CN114532542A - Sandwich freeze-dried excipient and preparation method thereof - Google Patents

Sandwich freeze-dried excipient and preparation method thereof Download PDF

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Publication number
CN114532542A
CN114532542A CN202210172072.9A CN202210172072A CN114532542A CN 114532542 A CN114532542 A CN 114532542A CN 202210172072 A CN202210172072 A CN 202210172072A CN 114532542 A CN114532542 A CN 114532542A
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sandwich
freeze
dispersion
preparation
mold cavity
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李和伟
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Changzhou Youdun Industrial Investment Co ltd
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Shandong Tantuo Agricultural Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F5/00—Coffee; Coffee substitutes; Preparations thereof
    • A23F5/24—Extraction of coffee; Coffee extracts; Making instant coffee
    • A23F5/36—Further treatment of dried coffee extract; Preparations produced thereby, e.g. instant coffee
    • A23F5/40—Further treatment of dried coffee extract; Preparations produced thereby, e.g. instant coffee using organic additives, e.g. milk, sugar
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F5/00—Coffee; Coffee substitutes; Preparations thereof
    • A23F5/24—Extraction of coffee; Coffee extracts; Making instant coffee
    • A23F5/36—Further treatment of dried coffee extract; Preparations produced thereby, e.g. instant coffee
    • A23F5/42—Further treatment of dried coffee extract; Preparations produced thereby, e.g. instant coffee using inorganic additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/015—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/238—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin from seeds, e.g. locust bean gum or guar gum
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/25—Exudates, e.g. gum arabic, gum acacia, gum karaya or tragacanth
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/269—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of microbial origin, e.g. xanthan or dextran
    • A23L29/27—Xanthan not combined with other microbial gums
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/269—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of microbial origin, e.g. xanthan or dextran
    • A23L29/274—Pullulan
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
    • Y02A40/90—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in food processing or handling, e.g. food conservation

Abstract

The invention belongs to the technical field of freeze-drying excipient, and particularly relates to a sandwich freeze-drying excipient and a preparation method thereof.

Description

Sandwich freeze-dried excipient and preparation method thereof
Technical Field
The invention belongs to the technical field of freeze-dried excipient preparations, and particularly relates to a sandwich freeze-dried excipient preparation and a preparation method thereof.
Background
The freeze-dried preparation has various varieties and is widely applied to the fields of medicines and foods at present, freeze-dried preparation products are packaged and stored in an anhydrous state, so that the situation that irritant substances such as preservatives and antibacterial agents need to be added into the products due to the existence of moisture is avoided, meanwhile, heating and drying are not needed in the production and preparation process, and heat-sensitive and unstable active components in the products can be well stored.
The addition of a disintegrant to a preparation to improve the disintegration properties has been widely studied at present, and the disintegrant is mixed with an active ingredient, a binder, a corrigent, etc. and then molded into a preparation. In the freeze-dried preparation, after the components are dissolved, the components are formed and freeze-dried to remove the solvent, so that substances which are unstable or insoluble in the solvent are often not suitable to be used as the components of the freeze-dried preparation, for example, effervescent agents which can be used as disintegrating agents, and when the components are dissolved and dispersed by using solvent water in the early stage of the preparation of the freeze-dried preparation, acid-base ion reactions can occur among the effervescent agents to be consumed. These factors greatly limit the use of this fraction in lyophilized formulations.
Disclosure of Invention
In order to solve the above technical problems, the present invention provides a sandwich freeze-dried excipient, comprising a preparation body and a sandwich component, wherein the sandwich component is wrapped in the preparation body in a relatively aggregated state, wherein the sandwich component wrapped in the preparation body also comprises the part of the sandwich component existing on the surface of the pore channel wall in the preparation body,
the above-mentioned "relatively aggregated state" is relative to the dispersed state of each component constituting the preparation itself in the preparation itself, each component constituting the preparation itself is substantially uniformly dispersed in the preparation itself,
the mass ratio of the sandwich component to the preparation body is 1: 0.4 to 10 parts by weight of a thermoplastic resin,
the preparation body is a matrix of the whole sandwich freeze-dried excipient, and comprises a binding agent and/or a skeleton agent on the components, but also can comprise some functional active ingredients and/or auxiliary components,
wherein the binder is at least one selected from pullulan, gelatin, xanthan gum, konjac gum, dextran, alginate gum, acacia, guar gum, agar, hydroxymethyl cellulose, carrageenan and pectin,
the skeleton agent is at least one selected from amino acids with 2-12 carbon atoms, the amino acids with 2-12 carbon atoms include glycine, arginine, serine, proline, alanine, aspartic acid, glutamic acid, hydroxyproline, isoleucine, leucine, phenylalanine, etc.,
the functional active ingredients and auxiliary ingredients in the preparation body generally refer to active ingredients and auxiliary ingredients which are stable and difficult to lose efficacy in a solvent environment,
the auxiliary components are selected from skeleton supporting agent, skin feeling modifier, antioxidant, correctant, essence, trans-mucosa, transdermal absorption promoter, pH regulator, etc.;
the center-fill ingredients include ingredients that are unstable in a solvent environment and/or ingredients that are relatively less soluble in a solvent, although other conventional ingredients may be included,
for example, effervescent disintegrating agents which are unstable in aqueous environment or active ingredients which are liable to lose efficacy when they are used in water, such as citric acid, malic acid, boric acid, tartaric acid, fumaric acid, sodium bicarbonate, sodium carbonate, etc.,
the term "relatively low solubility" as used herein means that the amount of the component added is not completely dissolved in the solvent amount in the entire macroscopic volume of the lyophilized preparation at normal temperature and normal pressure, and that the component having relatively low solubility in the solvent, such as active nutritional components having a large molecular weight and a high viscosity,
the other conventional ingredients mentioned above may be referred to the functional active ingredients and/or auxiliary ingredients mentioned above which constitute the bulk of the formulation.
