CN115154438A - Preparation method of enteric soft capsule and pelleting die thereof - Google Patents

Preparation method of enteric soft capsule and pelleting die thereof Download PDF

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CN115154438A
CN115154438A CN202210755032.7A CN202210755032A CN115154438A CN 115154438 A CN115154438 A CN 115154438A CN 202210755032 A CN202210755032 A CN 202210755032A CN 115154438 A CN115154438 A CN 115154438A
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coating
enteric
keeping
ethanol
purified water
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杨金山
魏欣
徐军
李新平
蔡振保
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Zhejiang Nutrasis Biotech Co ltd
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Zhejiang Nutrasis Biotech Co ltd
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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
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract

The invention provides a preparation method of an enteric soft capsule, which comprises a capsule body, an enteric solution and a coating film, wherein the enteric solution and the coating film are arranged outside the capsule body, 60-80% of purified water, 5-10% of ethanol and 1-5% of ammonia water are weighed according to the proportion of the enteric solution, 15-30% of film forming agent and 1-5% of moisture preserving agent are added under stirring, the stirring is carried out for 40-60 minutes, the mixture is sieved by an 80 sieve, the solid content is 10%, and the enteric coating solution is obtained, and the enteric coating solution coating step comprises the following steps: pouring the capsule body into a coating pan, starting a hot air system and an exhaust system, preheating for 20 minutes, washing the pills with 95% ethanol after preheating is finished, removing surface oil stains, spraying purified water for humidification, starting the coating pan and a liquid spraying system for coating, and spraying one or two uniform and complete coating layers on the surface of the capsule body to obtain the enteric soft capsule. The production process is safer, the coating film is more flexible, the adhesive force is better, the stability in long-term storage is better, and the coating film can still ensure that the coating film does not crack and fall off when being subjected to oscillation, impact or extrusion, so that the enteric performance of the coating film can be ensured.

Description

Preparation method of enteric soft capsule and pelleting die thereof
Technical Field
The invention relates to the technical field of medicine and food production processes, in particular to a preparation method of an enteric soft capsule and a pelleting die thereof.
Background
In recent years, enteric capsules have been widely developed. Enteric capsules are capsules whose outer shell is resistant to acids and therefore does not disintegrate in the stomach but disintegrates in the intestine, releasing the contents. Enteric capsules are used not only in the case where acid-unstable substances are contained as active ingredients, such as products containing sheep placenta, natto, probiotics and the like, which are made into enteric soft capsules to prevent the active ingredients from being destroyed and enable the active ingredients to be digested and absorbed in the small intestine to achieve the effect, but also in the case of substances which are expected to maintain the effect for a long time through slow release, and substances such as garlic, krill oil, fish oil and the like which are bad odor and aftertaste during expiration caused by digestion in the stomach.
As for the preparation method of enteric capsules, methods have been proposed so far, including the following: (a) raw material mixing method: preparing a solution comprising a moulded water soluble polymer and an acid insoluble polymer, mixing the solution with a suitable plasticiser to form a gel material into a gel skin; (b) coating method: soaking the capsule in 1-5% calcium chloride solution or standing in 3% formaldehyde acetone solution for 60min; (c) film coating: the surface is coated with a coating film made of enteric-coated materials.
Most of the existing enteric soft capsules are made of polymer synthetic materials, mainly including coating materials such as Cellulose Acetate Phthalate (CAP), acrylic resins, polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP) and the like, but the enteric soft capsules produced by adopting the materials have the following problems:
1. most fail to pass the GRAS certification in the United states and cannot be applied to food or drugs at will;
2. the coating solvent in the macromolecular synthetic material needs to adopt organic solvents such as ethanol, glycerol, acetone, triethyl citrate and the like, has low boiling point, is inflammable and explosive, has potential hazards of toxicity and safety, needs to strengthen explosion-proof and flame-proof measures and possibly remains of partial organic solvents;
3. the produced soft capsule has poor coating film adhesiveness and flexibility, is easily influenced by temperature and humidity, has poor stability in long-term storage, is easy to have the problems of coating film cracking and falling off and the like when being vibrated, impacted or extruded, and cannot ensure the enteric function of the product.
