阅读说明：本技术 一种活性油冻干制剂及其制备方法和应用 (Active oil freeze-dried preparation and preparation method and application thereof ) 是由 李和伟 于 2018-07-17 设计创作，主要内容包括：本发明涉及食品、药品及化妆品技术领域,公开了一种活性油冻干制剂及其制备方法和应用。本发明所述冻干制剂由包含活性油脂、选自2,6-二叔丁基对甲苯酚和特丁基对苯二酚中的一种或两种成分以及辅料的混合溶液冻干而成。本发明以2,6-二叔丁基对甲苯酚和/或特丁基对苯二酚作为与视黄醇等一类活性油脂冻干的稳定剂成分,能够极大程度地避免该类活性油脂的降解,增加冻干制剂的稳定性,消除了冻干工艺对该类活性油脂的降解影响,实现了活性油脂冻干制剂的大范围应用。(The invention relates to the technical field of foods, medicines and cosmetics, and discloses an active oil freeze-dried preparation as well as a preparation method and application thereof. The freeze-dried preparation is prepared by freeze-drying a mixed solution containing active oil, one or two components selected from 2, 6-di-tert-butyl-p-cresol and tert-butyl-hydroquinone and auxiliary materials. According to the invention, 2, 6-di-tert-butyl-p-cresol and/or tert-butyl-hydroquinone are/is used as the freeze-drying stabilizer component of the active oil such as retinol, so that the degradation of the active oil can be greatly avoided, the stability of the freeze-drying preparation is increased, the degradation influence of the freeze-drying process on the active oil is eliminated, and the large-scale application of the active oil freeze-drying preparation is realized.)

1. The active oil freeze-dried preparation is characterized by being prepared by freeze-drying a mixed solution containing active oil, one or two components selected from 2, 6-di-tert-butyl-p-cresol and tert-butyl-hydroquinone and auxiliary materials.

2. The lyophilized composition according to claim 1, wherein the 2, 6-di-tert-butyl-p-cresol constitutes 0.05 to 3% by mass of the mixed solution.

3. The lyophilized preparation according to claim 1, wherein the tert-butylhydroquinone is 0.05 to 1% by mass of the mixed solution.

4. The lyophilized preparation according to claim 1, wherein the active oil or fat is 0.01 to 50% by mass of the mixed solution.

5. The lyophilized preparation according to claim 1 or 4, wherein the active oil is one or more of retinol, retinoic acid, caprylic/capric glyceride, oily Ganoderma lucidum extract, tocopherol, and fat-soluble vitamin.

6. The lyophilized preparation according to claim 1, wherein the adjuvant is one or more of an adhesive, an emulsifier, a matrix support, a skin-feel modifier, an antioxidant, a flavoring agent, an essence, a transmucosal absorption enhancer, a transdermal absorption enhancer, and a pH adjuster.

7. The lyophilized formulation according to any one of claims 1 to 6, wherein the mixed solution further comprises one or more of dilauryl thiodipropionate, sodium ascorbate, and ascorbic acid.

8. The lyophilized formulation according to claim 7, wherein the dilauryl thiodipropionate is 0.05-5% by mass of the mixed solution.

9. The lyophilized formulation according to claim 7, wherein the sodium ascorbate or ascorbic acid is 0.01 to 3% by mass of the mixed solution.

10. Use of the lyophilized formulation of any one of claims 1-9 for the preparation of a food and/or chemical.

11. The method for preparing a lyophilized preparation according to claim 1, wherein the lyophilized composition is obtained by degassing, prefreezing, freeze-drying, and removing the solvent from a mixed solution comprising an active oil and one or two components selected from the group consisting of 2, 6-di-t-butyl-p-cresol and t-butylhydroquinone, and an auxiliary material.

Technical Field

The invention relates to the technical field of foods, medicines and cosmetics, in particular to an active oil freeze-dried preparation and a preparation method and application thereof.

Background

In foods, health-care foods, medicines and daily chemicals, active oil is a common active substance, and a plurality of active oils, such as retinol, caprylic/capric glyceride, oily ganoderma lucidum extract, retinoic acid, tocopherol, fat-soluble vitamin and the like, have strong physiological activity, but have poor stability, especially in a liquid preparation system. The active grease is easy to oxidize under the conditions of light, air, temperature and the like, so the active grease has the defects of very limited application range, high preparation process requirement, high cost and the like.

