seeking to obtain the desired properties. The use of numerical ranges by endpoints includes all numbers subsumed within that range and any range within that range, e.g., 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, 5, and the like.

the pH regulator is at least one of ascorbic acid, ascorbyl glucoside, lactobionic acid and mandelic acid, and maintains the pH value of the freeze-dried stock solution to be less than 3.

The micromolecular excipient and the macromolecule excipient are used cooperatively, so that the macromolecule excipient has better redissolution property on the basis of ensuring the molding. The pH regulator is further combined, so that the growth of microorganisms can be inhibited on the basis of not affecting the basic efficacy of the freeze-dried balls, and the risk of pollution of the freeze-dried balls in the ex-situ preparation process is effectively reduced. The pH regulator selected by the invention also has the whitening effect, and the forming of the freeze-dried balls is not affected.

In some embodiments, the mass percent of the small molecule excipient may also be 3%, 4%, 5%, 6%, 7%, 8%, 9%; the mass percentage of the macromolecular excipient can also be 0.2%, 0.3%, 0.5%, 0.6%, 0.8% and 0.9%.

In some embodiments, the molecular weight of the small molecule excipient is 150Da to 600Da and the molecular weight of the high molecule excipient is 100kDa to 5000kDa.

In some embodiments, the small molecule excipient is at least one of mannitol, sorbitol, sucrose, and trehalose. Preferably, the small molecule excipients are mannitol and trehalose.

In some embodiments, the polymeric excipient is at least one of pullulan, dextran, chitosan, sodium hyaluronate, polyvinylpyrrolidone, polyethylene glycol, and hydroxypropyl methylcellulose. Preferably, the polymeric excipient is pullulan or dextran.

In some embodiments, the total mass percent of the pH adjuster is 2% to 4%.

In some embodiments, the pH of the lyophilization stock solution is maintained at a value of 2 to 3.

In some embodiments, the physiologically acceptable skin care active is not limited and any one commonly used in the art may be selected, for example, a physiologically acceptable skin care active having whitening and freckle removing effects, a physiologically acceptable skin care active having moisturizing and moisturizing effects, a physiologically acceptable skin care active having oil control effects, a physiologically acceptable skin care active having wrinkle removing and anti-aging effects, a physiologically acceptable skin care active having sun protection effects, or two or more selected from those effects. It should be noted that, since the pH of the freeze-dried balls is required to be less than 3 in the present invention, the physiologically acceptable skin care active ingredient selected should be stably present at the pH, and may be one or more of nicotinamide, carnosine, tranexamic acid, glutathione, tea polyphenols and tannic acid.

The glutathione contains gamma-amide bond and sulfhydryl tripeptide, which is formed by combining glutamic acid, cysteine and glycine, has the whitening effect, can inhibit melanin generation to a certain extent, and also has the functions of delaying aging and integrating detoxification. The nicotinamide is also called niacinamide, is an amide compound of nicotinic acid, and has the main effects on the anti-aging aspect of skin, namely, can reduce and prevent dark complexion, yellowing and vegetable color of skin generated in the early aging process, can repair damaged skin cuticle lipid barrier and improve skin resistance; in addition, the water-retaining agent also has the effects of deep water-retaining and moisture-retaining. The tranexamic acid is also called tranexamic acid and tranexamic acid, can block melanin transmission and accelerate metabolism, and has a black spot removing effect which is approximately 50 times higher than that of vitamin C and approximately 10 times higher than that of fruit acid. The tannic acid is also called tannic acid, and has effects of controlling oil, preventing sunburn, brightening skin and tightening skin. The tea polyphenol is also called antioxidant, vitamin polyphenol and anti-hart, is a compound of polyhydroxy phenol compounds in tea, and consists of more than 30 phenol substances, and the main components are as follows: the flavonoid, the anthocyanidin, the flavonols, the anthocyanidins, the phenolic acid and the depsipelas 6 compounds, wherein the flavonoid is the most important, the content of the flavonoid can reach 60-80 percent, and the flavonoid has various physiological activities of oxidation resistance, radiation resistance, aging resistance and the like.

dissolving small molecular excipient, high molecular excipient, physiologically acceptable skin care active ingredient and pH regulator in water, filtering the obtained solution with filter element, freeze shaping in mold, demolding, and lyophilizing.