In the process of manufacturing the enteric soft capsules by equipment, a mould is the core of the equipment and determines the shape of a product and the loading amount of the product, and in the production process, the oil leakage of the product can be influenced by the temperature of a spraying body, the speed of a net pulling shaft and the temperature of a rubber drum of a pelleting press, but the influence of the mould is particularly important and directly influences the quality and the production efficiency of the product. The currently common pill pressing die mainly comprises a conventional die 20# (7 x 34), a suspension die 20# -1 (7 x 29), a suspension die 20# -2 (8 x 29) and a foreign die 20# (7 x 29), wherein the die cavities of the dies are distributed in 7 rows x 29 rows basically, the space between the die cavities is large, the pulling force of the rubber is large, the bonding time of the rubber is short, the seaming effect is poor, no inverted triangular protrusion exists between the die cavities, the pulling force of the rubber cannot be buffered, and by using the die, the seaming rate of the rubber is poor, the oil leakage rate of products is very high, and the production efficiency of the products is very low.
Disclosure of Invention
In order to solve some or some technical problems in the prior art, the invention provides a preparation method of an enteric soft capsule and a pelleting die thereof, the production process is safer, the coating film is more flexible, the adhesive force is better, the stability is better in long-term storage, and the coating film can still be ensured not to crack and fall off when being oscillated, impacted or extruded, so that the enteric performance can be ensured.
In order to solve the prior technical problems, the invention adopts the following scheme:
a preparation method of an enteric soft capsule comprises a capsule body, an intestinal solution and a coating film, wherein the intestinal solution and the coating film are arranged outside the capsule body, the intestinal solution comprises a film forming agent 15-30%, a humectant 1-5%, purified water 60-80%, ethanol 5-10% and ammonia water 1-5%, the intestinal solution is prepared by weighing 60-80% of purified water, 5-10% of ethanol and 1-5% of ammonia water according to the proportion, adding the film forming agent 15-30% and the moisture preserving agent 1-5% under stirring, stirring for 40-60 minutes, sieving by an 80 sieve to obtain an enteric coating solution with a solid content of 10%, and the enteric coating solution coating step comprises:
pouring the capsule body into a coating pot, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, keeping the temperature in the coating pot at 28-35 ℃, keeping the exhaust air volume larger than the air inlet volume to keep the negative pressure in the coating pot at 0.02-0.06Kpa, and preheating for 20 minutes;
step two, after preheating, opening a coating pan and a liquid spraying system for coating, maintaining the rotating speed of the coating pan at 2-12rpm, maintaining the temperature in the coating pan at 28-35 ℃, removing oil stains on the surface by using 95% ethanol to wash pills (3-5% by weight ratio), and then spraying purified water for humidification (3-10% by weight ratio) for later use;
and step three, maintaining the spraying amount of the coating liquid within a proper range, and spraying one or two uniform and complete coating layers on the surface of the capsule body to obtain the enteric soft capsule.
Further, the film forming agent comprises one or more of acrylic resin, cellulose, sodium alginate, stearic acid, pullulan, polydextrose and shellac.
Further, the humectant comprises one or more of glycerin, propylene glycol, polyethylene glycol, sorbitol solution, caprylic capric glyceride, triethyl citrate, malic acid, tartaric acid and phospholipid.
Further, the coating layer comprises shellac: 15-25%, sodium alginate: 5-10%, oil: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
Further, the preparation method of the coating layer comprises the following steps: firstly, weighing the weight of shellac, sodium alginate, glycerin, phospholipid, ammonia water, ethanol and purified water in a coating layer formula; then pouring the ammonia water, the ethanol and the purified water with required weight into a stirring barrel, starting the stirring water to form vortex, slowly adding the sodium alginate, the shellac and the glycerol with required weight, stirring for 45-60 minutes, and sieving with a 80-mesh sieve to obtain the enteric coating liquid.
Further, the capsule body is provided with two coating layers, the first coating layer is a gastric-soluble coating layer, the second coating layer is an enteric-soluble coating layer, and the gastric-soluble coating layer comprises 1-3% of sodium carboxymethylcellulose, 1-15% of hypromellose, 1-8% of polydextrose, 1-1.5% of phospholipid, 1-1.5% of malic acid, 50-80% of ethanol and 20-30% of purified water; the enteric coating layer comprises shellac: 15-25%, sodium alginate: 5-10%, glycerin: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
Further, the preparation method of the gastric-soluble coating layer comprises the steps of weighing the weight of hydroxypropyl methylcellulose, polydextrose, phospholipid, malic acid, ethanol and purified water in the coating layer formula, then pouring the ethanol and the purified water with the required weight into a stirring barrel, starting the stirring water to form vortex, slowly adding the hydroxypropyl methylcellulose, the polydextrose, the phospholipid and the malic acid with the required weight, stirring for 45-60 minutes, and then sieving with a 80-mesh sieve.
