CN113069424B - Probiotic saccharified freeze-dried flash-release tablet and preparation method thereof - Google Patents
Probiotic saccharified freeze-dried flash-release tablet and preparation method thereof Download PDFInfo
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- 235000018291 probiotics Nutrition 0.000 title claims abstract description 117
- 230000000529 probiotic effect Effects 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 238000004108 freeze drying Methods 0.000 claims abstract description 34
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 239000000853 adhesive Substances 0.000 claims abstract description 17
- 230000001070 adhesive effect Effects 0.000 claims abstract description 17
- 235000015097 nutrients Nutrition 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- 239000007788 liquid Substances 0.000 claims description 50
- 229920001218 Pullulan Polymers 0.000 claims description 35
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- 238000007710 freezing Methods 0.000 claims description 28
- 230000001804 emulsifying effect Effects 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 19
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- 241000901050 Bifidobacterium animalis subsp. lactis Species 0.000 claims description 17
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- 229940009289 bifidobacterium lactis Drugs 0.000 claims description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 14
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- FTSSQIKWUOOEGC-RULYVFMPSA-N fructooligosaccharide Chemical group OC[C@H]1O[C@@](CO)(OC[C@@]2(OC[C@@]3(OC[C@@]4(OC[C@@]5(OC[C@@]6(OC[C@@]7(OC[C@@]8(OC[C@@]9(OC[C@@]%10(OC[C@@]%11(O[C@H]%12O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%12O)O[C@H](CO)[C@@H](O)[C@@H]%11O)O[C@H](CO)[C@@H](O)[C@@H]%10O)O[C@H](CO)[C@@H](O)[C@@H]9O)O[C@H](CO)[C@@H](O)[C@@H]8O)O[C@H](CO)[C@@H](O)[C@@H]7O)O[C@H](CO)[C@@H](O)[C@@H]6O)O[C@H](CO)[C@@H](O)[C@@H]5O)O[C@H](CO)[C@@H](O)[C@@H]4O)O[C@H](CO)[C@@H](O)[C@@H]3O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O FTSSQIKWUOOEGC-RULYVFMPSA-N 0.000 claims description 13
- 229940107187 fructooligosaccharide Drugs 0.000 claims description 13
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000186660 Lactobacillus Species 0.000 description 2
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- LLQHSBBZNDXTIV-UHFFFAOYSA-N 6-[5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-4,5-dihydro-1,2-oxazol-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC1CC(=NO1)C1=CC2=C(NC(O2)=O)C=C1 LLQHSBBZNDXTIV-UHFFFAOYSA-N 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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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
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
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- A—HUMAN NECESSITIES
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- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
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- A—HUMAN NECESSITIES
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- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a probiotic saccharified freeze-dried flash-release tablet and a preparation method thereof. The unit dosage of the freeze-dried flash-release tablet comprises 10-20mg of probiotics, 8-12mg of a skeleton supporting agent, 13-20mg of an adhesive and 1-2mg of a probiotic nutritional agent. The probiotic saccharified freeze-dried flash-release tablet provided by the invention effectively solves the problems of tablet cracking and tablet shrinking in the freeze-drying process and in the inner package of a probiotic preparation, and can effectively prolong the effective period of the product. Because the probiotic nutrient is added in the prescription, the probiotic nutrient can play a role in proliferating the supplemented probiotics, thereby increasing the efficacy of the probiotic preparation after being taken.
Description
Technical Field
The invention belongs to the fields of pharmaceutical preparations, foods and health-care foods, and relates to a probiotic saccharified freeze-dried flash-release tablet and a preparation method thereof.
Background
The probiotics is a living bacterium preparation, can promote the balance of in vivo flora, promote the survival of beneficial bacteria by inhibiting or killing pathogenic bacteria, further regulate gastrointestinal flora, enhance the resistance of intestinal tract, and achieve the effect of treating dyspepsia such as abdominal distension, diarrhea, constipation and the like. The children, especially infants belong to the group with weak immunity, and the probiotic supplement taken by the group can improve the immunity, prevent various diseases, promote digestion and is beneficial to healthy growth. The existing probiotic supplements are usually drinks or dry powders, wherein the drinks need to be taken in a large dose and need to be added with additives such as sweeteners to improve taste, the dry powders need to be taken with water, the requirement on the temperature of the water during preparation is high, and the problem of inaccurate dosage can occur for infants due to the need of parental administration.