The freeze-drying excipient technology is a technology of adding a skeleton supporting agent and a binding agent into a flowable liquid, semisolid or solid active ingredient, or the flowable liquid, semisolid or solid contains the binding agent and the skeleton supporting agent, then pouring the flowable liquid, semisolid or solid into a forming mold, and forming the flowable liquid, semisolid or solid by a freeze-drying process, wherein a preparation prepared by the freeze-drying excipient technology is called a freeze-drying excipient.

The preparation adopts a freeze drying process, can protect part of unstable active ingredients from being damaged, and can generate a large number of micropores and pore passages through water sublimation, and has high disintegration and dissolution speed, so the preparation is widely applied and can be applied to a plurality of fields such as orally disintegrating tablets, quick-release tablets, chewable tablets, special cosmetics, medical appliances, health care products and the like.

However, unlike the generally unstable substances, the active oil substances undergo the freeze-drying process, and then the oxidation and decomposition speed of the active oil substances is increased due to a large number of micropores and pore channels, which becomes a great limiting factor for the freeze-drying process of the active oil substances.

Disclosure of Invention

In view of the above, the present invention aims to provide an active oil lyophilized preparation and a preparation method thereof, so that the lyophilized preparation can significantly reduce the degradation of active oil, maintain a high active ingredient content thereof, and have high stability.

In order to achieve the above purpose, the invention provides the following technical scheme:

a lyophilized preparation of active oil is prepared from active oil, one or two of 2, 6-di-tert-butyl-p-cresol and tert-butyl-hydroquinone, and adjuvant by lyophilizing. .

Aiming at the problem that the degradation of active ingredients is generally aggravated by the conventional freeze-dried preparation of active oil similar to retinol, caprylic/capric glyceride, oily ganoderma lucidum extract, retinoic acid, tocopherol, fat-soluble vitamin and the like, the invention selects 2, 6-di-tert-butyl-p-cresol and/or tert-butyl-hydroquinone as a stabilizer, and freeze-dries the stabilizer after combining with the active oil, thereby obviously reducing the degradation of the active oil and improving the content of the active oil.

Preferably, the 2, 6-di-tert-butyl-p-cresol accounts for 0.05 to 3 percent, more preferably 0.05 to 1 percent of the mixed solution in percentage by mass. In a specific embodiment of the present invention, the 2, 6-di-tert-butyl-p-cresol constitutes 0.05%, 0.06%, 0.1%, 0.2%, 1% or 3% of the mixed solution.

Preferably, the tert-butylhydroquinone accounts for 0.05 to 1% of the solution, more preferably 0.05 to 0.6% by mass. In particular embodiments of the invention, the tertbutyl hydroquinone comprises 0.05%, 0.06%, 0.12%, 0.24%, 0.6%, or 1% of the solution.

Preferably, the active oil and fat accounts for 0.01-50% of the mixed solution in percentage by mass. In a specific embodiment of the invention, the active oil and fat accounts for 0.01%, 0.2%, 0.4%, 0.5%, 1.72%, 5%, 8%, 10% or 50% of the mixed solution.

One or more than two of dilauryl thiodipropionate, sodium ascorbate and ascorbic acid can be continuously added on the basis of the components of the mixed solution;

preferably, the dilauryl thiodipropionate accounts for 0.05-5% of the mixed solution, and the sodium ascorbate or ascorbic acid accounts for 0.01-3% of the mixed solution in percentage by mass. In a specific embodiment of the invention, the dilauryl thiodipropionate accounts for 0.05%, 0.25% or 5% of the mixed solution, and the sodium ascorbate or ascorbic acid accounts for 0.01%, 0.1% or 3% of the mixed solution.

In a particular embodiment of the invention, the formulation according to the invention is selected in the form of a combination of one of the following:

active grease, 2, 6-di-tert-butyl-p-cresol and auxiliary materials;

active oil, tert-butyl hydroquinone and auxiliary materials;

active grease, 2, 6-di-tert-butyl p-cresol, tert-butyl hydroquinone and auxiliary materials;

active grease, 2, 6-di-tert-butyl-p-cresol, dilauryl thiodipropionate and auxiliary materials;

active grease, 2, 6-di-tert-butyl-p-cresol, sodium ascorbate and auxiliary materials;

active grease, 2, 6-di-tert-butyl-p-cresol, tert-butyl hydroquinone, dilauryl thiodipropionate and auxiliary materials;

active grease, 2, 6-di-tert-butyl p-cresol, tert-butyl hydroquinone, ascorbic acid and auxiliary materials;

more specifically, the formulation of the present invention is selected from one of the following:

0.2 percent of active grease, 0.1 percent of 2, 6-di-tert-butyl p-cresol and auxiliary materials;

0.4 percent of active grease, 0.06 percent of tert-butyl hydroquinone and auxiliary materials;

1.72 percent of active grease, 1 percent of 2, 6-di-tert-butyl-p-cresol, 0.6 percent of tert-butyl hydroquinone and auxiliary materials;

8 percent of active grease, 0.1 percent of 2, 6-di-tert-butyl-p-cresol, 0.25 percent of dilauryl thiodipropionate and auxiliary materials;

10% of active oil, 0.06% of 2, 6-di-tert-butyl-p-cresol, 0.1% of sodium ascorbate and auxiliary materials;

50% of active oil, 3% of 2, 6-di-tert-butyl-p-cresol and auxiliary materials;

5 percent of active grease, 0.2 percent of 2, 6-di-tert-butyl-p-cresol, 0.12 percent of tert-butyl hydroquinone, 0.05 percent of dilauryl thiodipropionate and auxiliary materials;

10 percent of active grease, 0.05 percent of 2, 6-di-tert-butyl-p-cresol, 1 percent of tert-butyl hydroquinone, 5 percent of dilauryl thiodipropionate and auxiliary materials;

0.01 percent of active grease, 0.05 percent of 2, 6-di-tert-butyl-p-cresol, 0.05 percent of tert-butyl hydroquinone, 0.01 percent of ascorbic acid and auxiliary materials;

0.5 percent of active grease, 0.1 percent of 2, 6-di-tert-butyl-p-cresol, 0.24 percent of tert-butyl hydroquinone, 3 percent of ascorbic acid and auxiliary materials;

the active oil is one or more than two of retinol, retinoic acid, caprylic/capric acid monoglyceride, caprylic/capric acid triglyceride, oily ganoderma lucidum extract, tocopherol and fat-soluble vitamin (such as beta-carotene).

The auxiliary materials are preferably one or more than two of adhesives, emulsifiers, skeleton supporting agents, skin feel modifiers, antioxidants, flavoring agents, essence, trans-mucosal absorption promoters, transdermal absorption promoters and pH regulators, and the types of the specific auxiliary materials can be selected according to the application field. In a specific embodiment of the present invention, the auxiliary materials are selected from the group consisting of emulsifiers, matrix support agents and binders.

Wherein the emulsifier is selected from one or more of anionic emulsifier, cationic emulsifier and nonionic emulsifier, and the mass percentage of the emulsifier in the mixed solution is determined by the addition amount of antioxidant and active matter; the binder is a freeze-dried binder or a combination of the freeze-dried binder and a low-temperature binder; the skeleton supporting agent is selected from one or more of sugar (such as maltose, trehalose, and the like), sugar alcohol (such as mannitol, sorbitol), amino acid with 2-12 carbon atoms (such as glycine, alanine, glutamic acid, and the like) and inorganic salt (such as sodium phosphate, aluminum silicate, and the like), and accounts for 1% -50% of the mixed solution by mass, preferably 3% -25%, and most preferably 5% -15%; the skin feeling modifier is selected from one or more of polymethyl silsesquioxane, tapioca starch, di-C12-13 alcohol malate, dimyristyl tartrate, PPG-15 stearyl alcohol ether, chinlon-12, and Vaccinium myrtillus seed oil; the antioxidant is selected from one or more than two of substances with antioxidant effect, such as vitamin C, vitamin E, anthocyanin, resveratrol, glutathione, superoxide dismutase, yeast/rice fermentation product filtrate, plant extract, beauveria bassiana extract, white truffle extract, fruit and vegetable extract, plant-derived polyphenol compounds and the like, and accounts for 0.05-3% of the mixed solution by mass, preferably 0.1-0.5% of the mixed solution by mass, and most preferably 0.1-0.3% of the mixed solution by mass; the flavoring agent and essence are respectively selected from one or more of herba Menthae flavor, chocolate flavor, fruit and vegetable flavor, flower and grass flavor, plant flavor, vanilla flavor, coffee flavor, tea flavor, corn flavor, lemon flavor, milk flavor, etc. or flavoring mixture; the trans-mucosal or transdermal absorption enhancer is one or more selected from lecithin, tween and span; the pH regulator is one or more selected from citric acid, sorbic acid, tartaric acid, lactic acid, malic acid, sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, calcium phosphate, potassium phosphate, and magnesium phosphate;