Further, the preparation method of the enteric coating layer comprises the steps of weighing the weight of shellac, sodium alginate, glycerin, phospholipid, ammonia water, ethanol and purified water in the formula of the coating layer, then pouring the ammonia water, the ethanol and the purified water with the required weight into a stirring barrel, starting stirring the water to form vortex, slowly adding the sodium alginate, the shellac and the glycerin with the required weight, stirring for 45-60 minutes, and then sieving with a 80-mesh sieve.
Further, the two-layer coating operation process of the capsule body comprises the following steps:
step A, pouring the soft capsules into a coating pan, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, the temperature in the coating pan at 28-35 ℃, keeping the exhaust air quantity greater than the air inlet air quantity to keep the negative pressure in the coating pan, and preheating for 20 minutes;
and step B, after preheating is finished, starting a coating pan and a liquid spraying system to coat, keeping the rotating speed of the coating pan at 6-12rpm, keeping the spraying amount of a coating liquid in a proper range, keeping the temperature in the coating pan at 28-35 ℃, spraying a first layer of uniform and complete coating film on the surface of the soft capsules, and continuously spraying a second layer of coating film after drying to obtain the product.
A pelleting die for manufacturing enteric soft capsules comprises a die body and a plurality of die cavities arranged on the die body, and is characterized in that: the die cavities adopt an inner double-slit structure, and an inverted triangle is arranged between every two adjacent die cavities.
Further, the die cavities are arranged in 8 rows by 29 columns or 8 rows by 37 columns, and the inverted triangle is three and is positioned between the elbows of the two die cavities.
Compared with the prior art, the invention has the beneficial effects that:
the solvent used by the coating material is water, the formula and the preparation method of the natural enteric coating material can make up the existing defects, compared with an organic solvent, the natural enteric coating material has no potential safety hazards such as toxicity, flammability and explosiveness, and the like, and the production process is safer, and the coating film of the enteric soft capsule prepared by the preparation method of the invention has higher toughness, better adhesive force and better stability in long-term storage than the coating film of the acrylic resin enteric coating soft capsule; when the enteric coating is oscillated, impacted or extruded, the coating film can still be ensured not to crack and fall off, and the enteric function of the product can be ensured.
By a seam optimization method in the enteric soft capsule pressing process; reduce capsule oil leak phenomenon, reduce the influence to follow-up capsule adhesion rate, make this soft capsule realize controllable in the production process, the rubber seam is level and smooth not have deckle edge, and the capsule adhesion is good, and the pliability is strong, and long-term storage stability is good, can not appear the coating film when receiving vibration, striking or extrusion and break the scheduling problem that drops, can ensure its enteric performance.
Drawings
FIG. 1 is a schematic structural view of a mold body of the present invention arranged in 8 rows × 29 columns.
FIG. 2 is a schematic structural view of a mold body according to the present invention, wherein the mold body is arranged in 8 rows and 37 columns;
in the figure: the mold comprises a mold body 1, a mold cavity 2 and an inverted triangle 3.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and the detailed description, and it should be noted that any combination of the embodiments or technical features described below can be used to form a new embodiment without conflict.
A preparation method of an enteric soft capsule comprises a capsule body, an intestinal solution and a coating film, wherein the intestinal solution and the coating film are arranged outside the capsule body, the intestinal solution comprises a film forming agent 15-30%, a humectant 1-5%, purified water 60-80%, ethanol 5-10% and ammonia water 1-5%, the intestinal solution is prepared by weighing 60-80% of purified water, 5-10% of ethanol and 1-5% of ammonia water according to the proportion, adding the film forming agent 15-30% and the moisture preserving agent 1-5% under stirring, stirring for 40-60 minutes, sieving by an 80 sieve to obtain an enteric coating solution with a solid content of 10%, and the enteric coating solution coating step comprises:
step one, pouring the capsule body into a coating pot, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, keeping the temperature in the coating pot at 28-35 ℃, keeping the exhaust air quantity larger than the air inlet air quantity to keep the negative pressure in the coating pot at 0.02-0.06Kpa, and preheating for 20 minutes;
step two, after preheating, opening a coating pan and a liquid spraying system for coating, keeping the rotating speed of the coating pan at 2-12rpm, keeping the temperature in the coating pan at 28-35 ℃, using 95% ethanol to wash pills (3-5% by weight of dosage) to remove surface oil stains, and then spraying purified water for humidification (3-10% by weight of dosage) for later use;
and step three, keeping the spraying amount of the coating liquid within a proper range, and spraying one or two uniform and complete coating layers on the surface of the capsule body to obtain the enteric soft capsule.
In a further improvement, the film forming agent comprises one or more of acrylic resin, cellulose, sodium alginate, stearic acid, pullulan, polydextrose and shellac.
In a further refinement, the humectant comprises one or more of glycerin, propylene glycol, polyethylene glycol, sorbitol solution, caprylic capric glyceride, triethyl citrate, malic acid, tartaric acid, and phospholipids.