The method comprises the following specific steps:

s1: placing the polymer excipient in water and heating to 70-90 ℃, and preserving heat until the polymer excipient is dissolved;

s2: cooling to 25-35 ℃, adding small molecular excipient and physiologically acceptable skin care active ingredient, dissolving, and adding pH regulator;

s3: filtering the solution, sterilizing, injecting into a mold, freezing and shaping, demolding, and freeze-drying.

In some embodiments, the filter cartridge used in the filter sterilization has a pore size of 0.2 μm to 0.5 μm. Preferably, the filter element has a pore size of 0.22. Mu.m.

In some embodiments, the material of the mold is not limited, and materials commonly used in the art may be selected, and a silica gel mold is preferred for convenience in demolding and uniform heat transfer.

In some embodiments, the freezing temperature of the mold after the injection of the liquid is between-20 ℃ and-30 ℃ for a period of between 0.5h and 1.5h.

In some embodiments, the lyophilization temperature is from-25 ℃ to 30 ℃ for a period of from 15 hours to 25 hours.

In some embodiments, the method of preparation further comprises the step of packaging the lyophilized product at a temperature of 35 ℃ to 45 ℃ in a non-oxidizing atmosphere having a humidity of less than 10%.

In some embodiments, the non-oxidizing atmosphere may be a nitrogen atmosphere, an argon atmosphere, or a helium atmosphere.

In some embodiments, the skin care product is a liquid skin care product or a solid skin care product, the liquid skin care product comprises at least one of an emulsion, a water agent, an oil agent and a spray, and the solid skin care product comprises at least one of a cream, a film agent and a gel agent.

In some embodiments, the skin care product comprises a lotion, a cream, a lotion, a pack.

Example 1

The pullulan and the dextran with the mass percent of 0.5 percent respectively are weighed, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 5 percent, trehalose with the mass percent of 5 percent, ascorbic acid with the mass percent of 2 percent, ascorbyl glucoside with the mass percent of 2 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Example 2

The pullulan with the mass percent of 0.5 percent is weighed and put into water and heated to 80 ℃ until the pullulan is completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 5%, ascorbic acid with the mass percent of 2% and glutathione with the mass percent of 0.1%, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Example 3

Dextran with mass percent of 0.5% is weighed and placed in water and heated to 80 ℃ until the dextran is completely dissolved. Then cooling to 30 ℃, adding 5% of trehalose, 2% of ascorbyl glucoside and 0.1% of glutathione by mass percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Example 4

The pullulan and the dextran with the mass percent of 0.1 percent and 0.4 percent are weighed and placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 4 percent, trehalose with the mass percent of 1 percent, ascorbyl glucoside with the mass percent of 2 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Example 5

The pullulan and the dextran with the mass percent of 0.25 percent respectively are weighed, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 2.5%, trehalose with the mass percent of 2.5%, ascorbic acid with the mass percent of 1%, ascorbyl glucoside with the mass percent of 1% and glutathione with the mass percent of 0.1%, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Example 6

The pullulan and the dextran with the mass percent of 0.4% and 0.1% are weighed respectively, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 4 percent, trehalose with the mass percent of 1 percent, ascorbic acid with the mass percent of 2 percent, ascorbyl glucoside with the mass percent of 1 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 1

This comparative example was prepared in substantially the same manner as in example 1 except that: no pH adjuster was added. The method comprises the following specific steps:

the pullulan and the dextran with the mass percent of 0.5 percent respectively are weighed, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 5 percent, trehalose with the mass percent of 5 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 2

This comparative example was prepared in substantially the same manner as in example 2, except that: no pH adjuster was added. The method comprises the following specific steps:

the pullulan with the mass percent of 0.5 percent is weighed and put into water and heated to 80 ℃ until the pullulan is completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 5% and glutathione with the mass percent of 0.1%, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 3