WO2013123623A1 discloses an orally disintegrating tablet and a preparation method thereof, the orally disintegrating tablet is prepared by adopting a freeze-drying method, and the components of the orally disintegrating tablet comprise effective dose of pharmaceutical active ingredients, a skeleton supporting agent, a binder and a suspending agent, wherein the binder consists of pullulan and an auxiliary binder, and the problems of slow disintegration and incomplete dissolution of the freeze-dried orally disintegrating tablet when a large dose of drugs is loaded are solved by utilizing the complex use of the pullulan and the auxiliary binder within a specific dosage range. However, the formulation requires the addition of auxiliary binders and suspending agents to increase the drug loading, the taste of the tablets is greatly affected, especially for children, the interest in continuous administration of the supplement is affected, and the activity of probiotics can be affected by pullulan and auxiliary binders.
CN 106963784 a discloses a probiotic supplement for rapid intraoral release. The probiotic supplement released quickly in the oral cavity can load high-dose probiotics and is quickly disintegrated in the oral cavity, meanwhile, the oral cavity has good taste, the survival rate of the probiotics in the preparation is high, and the oral cavity probiotic supplement is suitable for children, particularly infants to take. However, the freeze-dried flash-release tablet prepared according to the formula ratio has unstable structure, and the problem of tablet atrophy can occur through high-temperature high-humidity accelerated experiments.
Therefore, based on the defects existing on the existing basis, the development of a probiotic freeze-dried flash-release tablet which is faster in disintegration, better in taste and stable in structure is urgently needed.
Disclosure of Invention
The invention aims to provide a probiotic saccharified sugar-containing freeze-dried flash-release tablet and a preparation method thereof.
The unit dosage of the probiotic saccharified freeze-dried flash-release tablet provided by the invention comprises 10-20mg of probiotics, 8-12mg of a skeleton supporting agent and 13-20mg of an adhesive.
Further, the mass ratio of the adhesive to the skeleton supporting agent is 1.75-2:1, specifically 1.75:1, 1.76:1, 1.77:1, 1.82:1, 1.93:1, 1.94:1 or 1.95: 1.
Furthermore, the unit dose of the probiotic saccharide-containing freeze-dried flash-release tablet can also comprise 1-2mg, preferably 1.25mg and 1.75mg of probiotic nutrient.
The probiotics are selected from one or more of Lactobacillus rhamnosus (Lactobacillus rhamnous), Bifidobacterium lactis (Bifidobacterium lactis), Lactobacillus fermentum (Lactobacillus fermentum), Lactobacillus acidophilus (Lactobacillus acidophilus), Bifidobacterium animalis (Bifidobacterium animalis), Lactobacillus reuteri, Bifidobacterium breve (Bifidobacterium breve) and Lactobacillus fermentum. Preferably, the probiotics are selected from one or more of lactobacillus rhamnosus, bifidobacterium lactis and bifidobacterium breve.
Specifically, the probiotics can be a mixture of lactobacillus rhamnosus, bifidobacterium lactis and bifidobacterium breve in a mass ratio of (11-18) to 1:1 in sequence. The Lactobacillus rhamnosus can be Lactobacillus rhamnosus HN001, the Bifidobacterium lactis can be Bifidobacterium lactis HN019, and the Bifidobacterium breve can be Bifidobacterium breve M-16V.
The content of the probiotics in the unit dose of the freeze-dried flash-release tablet containing the probiotics and the sugar is 10-20mg, preferably 13-18mg, and specifically 14mg, 16mg, 17mg, 18mg or 20 mg.
According to one embodiment of the invention, the content of the probiotics in the unit dosage of the probiotic sugar-containing freeze-dried flash-release tablet is 16mg, and the probiotics are a mixture of lactobacillus rhamnosus, bifidobacterium lactis and bifidobacterium breve in a mass ratio of 14:1:1 in sequence. The Lactobacillus rhamnosus can be Lactobacillus rhamnosus HN001, the Bifidobacterium lactis can be Bifidobacterium lactis HN019, and the Bifidobacterium breve can be Bifidobacterium breve M-16V.
According to one embodiment of the invention, the content of the probiotics in the unit dosage of the probiotic sugar-containing freeze-dried flash-release tablet is 14mg, and the probiotics are a mixture of lactobacillus rhamnosus, bifidobacterium lactis and bifidobacterium breve in a mass ratio of 11:1:1 in sequence. The Lactobacillus rhamnosus can be Lactobacillus rhamnosus HN001, the Bifidobacterium lactis can be Bifidobacterium lactis HN019, and the Bifidobacterium breve can be Bifidobacterium breve M-16V.