In a still further improvement, the coating layer comprises shellac: 15-25%, sodium alginate: 5-10%, oil: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
In a further improvement, the preparation method of the coating layer comprises the following steps: firstly, weighing the weight of shellac, sodium alginate, glycerin, phospholipid, ammonia water, ethanol and purified water in a coating layer formula; then pouring the ammonia water, the ethanol and the purified water with required weight into a stirring barrel, starting the stirring water to form vortex, slowly adding the sodium alginate, the shellac and the glycerol with required weight, stirring for 45-60 minutes, and sieving with a 80-mesh sieve to obtain the enteric coating liquid.
The capsule is further improved in that the capsule body is provided with two coating layers, the first coating layer is a gastric-soluble coating layer, the second coating layer is an enteric-soluble coating layer, and the gastric-soluble coating layer comprises 1-3% of sodium carboxymethylcellulose, 1-15% of hypromellose, 1-8% of polydextrose, 1-1.5% of phospholipid, 1-1.5% of malic acid, 50-80% of ethanol and 20-30% of purified water; the enteric coating layer comprises shellac: 15-25%, sodium alginate: 5-10%, glycerin: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
The further improvement is that the preparation method of the gastric-soluble coating layer comprises the steps of weighing the weight of the hydroxypropyl methylcellulose, the polydextrose, the phospholipid, the malic acid, the ethanol and the purified water in the formula of the coating layer, then pouring the ethanol and the purified water with the required weight into a stirring barrel, starting the stirring water to form vortex, slowly adding the hydroxypropyl methylcellulose, the polydextrose, the phospholipid and the malic acid with the required weight, stirring for 45-60 minutes, and then sieving with a 80-mesh sieve.
The preparation method of the enteric coating layer is further improved by weighing the weight of the shellac, the sodium alginate, the glycerol, the phospholipid, the ammonia water, the ethanol and the purified water in the formula of the coating layer, then pouring the ammonia water, the ethanol and the purified water with the required weight into a stirring barrel, starting stirring the water to form vortex, slowly adding the sodium alginate, the shellac and the glycerol with the required weight, stirring for 45-60 minutes and then sieving with a 80-mesh sieve.
In a still further improvement, the two-layer coating operation process of the capsule body comprises the following steps:
step A, pouring the soft capsules into a coating pan, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, keeping the temperature in the coating pan at 28-35 ℃, keeping the exhaust air volume larger than the air inlet air volume to keep the negative pressure in the coating pan, and preheating for 20 minutes;
and step B, after preheating is finished, opening a coating pan and a liquid spraying system for coating, keeping the rotating speed of the coating pan at 6-12rpm, keeping the spraying amount of a coating liquid in a proper range, keeping the temperature in the coating pan at 28-35 ℃, spraying a first layer of uniform and complete coating film on the surface of the soft capsules, and continuously spraying a second layer of coating film after drying to obtain the product.
The invention provides a seam optimization method in the pressing process of an enteric soft capsule; this soft capsule production process is controllable, and the rubber seam is level and smooth not have deckle edge, and the capsule adhesion is good, and the pliability is strong, and long-term storage stability is good, can not appear the coating film when receiving oscillation, striking or extrusion and break the scheduling problem that drops, can ensure its enteric performance, reduces capsule oil leak phenomenon, reduces the influence to follow-up coating adhesion rate, soft capsule includes that the mould selects and rubber seam rate control.
The formula and the preparation method of the natural enteric coating material can make up the existing defects, and the main components of the enteric coating formula adopted by the invention pass the American GRAS certification, can be safely applied to related varieties of medicines and foods, and is safer compared with a high-molecular enteric coating material.
The coating material of the invention uses water as a solvent, and has no potential safety hazards such as toxicity, flammability and explosiveness compared with organic solvents, and the production process is safer.
The coating film of the enteric coated soft capsule prepared by the preparation method has higher toughness, better adhesive force and better stability in long-term storage than the coating film of the acrylic resin enteric coated soft capsule; when the enteric coating is oscillated, impacted or extruded, the coating film can still be ensured not to crack and fall off, and the enteric function of the product can be ensured.
Example 1
The soft capsule enteric coating layer comprises the following raw materials in percentage by weight:
shellac: 15-25%, sodium alginate: 5-10%, oil: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
Preparing an enteric coating layer:
1. weighing the weight of shellac, sodium alginate, glycerol, phospholipid, ammonia water, ethanol and purified water in the coating layer formula.