in the binder, the low-temperature binder is one or more than two of C1-C6 alcohol, grease, surfactant and high molecular polymer, and accounts for 1-20% of the mixed solution by mass, preferably 1-15% of the mixed solution by mass, and most preferably 4-10% of the mixed solution by mass; the freeze-drying binder is one or more than two of high molecular polymer, inorganic gel, cellulose ether, modified starch, hyaluronic acid, albumin, dextran, chitosan and products with different molecular weights, sodium alginate, PVP, PVA, polyethylene glycol, agar, polyamino acid, glycan and gelatin, and accounts for 1-20% of the mixed solution by mass, preferably 1-15% of the mixed solution by mass, and most preferably 4-10% of the mixed solution by mass.

The C1-C6 alcohol is selected from one or more of propylene glycol, butanediol, glycerol, 1, 2-butanediol, 1, 2-propanediol, 1, 3-butanediol, pentanediol, polyethylene glycol, polyglycerol, glycerol, diglycerol, etc.

The oil and fat is selected from one or more of polydimethylsiloxane, polyglycerol-6 octastearate, caprylic/capric triglyceride, glycerol tri (ethyl hexanoate), diisostearyl malate, polyglycerol-2 triisostearate, dipentaerythritol tri-hydroxystearate, phytosterol oleate, petrolatum, xanthan gum, glycerol tri (behenic acid/isostearic acid/eicosanedioic acid) ester, lecithin, hydrogenated polydecene, ethylhexyl methoxycinnamate, butter, mink oil, goose oil, shark liver oil, almond oil, olive oil, sesame oil, tea seed oil, ethylhexyl palmitate, shea butter, hexyl laurate, dioctyl carbonate, GTCC, propylheptyl caprylate, oleyl alcohol or triglyceride, etc.

The surfactant is one or more selected from Tween component, span component, PEG-20 glycerol triisostearate, polyglycerol-10 distearate, polyglycerol-2 oleate, potassium cocoyl glycinate, and potassium lauroyl glycinate.

The high molecular polymer is one or more than two of sodium alginate, lanolin, agar, polyvinyl alcohol methyl acrylate graft copolymer, carbomer resin, sodium hyaluronate, hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, modified paraffin, polyacrylamide, sodium polyacrylate, polyacrylic acid and derivatives thereof.

The inorganic gel is one or more of diatomite, bentonite, montmorillonite, hectorite and silica gel.

The cellulose ether binder is one or more of microcrystalline cellulose, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, etc.

The modified starch binder is selected from one or more of sodium polyacrylate grafted starch, pullulan, hydroxypropyl starch, hydroxypropyl methyl starch, pregelatinized starch, amylose, carboxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, etc.

The hyaluronic acid binder is one or more than two of sodium hyaluronate, hydrolyzed sodium hyaluronate, hyaluronic acid and hydrolyzed hyaluronic acid.

The polyamino acid is one or more than two of polyglutamic acid, polyalanine, polyaspartic acid, polylysine and the like.

The polysaccharide is selected from one or more of fucoidin, inulin, and dextran.

The glue binder is one or more of collagen, gelatin, hydrolyzed gelatin, arabic gum, xanthan gum, soybean protein gum, sclerotium rolfsii gum, biological sugar gum, carrageenan, guar gum, gellan gum, pectin, konjac gum, carrageenan, locust bean gum, locust bean gum, etc.

In the specific embodiment of the invention, a stability comparison test is carried out by taking retinol as an example, and the result shows that compared with the conventional stabilizer, the content of the lyophilized preparation of the invention is up to 60-90% after being placed for 72 hours after being lyophilized, while the content of the control lyophilized preparation adopting the conventional stabilizer is only 35-60%, and the difference between the two is up to 20-45%.

Meanwhile, in stability tests of other active grease such as caprylic/capric glyceride, beta-carotene, oily ganoderma lucidum extract, tocopherol and the like, compared with a freeze-dried preparation using conventional catechol, sodium pyrosulfate, sodium metabisulfite and ethylene diamine tetraacetic acid stabilizer, the freeze-dried preparation has higher stability, and the degradation loss of the active grease is greatly avoided;

based on the excellent technical effects, the invention provides the application of the freeze-dried composition in preparing foods and/or chemicals according to the applicable range of the freeze-dried preparation of the active oil. Wherein the food is preferably a health food, and the chemical is preferably a medicine and/or a daily chemical.