According to one embodiment of the invention, the content of the probiotics in the unit dosage of the probiotic sugar-containing freeze-dried flash-release tablet is 20mg, and the probiotics are a mixture of lactobacillus rhamnosus, bifidobacterium lactis and bifidobacterium breve in a mass ratio of 18:1:1 in sequence. The lactobacillus rhamnosus can be lactobacillus rhamnosus HN001, the bifidobacterium lactis can be bifidobacterium lactis HN019, and the bifidobacterium breve can be bifidobacterium breve M-16V.
The skeleton supporting agent is selected from mannitol or glycine, and preferably, the skeleton supporting agent is mannitol. The content of the skeleton support agent in the unit dose of the probiotic saccharified freeze-dried flash-release tablet is 8-12mg, preferably 9-10mg, and specifically 8mg, 9.5mg, 10mg, 11mg or 12 mg.
The adhesive is selected from pullulan or gelatin, and preferably, the adhesive is pullulan. The content of the adhesive in the unit dose of the probiotic saccharified freeze-dried flash-release tablet is 13-20mg, preferably 16-19mg, and specifically 15.5mg, 16.8mg, 17.85mg, 18.05mg, 19mg, 19.45mg or 20 mg.
The probiotic nutrient is at least one of the following substances with low water activity (Aw less than or equal to 0.1): fructooligosaccharides, galactooligosaccharides and lactooligosaccharides. Preferably, the probiotic nutritional agent is fructo-oligosaccharide with low water activity (Aw less than or equal to 0.1). The content of the probiotic nutrient in the unit dosage of the probiotic sugared freeze-dried flash-release tablet is 1-2mg, and specifically can be 1.75mg and 2 mg.
The invention also provides a preparation method of the probiotic saccharified sugar-containing freeze-dried flash-release tablet.
The invention provides a preparation method of a probiotic saccharified freeze-dried flash-release tablet, which comprises the following raw materials in percentage by mass and volume (g/100 ml): 2-4% of probiotics, 1.6-2.4% of skeleton supporting agent, 2.6-4% of adhesive, 0.2-0.4% of probiotics nutrient and the balance of purified water.
In the raw material of the invention, the content of the probiotics is preferably 2.6-3.6%, and specifically can be 2.8%, 3.2%, 3.4%, 3.6% or 4%.
In the raw material of the invention, the content of the skeleton supporting agent is preferably 1.8-2.0%, and specifically can be 1.6%, 1.9%, 2.0%, 2.2% or 2.4%.
In the raw material of the present invention, the content of the binder is preferably 3.2% to 3.8%, and specifically may be 3.1%, 3.36%, 3.57%, 3.61%, 3.8%, 3.89%, or 4%.
In the raw materials of the invention, the content of the probiotic nutrient is preferably 0.25-0.35%.
The preparation method of the probiotic saccharified sugar-containing freeze-dried flash-release tablet provided by the invention comprises the following steps:
1) dissolving the adhesive in water to obtain a feed liquid (1);
2) adding the probiotic nutrient, the skeleton supporting agent and the probiotics into the feed liquid (1), stirring to completely dissolve, and then supplementing the balance of water to obtain a feed liquid (2);
3) emulsifying the feed liquid (2);
4) injecting the emulsified material into a mold, quickly freezing, and freeze-drying to obtain the probiotic saccharified freeze-dried flash-release tablet.
In the step 3), the emulsification is performed in an emulsifying machine, and the rotation speed of the emulsifying machine is 5000-15000rpm, specifically 10000 rpm; the emulsifying time is 5-30min, specifically 10 min.
In the step 3), the method further comprises a degassing step after emulsification, preferably, the degassing is vacuum degassing for 1-20min, preferably 2-10 min.
In the step 4), the mold is an aluminum-plastic bubble plate.
In the step 4), the quick-freezing conditions are as follows: and (3) quick-freezing temperature: the temperature is between 80 ℃ below zero and 100 ℃ below zero, and the time is 5 to 10 minutes. The temperature of quick freezing is lower, the quick freezing time is shorter, and ice crystals formed in the preparation are finer, so that the preparation can be disintegrated in the oral cavity more quickly and has better taste.
In step 4) of the above method, the freeze-drying curve of the freeze-drying is as follows: keeping at 35 ℃ below zero for 1 to 2 hours; keeping the temperature of between 35 ℃ below zero and 25 ℃ below zero for 1 to 2 hours; keeping the temperature of between 25 ℃ below zero and 15 ℃ below zero for 2 to 3 hours, and keeping the temperature of between 15 ℃ below zero and 25 ℃ below zero for 3 to 5 hours.