2. Pouring the required weight of ammonia water, ethanol and purified water into a stirring barrel, starting the stirring water to form vortex, slowly adding the required weight of sodium alginate, shellac and glycerin, stirring for 45-60 minutes, and sieving with a 80-mesh sieve to obtain the enteric coating layer liquid.
Enteric coating process:
1. pouring the soft capsules into a coating pan, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, the temperature in the coating pan at 28-35 ℃, keeping the exhaust air volume greater than the air inlet air volume to keep the negative pressure in the coating pan, and preheating for 20 minutes;
2. after preheating, opening a coating pan and a liquid spraying system for coating, wherein the rotating speed of the coating pan is maintained at 6-12rpm, the spraying amount of a coating liquid is maintained within a proper range, the temperature in the coating pan is maintained at 28-35 ℃, and a layer of uniform and complete coating film is sprayed on the surface of the soft capsule to obtain the product.
Example 2
The enteric soft capsule is provided with two layers of coatings, wherein the first layer is a gastric-soluble coating, and the second layer is an enteric-soluble coating.
A first layer: 1-3% of sodium carboxymethylcellulose, 1-15% of hypromellose, 1-8% of polydextrose, 1-1.5% of phospholipid, 1-1.5% of malic acid, 50-80% of ethanol and 20-30% of purified water.
Preparing a gastric-soluble coating solution:
1. weighing the weight of hydroxypropyl methylcellulose, polydextrose, phospholipid, malic acid, ethanol and purified water in the coating layer formula.
2. Pouring the ethanol and the purified water with the required weight into a stirring barrel, starting the stirring water to form a vortex, slowly adding the hydroxypropyl methylcellulose, the polydextrose, the phospholipid and the malic acid with the required weight, stirring for 45-60 minutes, and sieving with a 80-mesh sieve to obtain the enteric coating liquid.
A second layer: shellac: 15-25%, sodium alginate: 5-10%, glycerin: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
Preparing enteric coating solution:
1. weighing the weight of shellac, sodium alginate, glycerol, phospholipid, ammonia water, ethanol and purified water in the coating layer formula.
2. Pouring the required weight of ammonia water, ethanol and purified water into a stirring barrel, starting the stirring water to form vortex, slowly adding the required weight of sodium alginate, shellac and glycerol, stirring for 45-60 minutes, and sieving with a 80-mesh sieve to obtain the enteric coating liquid. The coating operation process comprises the following steps:
1. pouring the soft capsules into a coating pan, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, keeping the temperature in the coating pan at 28-35 ℃, keeping the exhaust air volume greater than the air inlet air volume in the coating pan at negative pressure, and preheating for 20 minutes;
2. after preheating, opening a coating pan and a liquid spraying system for coating, keeping the rotating speed of the coating pan at 6-12rpm, keeping the spraying amount of a coating liquid in a proper range, keeping the temperature in the coating pan at 28-35 ℃, spraying a first layer of uniform and complete coating film on the surface of the soft capsule, and continuously spraying a second layer of coating film after drying to obtain the product.
The product effect experiment of the invention:
1. the enteric coated soft capsule products obtained in 2 embodiments of the invention are compared with enteric soft capsules coated by acrylic resin materials in coating film toughness and adhesion performance experiments:
1. experimental comparative protocol: and comparing the damage conditions of the two clothes and films by adopting an oscillation experiment.
1.1 packaging mode: 200cc transparent bottles are sealed by adding an aluminum pad, and each bottle is filled with 60 capsules and 6 bottles respectively. Respectively designated as sample a, sample B, sample C, sample D, sample E, and sample F.
1.2 placing the sample bottle in an oscillation tank of a full-automatic turnover type oscillator, and oscillating for 30 minutes by adopting an oscillation frequency of 60 revolutions per minute.
2. The results of experiments on acrylic resin enteric-coated products prepared using organic solvents were compared with the results of experiments on 2 examples prepared using the formulation and method of the present invention as follows:
Figure BDA0003719336690000101
the experimental results are as follows:
the coating films of 65 samples of the acrylic resin coated soft capsule samples have different degrees of cracking and falling off.
The enteric soft capsule sample coating film produced by the method of example 2 does not crack or fall off.
Experimental comparison results: the experimental result shows that compared with the acrylic resin coated enteric soft capsule, the enteric soft capsule prepared by the invention has better coating film toughness and adhesion performance and better stability in long-term storage.
2. Accelerated experimental investigation of sample stability
And after coating is finished, performing an accelerated test on the qualified sample. The capsules were packaged in PET bottles and placed in different environments for investigation. And (4) investigating items: resisting acid; appearance (presence or absence of cracking of the coating, cracking of the coating after kneading, whitening of the surface, whitening or cracking of the seams, etc.).