The invention also provides a preparation method of the sandwich freeze-dried excipient, which comprises the following steps: fully dispersing all components forming a preparation body in a solvent to form a dispersion liquid, adding a sandwich component into the dispersion liquid in the process of quickly freezing the dispersion liquid to obtain a mixture in which the sandwich component is frozen in a frozen dispersion liquid, freeze-drying the obtained mixture to obtain a sandwich freeze-dried excipient,
wherein the filling ingredients can be added in solid form or liquid form, for example, solid ingredients unstable in water environment need to be directly added in solid form (such as dry powder, the same below), ingredients with relatively low solubility in water can be added in solid form or added in liquid form such as suspension, turbid solution, etc.,
the mass ratio of the filling component to the dispersion liquid is 1: 1 to 50 of the total amount of the organic solvent,
the preparation method is characterized in that under a quick-freezing environment, the dispersion liquid initially has fluidity, and at the moment, the dispersion liquid is mixed with the sandwich component and filled in time, so that the dispersion liquid can be filled in a die cavity to realize shaping, but the dispersion liquid is completely frozen quickly, so that the contact time between the sandwich component and a liquid solvent in the whole preparation and forming process is very short, and even if the sandwich component is a substance sensitive to the solvent, only a small amount of the sandwich component is consumed or lost due to the very short contact time with the solvent, most of the sandwich component can be reserved and is reserved in a preparation body after freeze-drying.
Therefore, the preparation method of the scheme is particularly suitable for adding ingredients which are unstable in a solvent environment into a freeze-dried excipient as sandwich ingredients, for example, when the solvent is water and the sandwich ingredients contain effervescent disintegrating agents, only a small amount of the disintegrating agents react with water in the preparation process, the dispersion liquid is quickly frozen into ice, a part of gas generated by the reaction is even not overflowed and is remained in a frozen mixture, the remained effervescent disintegrating agents cannot react with each other as freely movable ions in the frozen dispersion liquid,
based on the above purpose, the specific operation of the preparation method can include the following (taking water as the solvent as an example):
for example
Fully dispersing all components forming a preparation body in water to form dispersion liquid, pre-freezing the obtained dispersion liquid until the dispersion liquid is in a flowable ice-water mixture state, filling a part of the dispersion liquid in the ice-water mixture state into a mold cavity, adding a sandwich component into the mold cavity, continuously filling the rest of the dispersion liquid in the ice-water mixture state into the mold cavity, simultaneously controlling the temperature of the mold cavity to quickly and fully freeze the dispersion liquid filled into the mold cavity, freeze-drying the frozen dispersion liquid mixture, demolding (or freeze-drying after demolding) to obtain a sandwich freeze-dried excipient,
the pre-freezing temperature is-200 ℃ to-60 ℃, the temperature of the die cavity is controlled to be-200 ℃ to-60 ℃,
and e.g.
Fully dispersing all components forming a preparation body in water to form dispersion liquid, filling the dispersion liquid into a mold cavity, freezing by controlling the temperature of the mold cavity, taking out the dispersion liquid which can flow in the mold cavity after the dispersion liquid close to the bottom of the mold cavity and the wall of the mold cavity is frozen into a solid shell, adding a sandwich component into a cavity of the solid shell, filling the previously taken out dispersion liquid into the mold cavity, simultaneously quickly and fully freezing the dispersion liquid filled into the mold cavity by controlling the temperature of the mold cavity, freeze-drying a frozen dispersion liquid mixture, demolding (or freeze-drying after demolding) to obtain a sandwich freeze-dried excipient,
wherein the temperature of the die cavity is controlled to be-200 ℃ to-60 ℃, the dispersion liquid which can still flow in the die cavity is taken out, the dispersion liquid is placed in a pre-freezing environment to keep the dispersion liquid in a flowing ice-water mixture state, and the dispersion liquid is re-filled into the die cavity under the ice-water mixture state,
it can be seen from the above measures that no stirring dispersion operation is performed after the filling ingredients are added to the dispersion liquid, because the mutual contact and interaction degree between the filling ingredients and the liquid water therein are greatly increased when the filling ingredients are stirred and dispersed in an ice-water mixture, even in a soft ice system with certain fluidity, which inevitably results in great consumption of the filling ingredients and also prevents the filling structure required by the scheme. In this embodiment, the sandwich component is added to the dispersion system in an aggregated state and in a relatively static manner, so as to prevent the sandwich component from diffusing in the dispersion system as much as possible, thereby significantly reducing the degree of contact and action between the sandwich component and the dispersion, particularly the liquid dispersion, and also to protect the sandwich component within the formulation by isolation as much as possible.