According to one embodiment of the invention, the lyophilization profile is: -35 ℃ for 60 minutes; -25 ℃ for 60 minutes; raising the temperature from-25 ℃ to-15 ℃, and keeping the temperature at-15 ℃ for 180 minutes; raising the temperature from-15 ℃ to-5 ℃, and keeping the temperature at-5 ℃ for 60 minutes; run at-5 deg.C to 25 deg.C for 30 minutes, and hold at 25 deg.C for 180 minutes.
Compared with the prior art, the invention has the following beneficial technical effects:
the probiotic saccharified freeze-dried flash-release tablet provided by the invention effectively solves the problems of tablet cracking and tablet shrinking in the freeze-drying process and in the inner package of a probiotic preparation, and can effectively prolong the effective period of the product. The probiotic nutrient is added into the prescription, so that the supplemented probiotics can be proliferated, and the effect of taking the probiotic preparation is improved.
Detailed Description
The present invention will be further illustrated with reference to the following examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Lactobacillus rhamnosus HN001 and Bifidobacterium lactis HN019 used in the following examples were purchased from Synechoblue Biotech, Inc. of Shanghai; bifidobacterium breve M-16V was purchased from Baishi (Shanghai) Biotech Co., Ltd.
Pullulan used in the following examples was purchased from Pioneer 26384; mannitol was purchased from Shandong Tianli pharmaceuticals, Inc.
The fructooligosaccharides used in the examples described below were QHT-FOS-P95S (WL), a product of biological origin, Quantum Gaokou (China).
Example 1 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process comprises the following steps:
1. measuring 350ml of purified water, placing the purified water in a beaker, heating the purified water in a water bath at 50 ℃, weighing the pullulan with the formula amount, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the pullulan to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the prescription amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500ml scale;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotation speed of 10000rpm for 10 minutes; the emulsified feed solution was vacuum degassed for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of an aluminum-plastic bubble-cap plate at a concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of-80 ℃ for pre-freezing for 10 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze-drying curve: -35 ℃ for 60 minutes; -25 ℃ for 60 minutes; raising the temperature from-25 ℃ to-15 ℃, and keeping the temperature at-15 ℃ for 180 minutes; raising the temperature from-15 ℃ to-5 ℃ and keeping the temperature at-5 ℃ for 60 minutes; run at-5 deg.C to 25 deg.C for 30 minutes, and hold at 25 deg.C for 180 minutes.
7. Sealing: and taking the blister plate out of the freeze dryer, and coating, packaging and cutting the blister plate on a sealing machine.
Example 2 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process comprises the following steps:
1. weighing 350ml of purified water, placing the purified water in a beaker, heating the water in a water bath at 50 ℃, weighing the pullulan with the prescription amount, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the pullulan to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the prescription amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500ml scale;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotating speed of 10000rpm for 10 minutes; the emulsified feed solution was vacuum degassed for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of an aluminum-plastic bubble-cap plate at a concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of 100 ℃ below zero for prefreezing for 5 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze drying curve: -35 ℃ for 60 minutes; -25 ℃ for 60 minutes; raising the temperature from-25 ℃ to-15 ℃, and keeping the temperature at-15 ℃ for 180 minutes; raising the temperature from-15 ℃ to-5 ℃ and keeping the temperature at-5 ℃ for 60 minutes; run at-5 deg.C to 25 deg.C for 30 minutes, and hold at 25 deg.C for 180 minutes.
7. Sealing: and (4) taking the blister plate out of the freeze dryer, and coating, packaging and slitting on a sealing machine.
Example 3 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process comprises the following steps:
1. weighing 350ml of purified water, placing the purified water in a beaker, heating the water in a water bath at 50 ℃, weighing the pullulan and the gelatin in the prescribed amount, sequentially adding the pullulan and the gelatin into the beaker, stirring the materials to be completely dissolved, and cooling the materials to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the prescription amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500ml scale;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotation speed of 10000rpm for 10 minutes; the emulsified feed solution was vacuum degassed for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of an aluminum-plastic bubble-cap plate at a concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble cap plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of-90 ℃ for pre-freezing for 8 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze drying curve: -35 ℃ for 60 minutes; -25 ℃ for 60 minutes; raising the temperature from-25 ℃ to-15 ℃, and keeping the temperature at-15 ℃ for 180 minutes; raising the temperature from-15 ℃ to-5 ℃ and keeping the temperature at-5 ℃ for 60 minutes; run at-5 deg.C to 25 deg.C for 30 minutes, and hold at 25 deg.C for 180 minutes.