1. The packaging method comprises the following steps: sealing 200cc transparent bottles with aluminum pads, and filling 60 capsules in each bottle, and filling 6 bottles respectively; respectively designated as sample a, sample B, sample C, sample D, sample E, and sample F.
2. The samples were individually placed at ambient temperature, 40 ℃, RH75% acceleration and-18 ℃ for 3 months.
3. The comparison of the experimental results of the acrylic resin enteric-coated product prepared by using the organic solvent and the products prepared by the formula and the preparation method of the invention in 2 examples is as follows:
Figure BDA0003719336690000111
Figure BDA0003719336690000121
Figure BDA0003719336690000131
the experimental results are as follows:
15-22% of the polyacrylic resin coated soft capsule samples have unqualified disintegration time due to different degrees of cracking and falling off of the coating film.
The enteric coated soft capsule sample of the embodiment 2 prepared by the coating formula and the preparation method of the invention has good film integrity and qualified disintegration time limit.
The experimental results show that the enteric soft capsule prepared by the coating formula and the preparation method has better coating film adhesiveness and flexibility, and compared with the enteric soft capsule prepared by the macromolecular synthetic enteric coating material, the enteric soft capsule prepared by the coating formula and the preparation method can not have the problem of coating film rupture under the conditions of oscillation, impact or extrusion, and can ensure the enteric performance.
As shown in fig. 1 and 2, a pelleting die for manufacturing enteric soft capsules comprises a die body 1 and a plurality of die cavities 2 arranged on the die body 1, wherein the die cavities 2 are of an inner double-slit structure, and an inverted triangle 3 is arranged between every two adjacent die cavities 2.
In a further improvement, the mold cavities 2 are arranged in 8 rows by 29 columns or 8 rows by 37 columns, and the inverted triangle 3 is three and is positioned between the bends of the two mold cavities 2.
The pill pressing effect of a pill pressing die commonly available on the market is tested and analyzed, and the influence of the weight gain with coating on the acid-resistant stability of the soft capsule coating is as follows, firstly, a sample comprises
(1) Conventional mold 20# (7 x 34) 1 ten thousand pellets (labeled "");
(2) suspension mold 20# -1 (7 × 29) 1 ten thousand pellets (marked "|");
(3) suspension mold 20# -2 (8 × 29) 0.5 ten thousand pellets (marked "x");
(4) foreign die 20# (7 × 29) 1 ten thousand pellets (no mark).
The analytical structure is as follows:
the weight of the coating is increased by 3.5 percent
Serial number Sample (I) Acid-resistant state for 15min Remarks for note
1 Conventional mold 20# (7 x 34) 6 grains of non-leakage oil Qualified
2 Suspension mould 20# -1 (7 x 29) 6 grains of non-leakage oil Qualified
3 Suspension mould20#-2(8*29) 6 grains of non-leakage oil Qualified
4 Foreign mould 20# (7X 29) 6 grains of non-leakage oil Qualified
The weight of the coating is increased by 4.5 percent
Figure BDA0003719336690000141
The weight of the coating is increased by 5.5 percent
Serial number Sample (I) Acid-resistant state for 60min Remarks to note
1 Conventional mold 20# (7 x 34) 1 granule leakage in 23min 1 swelling and enlargement
2 Suspension mould 20# -1 (7 x 29) 6 grains of non-leakage oil 3 swelling of the grains
3 Suspension mould 20# -2 (8 × 29) 6 grains of non-leakage oil Qualified
4 Foreign mould 20# (7X 29) 6 grains of non-leakage oil Qualified
And (3) analyzing according to the detection data:
seam line factors: the joint effect of the seam line has great influence on the acid resistance stability of the soft capsule coating, the experimental data reflects that the whole acid resistance of the soft capsule pressed by a conventional die 20# (7 x 34) is relatively poor, the vegetable pill is observed, the seam line is not flat and has obvious rough feeling, and most of oil leakage parts are positioned at the position; according to experimental data, the joint line factors have a large influence on the acid resistance of the soft capsule, and we directly exclude the worst group of samples (1) the conventional mold 20# (7 x 34), and focus on (2) suspending the mold 20# -1 (7 x 29); (3) suspension mold 20# -2 (8 × 29); (4) foreign mold 20# (7 × 29);
the weight of the coating is increased by 3.5 percent
Serial number Sample(s) Acid-resistant state for 15min Remarks for note
1 Suspension mould 20# -1 (7 x 29) 6 grains of non-leakage oil 3 swelling of the grains
2 Suspension mould 20# -2 (8 x 29) 6 grains of non-leakage oil 5 pieces of swelling
3 Foreign mould 20# (7X 29) 2 grains of oil leak /
The weight of the coating is increased by 4.5 percent
Serial number Sample (I) Acid-resistant state for 60min Remarks for note
1 Suspension mould 20# -1 (7 x 29) 6 grains of non-leakage oil 6 grains swelling
2 Suspension mould 20#-2(8*29) 6 grains of non-leakage oil 5 pieces of swelling