The invention has the beneficial effects that: the sandwich component is added in the process of quick-freezing the dispersion liquid, so that the dispersion liquid is prevented from influencing water-sensitive substances in the sandwich component in a liquid water form to the maximum extent, for example, an effervescent disintegrant can be well stored when being used as the sandwich component, and finally the disintegration speed of a freeze-dried finished product is higher; some nutrient active substances which are easy to lose efficacy when meeting water can also be used as sandwich components to be prepared into freeze-dried preparations, so that the range of material selection and product types of the freeze-dried preparations is greatly expanded,
meanwhile, the product of the scheme is sandwich-shaped in structure, and substances which are easy to lose efficacy in moisture and air environments are used as sandwich components, so that the quality guarantee period of the substances can be greatly prolonged compared with the conventional homogeneous freeze-drying preparation, because active substances are distributed on the conventional homogeneous freeze-drying preparation everywhere, the surface of the preparation is contacted with air after being taken out of a box, and a small amount of air and moisture can be attached to and enter a pore structure of the preparation, so that the active substances in the preparation can not be contacted and influenced. In the scheme, a layer of protective cover is added on the sandwich component, the sandwich component is far away from the surface of the preparation, and air and moisture are not easy to penetrate through the protective cover to enter the preparation, so that the effect of isolation and protection is achieved.
Detailed Description
Example 1
Preparation of vitamin C sandwich freeze-dried block:
approximate distribution of components in a single vitamin C sandwich lyophilized block:
(1) the components of the filling are as follows:
vitamin C100 mg
Citric acid 32mg
Sodium bicarbonate 16mg
(2) The preparation body is as follows:
Figure BDA0003517793340000041
the preparation process comprises the following steps:
(1) adding 2 parts by weight of pullulan, 32 parts by weight of glycerol, 1.2 parts by weight of guar gum, 32 parts by weight of white granulated sugar, 0.6 part by weight of neotame, 0.6 part by weight of beet red and 0.6 part by weight of sweet orange essence into 183 parts by weight of water, and fully stirring to obtain a solution,
(2) fully mixing 100 parts by weight of dry powder vitamin C, 32 parts by weight of dry powder citric acid and 16 parts by weight of dry powder sodium bicarbonate to obtain a sandwich component,
(3) keeping the bottom of the mold in contact with liquid nitrogen so as to keep the mold cavity at a freezing temperature of-170 ℃, filling 252mg of the solution obtained in the step (1) into the mold cavity at one time by using a filling pump (the bottom of the mold cavity is a square horizontal plane, the same applies below), freezing for about 1s until the solution close to the bottom and the wall of the mold cavity is frozen, then pumping out the solution which is still flowable at the center of the mold cavity so as to leave a solid shell which is attached to the wall of the mold cavity and is provided with a cavity with an upward opening in the mold cavity, wherein the pumped out solution is about 140mg, placing the pumped out solution in an environment at 0 ℃ as an ice-water mixture for temporary storage,
148mg of the dry powder-like mixture of the filling ingredients obtained in step (2) is added into the cavity of the frozen solid shell by a feeder at one time, then the filling pump fills the part of the solution extracted before into the cavity of the frozen solid shell at one time, the part of the solution filled subsequently is frozen rapidly because the mould is kept at the freezing temperature due to the contact with liquid nitrogen, and is combined with the solid shell to wrap the filling ingredients inside to obtain a filling structure, the fluidity of the ice-water mixture enables the ice-water mixture to fully fill the cavity without obvious air holes, part of the effervescent substances soaked by the ice-water mixture is subjected to dissolution reaction, and the released part of the gas is better remained in the frozen object,
(4) after keeping the frozen state in contact with liquid nitrogen in step (3) for 10 minutes (from the end of the last addition operation, the same applies hereinafter), the frozen product of the sandwich structure was subjected to freeze-drying treatment, and then, the vitamin C sandwich freeze-dried block in a similar cube shape was obtained by demolding.