This comparative example was prepared in substantially the same manner as in example 3, except that: no pH adjuster was added. The method comprises the following specific steps:

dextran with mass percent of 0.5% is weighed and placed in water and heated to 80 ℃ until the dextran is completely dissolved. Then cooling to 30 ℃, adding 5% of trehalose and 0.1% of glutathione by mass percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 4

This comparative example was prepared in substantially the same manner as in example 4, except that: no pH adjuster was added. The method comprises the following specific steps:

the pullulan and the dextran with the mass percent of 0.1 percent and 0.4 percent are weighed and placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 4 percent, trehalose with the mass percent of 1 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 5

This comparative example was prepared in substantially the same manner as in example 5 except that: no pH adjuster was added. The method comprises the following specific steps:

the pullulan and the dextran with the mass percent of 0.25 percent respectively are weighed, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 2.5%, trehalose with the mass percent of 2.5% and glutathione with the mass percent of 0.1%, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 6

This comparative example was prepared in substantially the same manner as in example 6, except that: no pH adjuster was added. The method comprises the following specific steps:

the pullulan and the dextran with the mass percent of 0.4% and 0.1% are weighed respectively, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 4 percent, trehalose with the mass percent of 1 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball is then placed in a freeze dryer, and sequentially raising the temperature from-25 ℃ to 30 ℃ and freeze-drying for 20 hours. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 7

This comparative example was prepared in substantially the same manner as in example 1 except that: the total mass percentages of pullulan and dextran are different. The method comprises the following specific steps:

the pullulan and the dextran with the mass percentage of 1 percent respectively are weighed, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 5 percent, trehalose with the mass percent of 5 percent, ascorbic acid with the mass percent of 2 percent, ascorbyl glucoside with the mass percent of 2 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 8

This comparative example was prepared in substantially the same manner as in example 1 except that: the total mass percentages of mannitol and trehalose are different. The method comprises the following specific steps:

the pullulan and the dextran with the mass percent of 0.5 percent respectively are weighed, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 0.5%, trehalose with the mass percent of 0.5%, ascorbic acid with the mass percent of 2%, ascorbyl glucoside with the mass percent of 2% and glutathione with the mass percent of 0.1%, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

Comparative example 9

This comparative example was prepared in substantially the same manner as in example 1 except that: the pH regulator is acetic acid and lactic acid. The method comprises the following specific steps:

the pullulan and the dextran with the mass percent of 0.5 percent respectively are weighed, placed in water and heated to 80 ℃ until the pullulan and the dextran are completely dissolved. Then cooling to 30 ℃, adding mannitol with the mass percent of 5 percent, trehalose with the mass percent of 5 percent, lactic acid with the mass percent of 2 percent, acetic acid with the mass percent of 2 percent and glutathione with the mass percent of 0.1 percent, and stirring until the mixture is completely dissolved. Then the solution is filtered and sterilized by a filter element with the diameter of 0.22 mu m and then is injected into a spherical silica gel mold (the silica gel mold injected with the liquid is frozen for 1 hour in a flat plate prefreezing device with the temperature of minus 25 ℃), and the ice ball is obtained after demoulding. The ice ball was then placed in a lyophilizer and freeze-dried for 20h at a temperature ranging from-25 ℃ to 30 ℃ in sequence. Packaging the lyophilized product in nitrogen atmosphere with humidity less than 10% at 40deg.C.

The freeze-dried spheres prepared in each example and comparative example were subjected to the relevant performance test as follows:

the molding property of the sphere is characterized by the shrinkage rate gamma of the diameter of the sphere, and the calculation method comprises the following steps: γ=1-a/b. Wherein a is the diameter of the freeze-dried ball after freeze-drying, and b is the diameter of the ice ball before freeze-drying. From the definition of the shrinkage rate gamma, the smaller the shrinkage rate is, the better the gamma freeze-drying forming property is.

The re-solubility of the spheres is characterized by the collapse time of the spheres after addition to water. The specific implementation method comprises the following steps: a single lyophilized pellet was added to deionized water and the time from when the pellet of the lyophilized pellet contacted the water surface until the pellet completely collapsed was calculated.