3 Foreign mould 20# (7X 29) 1 granule of oil leakage in 20min and 23min respectively 4 swelling with swelling
The weight of the coating is increased by 5.5 percent
Serial number Sample (I) Acid-resistant state for 60min Remarks for note
1 Suspension mould 20# -1 (7 x 29) 6 grains of non-leakage oil 3 swelling of the grains
2 Suspension mould 20# -2 (8 × 29) 6 grains of non-leakage oil Qualified
3 Foreign mould 20# (7X 29) 6 granules ofOil leakage Qualified
And (3) analysis:
the seam line factor: the joint effect of the seam line has great influence on the acid-resistant stability of the soft capsule coating, and the seam line is deep and has groove feeling when the plain pill with oil leakage is observed, and most of the oil leakage parts are positioned at the position; in a word, the seam line is a key factor influencing the acid-resistant stability of the soft capsule coating, the selection of a proper pelleting die is very key to the overall acid-resistant stability of the coating, and the actual coating weight increment can be reduced under the condition of ensuring better acid-resistant effect, so that the cost reduction effect is achieved.
After improving the mould, the chronic oil leak problem of ball crack is solved to double joint in the mould increases to increase the triangle-falling 3 between die cavity 2, solve the rubber problem of dragging, through the use of new mould, the product oil leak rate obviously descends, tests through control variable method, and experiment repetition 3 times obtains detailed data and sees the table:
oil leakage rate before and after 2019 year die replacement and seam ratio comparison (after drying)
Figure BDA0003719336690000161
The data in the table can show that after the new die is replaced in 2019 and 9 months, the oil leakage rate of the product is obviously reduced from 5.21 per thousand to 0.242 per thousand, and the seam rate of the product is improved by more than 20%.
By using the novel die, the oil leakage rate of the product is very low, the product quality is stable, the novel die adopts 8 rows of multiplied by 29 rows, 29 grains are more compared with the prior old die, the inner diameter of the die cavity 2 is increased, 3 outstanding inverted triangles 3 are added between the elbows of the adjacent die cavities 2, the problem of oil leakage caused by the fact that the balls are not cut cleanly at the elbows is effectively solved, and the die design drawing is shown in figure 1 below.
Through using this kind of novel mould, the product oil leak rate is very low, and product quality is stable, consequently considers improving product efficiency, arranges the mould design into: the method is characterized in that 93 balls are added in 8 rows by 37 columns, the rotating speed of a new die pellet press is increased by 3.0r/min, the output per hour is 4.17 ten thousand balls, the rotating speed of the pellet press is synchronously increased to 4.0r/min by using an encryption type die, the output per hour is 7.10 ten thousand balls, the oil leakage of products is not increased but tends to be reduced after a plurality of batches of experiments, the production efficiency is improved by more than 70%, and a die design diagram is shown in figure 2.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.

Claims (9)

1. A preparation method of enteric soft capsules is characterized by comprising the following steps: the enteric-coated capsule comprises a capsule body, and an enteric solution and a coating film which are arranged outside the capsule body, wherein the enteric solution comprises 15-30% of a film-forming agent, 1-5% of a humectant, 60-80% of purified water, 5-10% of ethanol and 1-5% of ammonia water, the intestinal solution is prepared by weighing 60-80% of purified water, 5-10% of ethanol and 1-5% of ammonia water according to the proportion, adding the 15-30% of the film-forming agent and 1-5% of a moisture preserving agent under stirring, stirring for 40-60 minutes, sieving by an 80 sieve, and obtaining the enteric-coated liquid with the solid content of 10%, and the enteric-coated liquid coating step comprises:
pouring the capsule body into a coating pot, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, keeping the temperature in the coating pot at 28-35 ℃, keeping the exhaust air volume larger than the air inlet volume to keep the negative pressure in the coating pot at 0.02-0.06Kpa, and preheating for 20 minutes;
step two, after preheating, opening a coating pan and a liquid spraying system for coating, keeping the rotating speed of the coating pan at 2-12rpm, keeping the temperature in the coating pan at 28-35 ℃, using 95% ethanol to wash pills (3-5% by weight of dosage) to remove surface oil stains, and then spraying purified water for humidification (3-10% by weight of dosage) for later use;
and step three, keeping the spraying amount of the coating liquid within a proper range, and spraying one or two uniform and complete coating layers on the surface of the capsule body to obtain the enteric soft capsule.