1000 vitamin C sandwich freeze-dried blocks are prepared according to the method, and are suspended, kept stand and exposed in a simulated air environment (25 ℃, the humidity is 60 percent and the same below) for 24 hours, and then a detection experiment is carried out (the suspension and the standing of the freeze-dried sample blocks are realized through the support of a hollow stainless steel wire mesh, so that all the surfaces of the sample blocks can be well contacted with the environment, and the state is kept for 24 hours, which is similar to the aging treatment of the sample blocks and the same below).
Example 2
Compared to example 1, only the adjustment in operation is made:
approximate distribution of components in a single vitamin C sandwich lyophilized block:
(1) the components of the filling are as follows:
vitamin C100 mg
Citric acid 32mg
Sodium bicarbonate 16mg
(2) The preparation body is as follows:
Figure BDA0003517793340000051
Figure BDA0003517793340000061
the preparation process comprises the following steps:
(1) adding 2 parts by weight of pullulan, 32 parts by weight of glycerol, 1.2 parts by weight of guar gum, 32 parts by weight of white granulated sugar, 0.6 part by weight of neotame, 0.6 part by weight of beet red and 0.6 part by weight of sweet orange essence into 183 parts by weight of water, fully stirring to obtain a solution, placing the solution in an environment at 0 ℃ to ensure that the solution is preserved in the state of ice-water mixture,
(2) fully mixing 100 parts by weight of dry powder vitamin C, 32 parts by weight of dry powder citric acid and 16 parts by weight of dry powder sodium bicarbonate to obtain a sandwich component,
(3) keeping the bottom of the mould in contact with liquid nitrogen so as to keep the mould cavity at a freezing temperature of-170 ℃, filling 126mg of the ice-water mixture obtained in the step (1) into the mould cavity at one time by a filling pump, then adding 148mg of the dry powder-shaped sandwich component mixture obtained in the step (2) into the mould cavity at one time by a feeder, finally filling 126mg of the ice-water mixture obtained in the step (1) into the mould cavity at one time by the filling pump and quickly freezing (the ice-water mixture has fluidity which enables the ice-water mixture to fully fill the mould cavity and has no obvious air holes left), wherein part of effervescent agent substances soaked by the ice-water mixture are subjected to a dissolving reaction, and released part of gas is better remained in frozen matters,
(4) and (4) keeping the frozen state contacted with liquid nitrogen in the step (3) for 10 minutes, then carrying out freeze-drying treatment on the frozen object with the sandwich structure, and then demoulding to obtain the vitamin C sandwich freeze-dried block with the shape of a similar cube.
1000 vitamin C sandwich freeze-dried blocks are prepared according to the method, suspended, kept stand and exposed in a simulated air environment for 24 hours, and then a detection experiment is carried out.
Comparative example 1
In contrast to examples 1 and 2, only in operation, the formulation body was mixed with the center-fill ingredients in a soft ice state and injection molded:
approximate distribution of components in a single lyophilized block of vitamin C:
(1) the components of the filling are as follows:
vitamin C100 mg
Citric acid 32mg
Sodium bicarbonate 16mg
(2) The preparation body is as follows:
Figure BDA0003517793340000071
the preparation process comprises the following steps:
(1) adding 2 parts by weight of pullulan, 32 parts by weight of glycerol, 1.2 parts by weight of guar gum, 32 parts by weight of white granulated sugar, 0.6 part by weight of neotame, 0.6 part by weight of beet red and 0.6 part by weight of sweet orange essence into 183 parts by weight of water, placing the mixture in water at the temperature of minus 5 ℃, fully stirring the mixture, preparing the mixture into soft ice,
(2) fully mixing 100 parts by weight of dry powder vitamin C, 32 parts by weight of dry powder citric acid and 16 parts by weight of dry powder sodium bicarbonate to obtain a sandwich component,
(3) keeping the bottom of the mold in contact with liquid nitrogen so as to keep the mold cavity at a freezing temperature of-170 ℃, respectively mixing 252mg of the soft ice obtained in the step (1) and 148mg of the sandwich component obtained in the step (2) together by a filling pump (until the powdery materials are all stuck by the soft ice and no independent powder exists) to obtain an injection molding mixture, filling the injection molding mixture into the mold cavity by the filling pump and quickly freezing (the fluidity of the soft ice mixture enables the soft ice mixture to fully fill the mold cavity without obvious air hole residues),
(4) and (4) keeping the frozen state contacted with liquid nitrogen in the step (3) for 10 minutes, performing freeze-drying treatment on the frozen object, and then demolding to obtain the vitamin C freeze-dried block in a similar cube shape.
1000 vitamin C freeze-dried blocks are prepared according to the method, suspended, kept stand and exposed in a simulated air environment for 24 hours, and then detection experiments are carried out.