And (3) microorganism detection: according to the preparation method in each example and comparative example, 10 pieces of each freeze-dried pellet were dissolved in 10g of water, respectively, and left in the atmosphere of the same environment for 24 hours, and were subjected to microorganism detection.

The test results are shown in table 1:

table 1 freeze-dried pellet performance test results

	Microorganism detection result (cfu/mL)	Shrinkage gamma	Resolubility(s)
				Example 1	0	0.05	2.3
Example 2	0	0.07	2.1
				Example 3	0	0.08	2.9
Example 4	0	0.06	3.2
				Example 5	0	0.10	3.5
Example 6	0	0.08	3.2
				Comparative example 1	＞500	0.02	2.7
Comparative example 2	240	0.07	2.3
				Comparative example 3	136	0.06	2.7
Comparative example 4	＞500	0.06	3.4
				Comparative example 5	150	0.09	2.0
Comparative example 6	129	0.03	1.9
				Comparative example 7	0	0.02	93
Comparative example 8	0	0.55	>120
				Comparative example 9	0	0.74	>120

As is clear from Table 1, the freeze-dried pellets of examples 1 to 6 did not grow microorganisms in the open environment, and had a low risk of microorganisms, whereas the freeze-dried pellets of comparative examples 1 to 6 were contaminated with microorganisms to different degrees in the same environment. The results demonstrate that the addition of pH adjuster significantly reduces the risk of contamination of the lyophilized pellet by microorganisms. Meanwhile, the shrinkage of the freeze-dried pellets in examples 1 to 6 was small, indicating that the molding properties were good. The shorter collapse time also indicates that the freeze-dried spheres possess better re-solubility.

In contrast, comparative examples 7, 8 and 9 each used a different content of a polymer excipient, a small-molecule excipient and a different pH adjuster than in example 1. As can be seen from the experimental results, although the freeze-dried pellets of comparative examples 7, 8 and 9 also have lower microbial risk, excessive polymer excipient (comparative example 7) can significantly reduce the reconstitution speed; the use level of the small-molecule excipient is reduced (comparative example 8), and the re-solubility of the freeze-dried balls is obviously deteriorated while the forming performance of the freeze-dried balls is reduced; other pH adjustment is selected, and the forming and re-dissolving performance of the freeze-dried balls can be reduced.

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.

The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims

1. The freeze-dried ball is characterized by comprising the following components in percentage by mass:

the pH regulator is at least one of ascorbic acid and ascorbyl glucoside, and the pH value of the freeze-dried stock solution is maintained to be 2-3;

the small-molecule excipient is at least one of mannitol and trehalose, and the high-molecule excipient is at least one of pullulan and dextran;

the physiologically acceptable skin care active ingredient is at least one of nicotinamide, carnosine, tranexamic acid, glutathione, tea polyphenols and tannic acid.

2. A method of preparing the lyophilized pellet as defined in claim 1, comprising the steps of:

dissolving the small molecular excipient, the high molecular excipient, the physiologically acceptable skin care active ingredient and the pH regulator in water, injecting the obtained solution into a mold, freezing and shaping, demolding and freeze-drying.

3. The method for preparing freeze-dried balls according to claim 2, wherein the solution is sterilized by filtration, and the pore size of the filter element used for the filtration and sterilization is 0.2-0.5 μm.

4. The method for preparing freeze-dried pellets according to claim 2, wherein the temperature of freeze-setting after the solution is injected into the mold is-20 ℃ to-30 ℃.

5. The method for preparing freeze-dried balls according to claim 2, wherein the freeze-drying temperature is-25 ℃ to 30 ℃ and the time is 15h to 25h.

6. The method of any one of claims 2 to 5, further comprising the step of packaging the lyophilized product at 35 ℃ to 45 ℃ in a non-oxidizing atmosphere having a humidity of less than 10%.

7. A skin care product comprising the lyophilized pellet of claim 1.

8. The skin care product according to claim 7, wherein the skin care product is a liquid skin care product or

A solid skin care product, wherein the liquid skin care product comprises at least one of emulsion, water agent, oil agent and spray,

the solid skin care product comprises at least one of ointment, cream, film and gel.