7. Sealing: and (4) taking the blister plate out of the freeze dryer, and coating, packaging and slitting on a sealing machine.
Example 4 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process comprises the following steps:
1. weighing 350ml of purified water, placing the purified water in a beaker, heating the purified water in a water bath at 50 ℃, weighing gelatin with the prescribed amount, sequentially adding the gelatin into the beaker, stirring the gelatin to completely dissolve the gelatin, and cooling the gelatin to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the prescription amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500ml scale;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotating speed of 10000rpm for 10 minutes; the emulsified feed solution was degassed under vacuum for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of an aluminum-plastic bubble-cap plate at a concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of-80 ℃ for pre-freezing for 10 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze drying curve: holding at-35 ℃ for 60 minutes; -25 ℃ for 60 minutes; raising the temperature from-25 ℃ to-15 ℃, and keeping the temperature at-15 ℃ for 180 minutes; raising the temperature from-15 ℃ to-5 ℃ and keeping the temperature at-5 ℃ for 60 minutes; run at-5 deg.C to 25 deg.C for 30 minutes, and hold at 25 deg.C for 180 minutes.
7. Sealing: and taking the blister plate out of the freeze dryer, and coating, packaging and cutting the blister plate on a sealing machine.
Comparative example 1 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process is the same as in example 1.
Probiotic sugared freeze-drying flash-release tablet forming experiment
Purpose of the experiment: observation of the Effect of binder to proppant ratio on the stability of lyophilized flash Release tablets
The experimental method comprises the following steps: samples of the probiotic saccharified freeze-dried flash-release tablets prepared in example 1, example 2, example 3, example 4 and comparative example 1 were placed in a stability test chamber (temperature 40 ℃, relative humidity 70%). Taking out after one month, and observing whether the shrinkage phenomenon exists or not by naked eyes.
The experimental results are as follows:
| sample (I) | Whether to shrink the slice | Degree of shrinkage |
| Example 1 | Whether or not | / |
| Example 2 | Whether or not | / |
| Example 3 | Whether or not | / |
| Example 4 | Whether or not | / |
| Comparative example 1 | Is that | 64.3％ |
The newly prepared tablet is in a truncated cone shape with the diameter of 12mm at the bottom, the diameter of 18mm at the top and the height of 5 mm; the tablet of comparative example 1 after being left for one month under accelerated conditions was in the shape of a circular truncated cone having a bottom diameter of 12mm, a top diameter of 14.4mm, and a height of 2 mm; according to the cone volume formula: 1/3S h, the volume of the original tablet was calculated to be 895mm 3 The volume of the tablet after compression is 320mm 3 The volume ratio of the two is 35.7 percent, namely the degree of shrinkage is 64.3 percent.
And (4) conclusion:
the ratio of the adhesive to the proppant has a remarkable influence on the stability of the freeze-dried flash-release tablet, and the freeze-dried flash-release tablet prepared by the formula with the mass ratio of the pullulan to the mannitol of 1:1 in the comparative example 1 has a remarkable tablet shrinkage phenomenon after being accelerated for one month in a stability experiment box. The freeze-dried flash-release tablets prepared by the formula in which the mass ratio of pullulan and gelatin to mannitol serving as adhesives in the embodiments 1, 2, 3 and 4 is 1.75: 1-2.0: 1 have no phenomenon of tablet shrinkage.
Comparative example 2 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
preparation process referring to example 1, only in step 2, fructooligosaccharide was not added.
Lactobacillus detection experiment of probiotic saccharified freeze-dried flash-release tablet
Purpose of the experiment: and detecting the proliferation effect of the fructo-oligosaccharide on the probiotics in the probiotic saccharified sugar freeze-dried flash-release tablet.
The experimental method comprises the following steps: after the probiotic sugared freeze-dried flash-release tablets prepared in example 1 and comparative example 2 were placed at normal temperature for one month, the total number of lactic acid bacteria was measured and compared. The test method adopts GB 4789.35 lactic acid bacteria test for food safety national standard food microbiology test.
The experimental results are as follows:
and (4) conclusion:
the probiotic nutrient, namely fructo-oligosaccharide, is added into the prescription, so that the probiotic in the freeze-dried flash-release tablet can be proliferated.
Example 5 preparation of probiotic saccharose-containing lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process is the same as in example 1.