Comparative example 2
In contrast to example 2, only operationally, the center-fill ingredients were added to the mold cavity first, and the entire formulation bulk mix was added once more:
approximate distribution of components in a single vitamin C sandwich lyophilized block:
(1) the components of the sandwich:
vitamin C100 mg
Citric acid 32mg
Sodium bicarbonate 16mg
(2) The preparation body is as follows:
Figure BDA0003517793340000081
the preparation process comprises the following steps:
(1) adding 2 parts by weight of pullulan, 32 parts by weight of glycerol, 1.2 parts by weight of guar gum, 32 parts by weight of white granulated sugar, 0.6 part by weight of neotame, 0.6 part by weight of beet red and 0.6 part by weight of sweet orange essence into 183 parts by weight of water, fully stirring to obtain a solution, placing the solution in an environment at 0 ℃ to ensure that the solution is preserved in the state of ice-water mixture,
(2) fully mixing 100 parts by weight of dry powder vitamin C, 32 parts by weight of dry powder citric acid and 16 parts by weight of dry powder sodium bicarbonate to obtain a sandwich component,
(3) keeping the bottom of the mould in contact with liquid nitrogen so as to keep the mould cavity at a freezing temperature of-170 ℃, firstly adding 148mg of the dry powder-shaped sandwich component mixture obtained in the step (2) into the mould cavity through a feeder, then filling 252mg of the ice-water mixture obtained in the step (1) into the mould cavity through a filling pump at one time and quickly freezing (the fluidity of the ice-water mixture enables the ice-water mixture to fully fill the mould cavity without obvious air hole residues), wherein part of a small part of effervescent agent substances soaked by the ice-water mixture is subjected to dissolution reaction, and released part of gas is better remained in frozen objects,
(4) and (4) keeping the frozen state contacted with liquid nitrogen in the step (3) for 10 minutes, then carrying out freeze-drying treatment on the frozen object with the sandwich structure, and then demoulding to obtain the vitamin C sandwich freeze-dried block with the shape of a similar cube.
1000 vitamin C sandwich freeze-dried blocks are prepared according to the method, suspended, kept stand and exposed in a simulated air environment for 24 hours, and then a detection experiment is carried out.
From the above examples and comparative examples, 20 vitamin C sandwich lyophilized blocks (vitamin C lyophilized blocks) were randomly selected for disintegration performance test, and the average number was taken as the disintegration time of the product of the example, as shown in table 1:
the detection operation is as follows: the individual sandwich lyophilized pieces (lyophilized pieces) were placed in 100mL of normal temperature (37 ℃) water, and the disintegration time period (measured from the moment of entry into the water until the formulation disintegrated in the water until the solution became clear) was observed and recorded,
TABLE 1
Figure BDA0003517793340000091
The test results in table 1 illustrate that: in the process of mixing the ice cream and the effervescent agent, the effervescent agent and an ice water system are continuously in mutual frictional contact, so that the effervescent agent is greatly reacted and lost at the moment, and the amount of the effervescent agent which can be reserved is small, so that the formed preparation mainly depends on the porous structure of the preparation to realize disintegration, but not mainly depends on the effervescent agent to prolong the disintegration time; in contrast, in comparative example 2, the effervescent agent powder is located at the bottom of the mold cavity when the ice-water mixture is poured, and the position of the effervescent agents is not changed greatly after the rapid freezing and molding, so that the effervescent agents are more concentrated at the position close to the surface of the preparation body in the preparation after demolding, and when the surface of the preparation body is in contact with the environment, some air and moisture in the environment are easy to contact the part of the effervescent agents to cause reaction and consumption, and the amount of the effervescent agents left in the disintegration experiment stage in the preparation is reduced.
From the above examples and comparative examples, 20 vitamin C sandwich lyophilized blocks (vitamin C lyophilized blocks) were randomly selected for vitamin C activity reduction test, and the average value was taken as the activity reduction degree of the product in this example, and the specific test procedures were as follows: fully dissolving a single sample block in deionized water (the mass ratio of the sample block to the deionized water is 1: 20), measuring 2.5mL of deionized water (namely sample liquid) in which the sample block is dissolved, adding 18mL of deionized pure water and 2mL of acetone, shaking up, continuously adding 3mL of dilute acetic acid with the concentration of 0.05mol/L and 1mL of starch indicator, shaking up, and then adopting an iodine solution (I)2Concentration 0.1mol/L), until the system turns blue and does not fade for 30 seconds, the content of vitamin C in the sample block is calculated by the volume of iodine solution consumed by the titration, and the percentage of vitamin C loss is calculated by comparison with the amount of vitamin C dosed in the preparation process (100mg), i.e. "percentage of activity reduction" in the table below:
TABLE 2
Percent reduction of Activity
Example 1 7.8％
Example 2 9.5％
Contrast experimentExample 1 25.6％
Comparative example 2 32.2％
The test results in table 2 illustrate: comparative example 1 a part of vitamin C is deactivated during the mixing process of soft ice and vitamin C, and meanwhile, in the preparation prepared in comparative example 1, the vitamin C can be relatively uniformly dispersed in the preparation, which does not belong to the sandwich structure of the scheme, so when the preparation is placed in a simulated air environment, the influence of air and moisture permeation in the environment can also cause a part of the vitamin C close to the surface of the preparation to be deactivated, and finally the activity of the preparation is reduced; in comparative example 2, vitamin C and other powder materials filled in the core are more concentrated at the position close to the surface of the preparation body, and a part of vitamin C is lost due to the infiltration influence of air and moisture in the environment,
and since vitamin C is concentrated at a position close to the surface of the preparation in comparative example 2, and vitamin C is only uniformly dispersed and randomly close to the surface of the preparation in comparative example 1, it can be seen that the amount of vitamin C close to the surface of the preparation is more in comparative example 2, so the vitamin C failure caused by the above-mentioned position effect is more obvious in comparative example 2.