2. The method for preparing enteric soft capsules according to claim 1, characterized in that: the film forming agent comprises one or more of acrylic resin, cellulose, sodium alginate, stearic acid, pullulan, polydextrose and shellac.
3. The method for preparing enteric soft capsules according to claim 2, characterized in that: the humectant comprises one or more of glycerol, propylene glycol, polyethylene glycol, sorbitol solution, caprylic capric glyceride, triethyl citrate, malic acid, tartaric acid and phospholipid.
4. The method for preparing enteric soft capsules according to claim 1, characterized in that: the coating layer comprises shellac: 15-25%, sodium alginate: 5-10%, oil: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
5. The method for preparing enteric soft capsules according to claim 4, characterized in that: the preparation method of the coating layer comprises the following steps: firstly, weighing the weight of shellac, sodium alginate, glycerin, phospholipid, ammonia water, ethanol and purified water in a coating layer formula; then pouring the ammonia water, the ethanol and the purified water with required weight into a stirring barrel, starting the stirring water to form vortex, slowly adding the sodium alginate, the shellac and the glycerol with required weight, stirring for 45-60 minutes, and sieving with a 80-mesh sieve to obtain the enteric coating liquid.
6. The method for preparing enteric soft capsules according to claim 1, characterized in that: the capsule body is provided with two coating layers, the first coating layer is a gastric-soluble coating layer, the second coating layer is an enteric-soluble coating layer, and the gastric-soluble coating layer comprises 1-3% of sodium carboxymethylcellulose, 1-15% of hypromellose, 1-8% of polydextrose, 1-1.5% of phospholipid, 1-1.5% of malic acid, 50-80% of ethanol and 20-30% of purified water; the enteric coating layer comprises shellac: 15-25%, sodium alginate: 5-10%, glycerin: 1.5-2.5%, phospholipid: 1-2.5%, ammonia water: 1.5-2.5%, ethanol: 5-10%, purified water: 60 to 70 percent.
7. The method for preparing enteric soft capsules according to claim 6, characterized in that: the two-layer coating operation process of the capsule body comprises the following steps:
step A, pouring the soft capsules into a coating pan, starting a hot air system and an exhaust system, keeping the air inlet temperature at 40-50 ℃, keeping the temperature in the coating pan at 28-35 ℃, keeping the exhaust air volume larger than the air inlet air volume to keep the negative pressure in the coating pan, and preheating for 20 minutes;
and step B, after preheating is finished, starting a coating pan and a liquid spraying system to coat, keeping the rotating speed of the coating pan at 6-12rpm, keeping the spraying amount of a coating liquid in a proper range, keeping the temperature in the coating pan at 28-35 ℃, spraying a first layer of uniform and complete coating film on the surface of the soft capsules, and continuously spraying a second layer of coating film after drying to obtain the product.
8. A pelleting die for manufacturing enteric soft capsules comprises a die body and a plurality of die cavities arranged on the die body, and is characterized in that: the die cavities adopt an inner double-slit structure, and an inverted triangle is arranged between every two adjacent die cavities.
9. The method of claim 1, wherein: the die cavities are arranged in 8 rows by 29 columns or 8 rows by 37 columns, and the inverted triangle is three and is positioned between the elbows of the two die cavities.
CN202210755032.7A 2022-06-29 2022-06-29 Preparation method of enteric soft capsule and pelleting die thereof Pending CN115154438A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816259A (en) * 1987-02-12 1989-03-28 Chase Chemical Company, L.P. Process for coating gelatin capsules
CN102614153A (en) * 2012-04-16 2012-08-01 广东仙乐制药有限公司 Natural enteric soft capsule and preparation method thereof
CN103330695A (en) * 2013-06-05 2013-10-02 绍兴康可胶囊有限公司 Preparation method for enteric plant cellulose hard hollow capsules
JP2015086158A (en) * 2013-10-30 2015-05-07 株式会社ファンケル Controlled release type soft capsule agent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816259A (en) * 1987-02-12 1989-03-28 Chase Chemical Company, L.P. Process for coating gelatin capsules
CN102614153A (en) * 2012-04-16 2012-08-01 广东仙乐制药有限公司 Natural enteric soft capsule and preparation method thereof
CN103330695A (en) * 2013-06-05 2013-10-02 绍兴康可胶囊有限公司 Preparation method for enteric plant cellulose hard hollow capsules
JP2015086158A (en) * 2013-10-30 2015-05-07 株式会社ファンケル Controlled release type soft capsule agent

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Application publication date: 20221011