Comparative example 3 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process comprises the following steps:
1. weighing 350ml of purified water, placing the purified water in a beaker, heating the water in a water bath at 50 ℃, weighing the pullulan with the prescription amount, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the pullulan to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the formula amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500 ml;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotating speed of 10000rpm for 10 minutes; the emulsified feed solution was degassed under vacuum for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of an aluminum-plastic bubble-cap plate at a concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble plate filled with the feed liquid into a low-temperature refrigerator at minus 60 ℃ for pre-freezing for 30 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze-drying curve: -35 ℃ for 60 minutes; -25 ℃ for 60 minutes; raising the temperature from-25 ℃ to-15 ℃, and keeping the temperature at-15 ℃ for 180 minutes; raising the temperature from-15 ℃ to-5 ℃, and keeping the temperature at-5 ℃ for 60 minutes; run at-5 deg.C to 25 deg.C for 30 minutes, and hold at 25 deg.C for 180 minutes.
7. Sealing: and (4) taking the blister plate out of the freeze dryer, and coating, packaging and slitting on a sealing machine.
Comparative example 4 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows: same as example 5
The preparation process comprises the following steps:
1. weighing 350ml of purified water, placing the purified water in a beaker, heating the water in a water bath at 50 ℃, weighing the pullulan with the prescription amount, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the pullulan to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the formula amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500 ml;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotating speed of 10000rpm for 10 minutes; the emulsified feed solution was degassed under vacuum for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of the aluminum-plastic bubble plate at the concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble plate filled with the feed liquid into a low-temperature refrigerator at minus 60 ℃ for pre-freezing for 30 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze drying curve: -35 ℃ for 60 minutes; -25 ℃ for 60 minutes; raising the temperature from-25 ℃ to-15 ℃, and keeping the temperature at-15 ℃ for 180 minutes; raising the temperature from-15 ℃ to-5 ℃, and keeping the temperature at-5 ℃ for 60 minutes; run at-5 deg.C to 25 deg.C for 30 minutes, and hold at 25 deg.C for 180 minutes.
7. Sealing: and taking the blister plate out of the freeze dryer, and coating, packaging and cutting the blister plate on a sealing machine.
Determination of oral disintegration time limit of probiotic saccharified freeze-dried flash-release tablet
Purpose of the experiment: influence of different quick-freezing temperatures on disintegration time of the freeze-dried quick-release tablet containing the saccharified sugar of the probiotics.
The experimental method comprises the following steps: the probiotic saccharified freeze-dried flash-release tablets prepared in example 1, example 2, example 3, example 4, example 5, comparative example 3 and comparative example 4 were subjected to disintegration time measurement. The disintegrating basket is fixed on a bracket and is immersed into a 1000ml cup, about 900ml of water with the temperature of 37 +/-1 ℃ is contained in the cup, and the bottom of the basket is 15 +/-1 mm below the water surface. Sample 1 tablet was placed in a disintegration basket and the time to complete disintegration and passage through a 710 μm mesh was recorded.
The experimental results are as follows:
| sample (I) | Disintegration time limit(s) |
| Example 1 | 6 |
| Example 2 | 4 |
| Example 3 | 5 |
| Example 4 | 6 |
| Example 5 | 6 |
| Comparative example 3 | 10 |
| Comparative example 4 | 10 |
And (4) conclusion:
the temperature of quick freezing is lower, and ice crystals formed in the freeze-dried quick-release tablets are finer and more uniform, so that the freeze-dried quick-release tablets are disintegrated more quickly.
Example 6 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process is the same as in example 1.
Comparative example 5 preparation of probiotic sugared lyophilized flash-release tablets
The prescription composition is as follows:
the preparation process comprises the following steps:
1. measuring 350ml of purified water, placing the purified water in a beaker, heating the purified water in a water bath at 50 ℃, weighing the pullulan with the formula amount, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the pullulan to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the prescription amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500ml scale;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotation speed of 10000rpm for 10 minutes; the emulsified feed solution was degassed under vacuum for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of an aluminum-plastic bubble-cap plate at a concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of-80 ℃ for pre-freezing for 10 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze-drying curve: -20 ℃ for 100 minutes; raising the temperature from-20 ℃ to 10 ℃ for 200 minutes; the temperature is raised from 10 ℃ to 30 ℃ and kept at 30 ℃ for 180 minutes.
7. Sealing: and (4) taking the blister plate out of the freeze dryer, and coating, packaging and slitting on a sealing machine.