Example 3
Preparation of black tea extract sandwich freeze-dried block:
approximate distribution of components in individual black tea extract sandwich lyophilized blocks:
(1) the components of the filling are as follows:
black tea extract 10mg
Malic acid 42mg
Sodium bicarbonate 20mg
(2) The preparation body is as follows:
xanthan gum 280mg
Acacia gum 170mg
150mg of white granulated sugar
The preparation process comprises the following steps:
(1) adding 280 parts by weight of xanthan gum, 170 parts by weight of Arabic gum and 150 parts by weight of white granulated sugar into 2500 parts by weight of water, fully stirring to obtain a solution,
(2) mixing 10 weight parts of dry powder black tea extract, 42 weight parts of dry powder malic acid, and 20 weight parts of dry powder sodium bicarbonate to obtain sandwich component,
(3) keeping the bottom of the mold in contact with liquid nitrogen so as to keep the temperature of the mold cavity at-170 ℃, filling 3100mg of the solution obtained in the step (1) into the mold cavity at one time by a filling pump (the bottom of the mold cavity is a circular horizontal plane), freezing for about 3s until the solution close to the bottom and the wall of the mold cavity is frozen, then extracting the solution which is still flowable at the center of the mold cavity so as to leave a solid shell which is attached to the wall of the mold cavity and has a cavity with an upward opening in the mold cavity, wherein the extracted solution is about 1300mg, and temporarily storing the extracted solution as an ice-water mixture in an environment at 0 ℃,
adding 72mg of the dry powder-like sandwich component mixture obtained in the step (2) into a cavity of a frozen solid shell at one time through a feeder, filling the part of the solution extracted previously into the cavity of the frozen solid shell at one time through a filling pump, wherein the part of the solution filled subsequently is also frozen rapidly because the mould is kept at a freezing temperature due to contact with liquid nitrogen and is combined with the solid shell to wrap the sandwich component in the cavity to obtain a sandwich structure, the fluidity of the ice-water mixture enables the ice-water mixture to fully fill the cavity without obvious air hole residues, part of a small part of effervescent agent substances soaked by the ice-water mixture is subjected to a dissolution reaction, and a released part of gas is better remained in a frozen object,
(4) and (4) keeping the frozen state contacted with liquid nitrogen in the step (3) for 10 minutes, then carrying out freeze-drying treatment on the frozen object with the sandwich structure, and then demoulding to obtain the black tea sandwich freeze-dried block with the shape similar to a cylinder.
300 black tea sandwich freeze-dried blocks are prepared according to the method, suspended, kept stand and exposed in a simulated air environment for 24 hours, and then a disintegration detection experiment is carried out, wherein the specific experiment operation is the same as the above. The disintegration time was 15.1 s.
Comparative example 3
In contrast to example 3, only operationally, the formulation bulk is mixed with the center-fill ingredients in a soft ice state and then injection molded:
approximate distribution of components in individual black tea extract sandwich lyophilized blocks:
(1) the components of the filling are as follows:
black tea extract 10mg
Malic acid 42mg
Sodium bicarbonate 20mg
(2) The preparation body is as follows:
xanthan gum 280mg
Acacia gum 170mg
150mg of white granulated sugar
The preparation process comprises the following steps:
(1) adding 280 parts by weight of xanthan gum, 170 parts by weight of Arabic gum and 150 parts by weight of white granulated sugar into 2500 parts by weight of water, placing the mixture at the temperature of minus 5 ℃ and stirring fully, preparing the mixture into soft ice,
(2) mixing 10 weight parts of dry powder black tea extract, 42 weight parts of dry powder malic acid, and 20 weight parts of dry powder sodium bicarbonate to obtain sandwich component,
(3) keeping the bottom of the mold in contact with liquid nitrogen so as to keep the mold cavity at a freezing temperature of-170 ℃, respectively mixing 3100mg of the soft ice obtained in the step (1) and 72mg of the sandwich component obtained in the step (2) together by a filling pump (until the powdery materials are all stuck by the soft ice and no independent powder exists) to obtain an injection molding mixture, filling the injection molding mixture into the mold cavity by the filling pump (the bottom of the mold cavity is a circular horizontal plane) and quickly freezing (the fluidity of the soft ice mixture enables the soft ice mixture to fully fill the mold cavity without obvious air hole residues),
(4) after keeping the frozen state in contact with liquid nitrogen in step (3) for 10 minutes, the frozen product was subjected to freeze-drying treatment, and then demolded to obtain a freeze-dried block of black tea in a shape of a cylinder-like body.