In addition, the invention also provides a preparation method of the freeze-dried preparation, which comprises the steps of degassing, pre-freezing, freeze-drying and removing a solvent of a solution containing active oil, one or two components selected from 2, 6-di-tert-butyl-p-cresol and tert-butyl-hydroquinone and auxiliary materials to obtain the freeze-dried preparation.

The preparation method of adding dilauryl thiodipropionate, sodium ascorbate, ascorbic acid and the like additionally is prepared by adding the components together on the basis of the preparation method and freeze-drying.

According to the technical scheme, 2, 6-di-tert-butyl-p-cresol and/or tert-butyl hydroquinone are/is used as the freeze-drying stabilizer component of the active oil such as retinol, so that the degradation of the active oil can be greatly avoided, the stability of a freeze-drying preparation is improved, the degradation influence of a freeze-drying process on the active oil is eliminated, and the large-scale application of the active oil freeze-drying preparation is realized.

Detailed Description

The invention discloses an active oil freeze-dried preparation, a preparation method and application thereof, and a person skilled in the art can realize the preparation by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the lyophilized preparation of the present invention and the method and application of the same have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that the techniques of the present invention can be implemented and applied by modifying or appropriately changing and combining the lyophilized preparation and the method and application of the same described herein without departing from the contents, spirit and scope of the present invention.

In a specific example, the method for detecting retinol in a retinol lyophilized preparation is as follows:

1. and (3) standard substance: VA alcohol (sigma, batch number: # BCBR0155V)

2. Blank control: diluent (0.5% BHT (2.6 di-tert-butyl-4-methylphenol) methanol ethyl acetate 1:1

3. Experimental facility and glass instrument

A high performance liquid chromatograph with an ultraviolet detector; liquid chromatography column: c18(150 x 4.6mm 5 μm); an electronic analytical balance; volumetric flask: various specifications

4. Experimental reagent

Purified water; methanol: HPLC grade: acetonitrile: HPLC grade; ethyl acetate HPLC grade; BHT analytical grade

5. Chromatographic conditions

A chromatographic column: LabTech C18150 mm 4.6mm, 5 μm

Mobile phase: methanol: acetonitrile 65:35(V/V)

Flow rate: 0.5ml/min

Detection wavelength: 326nm

Sample introduction amount: 20 mu l of the mixture; sample introduction time: 30 minutes

6. The method comprises the following steps:

1) preparing a standard stock solution:

20mgVA alcohol standard (sigma, lot # BCBR0155V) is weighed, added into the diluent to dissolve to a constant volume of 10ml, and shaken up. 2000ug/ml solution was prepared. After shaking up, 250ul of mother liquor is sucked into a 10ml volumetric flask, and the diluted solution is constant volume to scale and then shaken up. 2) Determination of component content of sample solution

Weighing a certain amount of essence pieces placed at 70 ℃ for different time (0 hour, 72H) respectively, placing into a 25ml volumetric flask, adding about 2ml of purified water, shaking, dissolving, adding about 20ml of diluent, ultrasonically extracting for 5min, cooling to room temperature, fixing volume to scale, shaking up, transferring into an EP tube, centrifuging for 2min at 3500 rpm, and taking supernatant and filtering. Ultrasonic degassing.

3) Content calculation

The formula:

c1: concentration of standard stock solution

Cx: concentration of sample solution

P1: average value of peak area of standard solution of continuously feeding 5 needles

Px: peak area value of sample solution

TABLE 1 Standard measurement data

In the actual test, the retinol solution (0.4%) was directly lyophilized without any stabilizer added, and was not tested after 60 hours in air, and retinol was degraded to 0.

And other active oil such as caprylic/capric glyceride, beta-carotene, oily ganoderma lucidum extract, tocopherol, etc. are directly freeze-dried without adding a stabilizer, and are detected after being placed in the air for 72 hours or 7 days, and the active oil is greatly lost, and some active oil tends to be 0.

Meanwhile, in the embodiment of the invention, except for the difference between the examples and the comparative examples in the comparative test, the rest test conditions are kept consistent, and the comparability of the examples and the comparative examples is ensured.

The solution comprises active grease, one or two components selected from 2, 6-di-tert-butyl-p-cresol and tert-butyl-hydroquinone (or one or more of dilauryl thiodipropionate, sodium ascorbate and ascorbic acid are added on the basis), and auxiliary materials, and water is added to make up to 100%.

The freeze-dried composition of active oil provided by the present invention, its preparation method and application are further described below.