Comparative example 6 preparation of probiotic sugared lyophilized flash Release tablet
The prescription composition is as follows: same as example 5
The preparation process comprises the following steps:
1. measuring 350ml of purified water, placing the purified water in a beaker, heating the purified water in a water bath at 50 ℃, weighing the pullulan with the formula amount, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the pullulan to room temperature;
2. weighing fructo-oligosaccharide, mannitol and probiotics according to the prescription amount, adding into the feed liquid (1), stirring to completely dissolve, and fixing the volume of purified water to 500ml scale;
3. emulsification and degassing: emulsifying the feed liquid (2) in an emulsifying machine at the rotation speed of 10000rpm for 10 minutes; the emulsified feed solution was degassed under vacuum for 10 minutes.
4. Filling: respectively filling the feed liquid (3) into the bubble holes of an aluminum-plastic bubble-cap plate at a concentration of 0.5 ml/piece;
5. quick-freezing: placing the bubble plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of-80 ℃ for pre-freezing for 10 minutes;
6. freeze-drying: transferring the pre-frozen bubble plate to a freeze dryer plate layer, and operating the following freeze drying curve: -20 ℃ for 100 minutes; raising the temperature from-20 ℃ to 10 ℃ for 200 minutes; the temperature was increased from 10 ℃ to 30 ℃ and maintained at 30 ℃ for 180 minutes.
7. Sealing: and (4) taking the blister plate out of the freeze dryer, and coating, packaging and slitting on a sealing machine.
Molding experiment of probiotic saccharified sugar-containing freeze-dried flash-release tablet
Purpose of the experiment: the effect of different lyophilization profiles on the moldability and stability of lyophilized flash release tablets was tested.
The experimental method comprises the following steps: after the probiotic saccharified freeze-dried flash-release tablets prepared in the examples 5 and 6 and the comparative examples 5 and 6 are taken out of the box, whether the structure of the freeze-dried flash-release tablets collapses or contracts is observed by naked eyes.
The experimental results are as follows:
| sample (I) | Whether or not to collapse | Whether to shrink the slice | Shrinking sheetDegree |
| Example 5 | Whether or not | Whether or not | 0％ |
| Example 6 | Whether or not | Whether or not | 0％ |
| Comparative example 5 | Is that | Is that | 50％ |
| Comparative example 6 | Is that | Is that | 40％ |
And (4) conclusion:
the determined eutectic temperature of the materials is-26 ℃, the first stage temperature of the sublimation drying of the freeze-drying curves used in the comparative example 5 and the comparative example 6 is-20 ℃ which is higher than the eutectic temperature of the materials, so that the materials are melted in the freeze-drying process, the framework is collapsed, and finally the shrinking phenomenon occurs. The freeze-drying curves used in examples 5 and 6 were maintained at-35 ℃ which was 9 ℃ lower than the eutectic temperature for 1-2 hours, forming a stable framework structure with intact tablet shapes.
Claims (6)
1. A probiotic saccharified lyophilized flash-release tablet comprises probiotic 10-20mg, skeleton supporting agent 8-12mg, adhesive 13-20mg, and probiotic nutritional agent 1-2 mg;
the probiotics is a mixture of lactobacillus rhamnosus, bifidobacterium lactis and bifidobacterium breve with the mass ratio of (11-18) to 1:1 in sequence;
the skeleton supporting agent is mannitol;
the adhesive is selected from pullulan or gelatin;
the probiotic nutrient is fructo-oligosaccharide;
the mass ratio of the adhesive to the framework support agent is 1.75-2: 1;
the preparation method of the probiotic saccharified freeze-dried flash-release tablet comprises the following steps:
1) dissolving the adhesive in water to obtain a feed liquid (1);
2) adding the probiotic nutritional agent, the skeleton supporting agent and the probiotics into the feed liquid (1), stirring to completely dissolve, and then supplementing the rest of water to obtain a feed liquid (2);
3) emulsifying the feed liquid (2);
4) injecting the emulsified material into a mold, quickly freezing, and freeze-drying to obtain the probiotic saccharified sugar-containing freeze-dried flash-release tablet;
in the step 4), the quick-freezing conditions are as follows: and (3) quick-freezing temperature: the temperature is minus 80 to minus 100 ℃ and the time is 5 to 10 minutes;
the freeze-drying curve for freeze-drying is as follows: keeping at 35 ℃ below zero for 1 to 2 hours; keeping the temperature of between 35 ℃ below zero and 25 ℃ below zero for 1 to 2 hours; keeping the temperature of between 25 ℃ below zero and 15 ℃ below zero for 2 to 3 hours, and keeping the temperature of between 15 ℃ below zero and 25 ℃ below zero for 3 to 5 hours.