300 black tea freeze-dried blocks are prepared according to the method, suspended, kept stand and exposed in a simulated air environment for 24 hours, and then a disintegration detection experiment is carried out, wherein the specific experimental operation is as above. The disintegration time was 57.4 s.
Example 4
Preparation of coffee sandwich freeze-dried block:
approximate distribution of components in the coffee sandwich lyophilized cake:
(1) the components of the filling are as follows:
coffee powder 100mg
Tartaric acid 20mg
Sodium bicarbonate 7mg
(2) The preparation body is as follows:
Figure BDA0003517793340000121
the preparation process comprises the following steps:
(1) adding 45 parts by weight of konjac glucomannan, 22 parts by weight of dextran, 23 parts by weight of glycine and 180 parts by weight of white granulated sugar into 900 parts by weight of water, fully stirring to obtain a solution,
(2) fully mixing 100 weight parts of coffee powder, 20 weight parts of dry powder tartaric acid and 7 weight parts of dry powder sodium bicarbonate to obtain a sandwich component,
(3) keeping the bottom of the mold in contact with liquid nitrogen so as to keep the mold cavity at a freezing temperature of-170 ℃, filling 1170mg of the solution obtained in the step (1) into the mold cavity at one time by using a filling pump (the bottom of the mold cavity is a square horizontal plane), freezing for about 2s until the solution close to the bottom and the wall of the mold cavity is frozen, extracting the solution which is still flowable at the center in the mold cavity so as to leave a solid shell which is attached to the wall of the mold cavity and is provided with a cavity with an upward opening in the mold cavity, wherein the extracted solution is about 410mg, placing the extracted solution in an environment at 0 ℃ as an ice-water mixture for temporary storage,
127mg of the dry powder-like sandwich component mixture obtained in the step (2) is added into a cavity of a frozen solid shell at one time through a feeder, then the part of the solution extracted before is filled into the cavity at one time through a filling pump, the part of the solution filled subsequently is also frozen rapidly because the mould is kept at a freezing temperature due to the contact with liquid nitrogen and is combined with the solid shell before to wrap the sandwich component inside to obtain a sandwich structure, the fluidity of the ice-water mixture enables the ice-water mixture to fully fill the cavity without obvious air hole residues, part of a small part of effervescent agent substances soaked by the ice-water mixture is subjected to a dissolution reaction, and the released part of gas is better remained in a frozen object,
(4) and (4) keeping the frozen state contacted with liquid nitrogen in the step (3) for 10 minutes, then carrying out freeze-drying treatment on the frozen object with the sandwich structure, and then demoulding to obtain the coffee sandwich freeze-dried block with the shape of a cuboid.
100 coffee sandwich freeze-dried blocks are prepared according to the method, suspended, kept stand and exposed in a simulated air environment for 24 hours, and then a disintegration detection experiment is carried out, wherein the specific experimental operation is as above. The disintegration time was 11.6 s.
Comparative example 4
In contrast to example 4, only operationally, the center-fill ingredients were added to the mold cavity first, and the entire formulation bulk mix was added once more:
(1) the components of the filling are as follows:
coffee powder 100mg
Tartaric acid 20mg
Sodium bicarbonate 7mg
(2) The preparation body is as follows:
Figure BDA0003517793340000131
Figure BDA0003517793340000141
the preparation process comprises the following steps:
(1) adding 45 weight parts of konjac glucomannan, 22 weight parts of dextran, 23 weight parts of glycine and 180 weight parts of white granulated sugar into 900 weight parts of water, stirring to obtain a solution, storing the solution in an ice-water mixture state at 0 ℃,
(2) fully mixing 100 weight parts of coffee powder, 20 weight parts of dry powder tartaric acid and 7 weight parts of dry powder sodium bicarbonate to obtain a sandwich component,
(3) keeping the bottom of the mould in contact with liquid nitrogen so as to keep the mould cavity at the freezing temperature of-170 ℃, firstly adding 127mg of the dry powder-shaped sandwich component mixture obtained in the step (2) into the mould cavity through a feeder, then filling 1170mg of the ice-water mixture obtained in the step (1) into the mould cavity through a filling pump for one time and quickly freezing (the fluidity of the ice-water mixture enables the ice-water mixture to fully fill the mould cavity without obvious air hole residues), wherein part of a small part of effervescent agent substances soaked by the ice-water mixture is subjected to dissolution reaction, and released part of gas is better remained in frozen objects,
(4) and (4) keeping the frozen state contacted with liquid nitrogen in the step (3) for 10 minutes, then carrying out freeze-drying treatment on the frozen object with the sandwich structure, and then demoulding to obtain the coffee sandwich freeze-dried block with the shape of a cuboid.
100 coffee sandwich freeze-dried blocks are prepared according to the method, suspended, kept stand and exposed in a simulated air environment for 24 hours, and then a disintegration detection experiment is carried out, wherein the specific experimental operation is as above. The disintegration time was 29.1 s.

Claims (9)

1. A sandwich freeze-dried excipient preparation is characterized in that: the sandwich freeze-dried excipient preparation comprises a preparation body and sandwich components, wherein the sandwich components are wrapped in the preparation body in a relatively aggregated state.
2. The sandwich lyophilized excipient formulation of claim 1, wherein: the center-fill composition includes a composition that is unstable in a solvent environment.
3. The sandwich lyophilized excipient formulation of claim 2, wherein: the ingredients unstable in solvent environment comprise effervescent disintegrating agent unstable in water and/or active ingredients easy to lose efficacy in water.
4. The sandwich lyophilized excipient formulation of claim 1, wherein: the center-fill composition comprises a composition that is relatively less soluble in a solvent.
5. The sandwich lyophilized excipient formulation of claim 1, wherein: the preparation body comprises a binder and/or a skeleton agent in components.
6. The sandwich lyophilized excipient formulation of claim 5, wherein: the preparation body also comprises an active ingredient and/or an auxiliary ingredient, the active ingredient and the auxiliary ingredient are stable and difficult to lose efficacy in water environment, and the auxiliary ingredient is selected from a skeleton supporting agent, a skin feel modifier, an antioxidant, a flavoring agent, essence, a trans-mucosal membrane, a transdermal absorption enhancer and a pH regulator.
7. A method of preparing a filled lyophilized excipient formulation according to any one of claims 1 to 6, characterized in that: the preparation method comprises the steps of fully dispersing all components forming the preparation body in a solvent to form a dispersion liquid, adding the sandwich component into the dispersion liquid in the process of quickly freezing the dispersion liquid to obtain a mixture of the sandwich component frozen in the frozen dispersion liquid, and freeze-drying the mixture to obtain the sandwich freeze-dried excipient.
8. The method of preparing a sandwich lyophilized excipient formulation of claim 7, wherein: the preparation method comprises the steps of fully dispersing all components forming the preparation body in a solvent to form the dispersion, pre-freezing the obtained dispersion until the dispersion is in a flowable solid-liquid mixture state, filling a part of the dispersion in the solid-liquid mixture state into a mold cavity, adding the sandwich component into the mold cavity, filling the rest of the dispersion in the solid-liquid mixture state into the mold cavity, simultaneously controlling the temperature of the mold cavity to quickly and fully freeze the dispersion filled into the mold cavity, and freeze-drying and demolding or freeze-drying the frozen dispersion mixture to obtain the sandwich freeze-dried preparation.
9. The method of preparing a sandwich lyophilized excipient formulation of claim 7, wherein: the preparation method comprises the steps of fully dispersing all components forming the preparation body in a solvent to form the dispersion, filling the dispersion into a mold cavity, freezing the dispersion by controlling the temperature of the mold cavity until the dispersion close to the bottom of the mold cavity and the wall of the mold cavity is frozen into a solid shell, taking out the dispersion which can flow in the mold cavity, adding the sandwich component into a cavity of the solid shell, filling the dispersion taken out before into the mold cavity, simultaneously fully freezing the dispersion filled into the mold cavity rapidly by controlling the temperature of the mold cavity, and freeze-drying and demolding or freeze-drying the frozen dispersion mixture to obtain the sandwich freeze-dried excipient.
CN202210172072.9A 2022-02-24 2022-02-24 Sandwich freeze-dried excipient and preparation method thereof Pending CN114532542A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4178695A (en) * 1977-09-19 1979-12-18 Angelo Erbeia New process for preparing pharmaceutical, cosmetic or diagnostic formulations
CN106466228A (en) * 2015-08-14 2017-03-01 董玲 A kind of multi-mould prepares method of lyophilized excipient of arbitrary shape and products thereof
CN107714654A (en) * 2016-08-11 2018-02-23 董玲 A kind of lyophilized formulations and preparation method thereof
CN110393703A (en) * 2018-04-25 2019-11-01 山东坦途农业科技有限公司 A kind of lyophilized excipient of ascorbic acid and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4178695A (en) * 1977-09-19 1979-12-18 Angelo Erbeia New process for preparing pharmaceutical, cosmetic or diagnostic formulations
CN106466228A (en) * 2015-08-14 2017-03-01 董玲 A kind of multi-mould prepares method of lyophilized excipient of arbitrary shape and products thereof
CN107714654A (en) * 2016-08-11 2018-02-23 董玲 A kind of lyophilized formulations and preparation method thereof
CN110393703A (en) * 2018-04-25 2019-11-01 山东坦途农业科技有限公司 A kind of lyophilized excipient of ascorbic acid and preparation method thereof

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