2. The probiotic saccharified freeze-dried flash-release tablet according to claim 1, characterized in that:
the content of the probiotics in the unit dosage of the probiotic sugared freeze-dried flash release tablet is 13-18 mg;
the content of the skeleton supporting agent in the unit dosage of the probiotic saccharified freeze-dried flash-release tablet is 9-10 mg;
the content of the adhesive in the unit dosage of the probiotic saccharified freeze-dried flash-release tablet is 16-19 mg;
the content of the probiotic nutritional agent in the unit dosage of the probiotic freeze-dried sugar-containing flash-release tablet is 1.75 mg.
3. The preparation method of the probiotic saccharified sugar-containing freeze-dried flash-release tablet as claimed in claim 1 or 2, wherein the raw materials are the following substances in percentage by mass and volume: 2-4% of probiotics, 1.6-2.4% of skeleton supporting agent, 2.6-4% of adhesive, 0.2-0.4% of probiotics nutrient and the balance of water;
the preparation method comprises the following steps:
1) dissolving the adhesive in water to obtain a feed liquid (1);
2) adding the probiotic nutrient, the skeleton supporting agent and the probiotics into the feed liquid (1), stirring to completely dissolve, and then supplementing the balance of water to obtain a feed liquid (2);
3) emulsifying the feed liquid (2);
4) injecting the emulsified material into a mold, quickly freezing, and freeze-drying to obtain the probiotic saccharified freeze-dried flash-release tablet;
in the step 4), the quick-freezing conditions are as follows: and (3) quick-freezing temperature: the temperature is minus 80 to minus 100 ℃ and the time is 5 to 10 minutes;
the freeze-drying curve for freeze-drying is as follows: keeping at 35 ℃ below zero for 1 to 2 hours; keeping the temperature between 35 ℃ below zero and 25 ℃ below zero for 1 to 2 hours; keeping the temperature between 25 ℃ below zero and 15 ℃ below zero for 2 to 3 hours, and keeping the temperature between 15 ℃ below zero and 25 ℃ below zero for 3 to 5 hours.
4. The production method according to claim 3, characterized in that: in the step 3), the emulsification is carried out in an emulsifying machine, and the rotating speed of the emulsifying machine is 5000-15000 rpm; the emulsifying time is 5-30 min;
in the step 3), a degassing step is further included after the emulsification.
5. The method of claim 4, wherein: the degassing is vacuum degassing for 1-20 min.
6. The method of claim 5, wherein: and the vacuum degassing time is 2-10 min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202110366080.2A CN113069424B (en) | 2021-04-06 | 2021-04-06 | Probiotic saccharified freeze-dried flash-release tablet and preparation method thereof |
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| CN202110366080.2A CN113069424B (en) | 2021-04-06 | 2021-04-06 | Probiotic saccharified freeze-dried flash-release tablet and preparation method thereof |
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| Publication Number | Publication Date |
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| CN113069424B true CN113069424B (en) | 2022-08-30 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689649A (en) * | 2004-04-30 | 2005-11-02 | 量子高科（北京）研究院有限公司 | Oral cavity quick dissolving preparation and production method thereof |
| WO2009051510A1 (en) * | 2007-10-15 | 2009-04-23 | Obschestvo S Ogranichennoy Otvetstvennostyu 'sibbiosan' | Immobilised and lyophilised complex probiotic preparation and a method for the production thereof |
| CN106963784A (en) * | 2016-01-13 | 2017-07-21 | 北京量子高科制药科技有限公司 | The Probiotic supplement and preparation method of quick release in oral cavity |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689649A (en) * | 2004-04-30 | 2005-11-02 | 量子高科（北京）研究院有限公司 | Oral cavity quick dissolving preparation and production method thereof |
| WO2009051510A1 (en) * | 2007-10-15 | 2009-04-23 | Obschestvo S Ogranichennoy Otvetstvennostyu 'sibbiosan' | Immobilised and lyophilised complex probiotic preparation and a method for the production thereof |
| CN106963784A (en) * | 2016-01-13 | 2017-07-21 | 北京量子高科制药科技有限公司 | The Probiotic supplement and preparation method of quick release in oral cavity |
Non-Patent Citations (1)
| Title |
|---|
| 复合真空冷冻干燥益生菌粉的研制;李情敏等;《食品工业》;20160120(第01期);第129-133页 * |
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