WO2023273255A1 - 软胶囊囊壳及软胶囊 - Google Patents

软胶囊囊壳及软胶囊 Download PDF

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Publication number
WO2023273255A1
WO2023273255A1 PCT/CN2021/142080 CN2021142080W WO2023273255A1 WO 2023273255 A1 WO2023273255 A1 WO 2023273255A1 CN 2021142080 W CN2021142080 W CN 2021142080W WO 2023273255 A1 WO2023273255 A1 WO 2023273255A1
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WIPO (PCT)
Prior art keywords
starch
soft capsule
gelling agent
gum
capsule shell
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PCT/CN2021/142080
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English (en)
French (fr)
Inventor
陈洁伟
李绪发
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仙乐健康科技股份有限公司
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Application filed by 仙乐健康科技股份有限公司 filed Critical 仙乐健康科技股份有限公司
Priority to JP2022533325A priority Critical patent/JP7523544B2/ja
Priority to AU2021416460A priority patent/AU2021416460B2/en
Priority to EP21918101.3A priority patent/EP4134071A4/en
Priority to US17/793,564 priority patent/US20240293330A1/en
Priority to CA3167596A priority patent/CA3167596A1/en
Publication of WO2023273255A1 publication Critical patent/WO2023273255A1/zh

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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
    • A61K9/4816—Wall or shell material
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—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

Definitions

  • the application relates to the field of food or medicine, in particular to a soft capsule shell and a soft capsule.
  • enteric-coated soft capsules are mainly coated.
  • Soft capsules are produced first and then coated to obtain the effect of enteric coating.
  • research in recent years has mainly adopted one-step molding for the preparation of enteric-coated soft capsules, that is, adding enteric-coated materials during the sol process, pressing pellets into pellets, and finally drying. It comes in uncoated form which does not require a separate coating.
  • This type of non-coated enteric-coated soft capsule can improve the storage durability of the coated soft capsule, and compared with the traditional preparation process, the process is simplified, the efficiency is improved, and the cost is reduced.
  • the non-coated enteric soft capsule can be prepared by using gelatin and pectin composition, carrageenan and acrylic resin composition, high and low acyl gellan gum and starch composition.
  • patent CN106456558A proposes gelatin and low methoxyl pectin to prepare soft capsules, but after monovalent and divalent cations react with pectin, the enteric properties of soft capsules are deteriorated, and long-term storage makes the enteric properties of soft capsules further improved. Deterioration, and gelatin is easy to cross-link due to aging or due to the reaction with compounds such as aldehydes, although it can withstand acid in artificial gastric juice, it cannot be broken and disintegrated in intestinal juice.
  • Patent CN105263462A proposes to prepare soft capsules from film materials composed of carrageenan composition, methacrylic acid copolymer, modified starch and plasticizer.
  • EP3010493A1 proposes a film composition for gastric acid-resistant soft capsules, which is obtained by mixing high-acyl gellan gum, low-acyl gellan gum, starch and plasticizers. It is easy to pre-gel in the process of soft capsule skin, which makes the rubber skin rough and uneven, poor in formability, and prone to oil leakage.
  • enteric-coated soft capsules with gelatin system
  • scope of application of the contents is small.
  • synthetic resins in the carrageenan system cannot be added to soft capsules.
  • the formability of gellan gum system is poor, and it is easy to Oil spill etc.
  • Those skilled in the art need enteric-coated soft capsules that solve the above-mentioned technical problems.
  • the state of starch in the soft capsule shell is granular starch or broken chain segments of granular starch, wherein the average particle size of the starch granules is between 10 microns and 50 microns.
  • the content of starch granules accounts for the ratio of 0% to 3% of the capsule skin of the soft capsule, the network structure of gellan gum in the capsule skin of the soft capsule can support the mechanical force produced by the hardening of the soft capsule in simulated artificial gastric juice, thereby It is guaranteed not to rupture in the simulated artificial gastric juice, but to rupture in the artificial intestinal juice, and finally achieve the effect of soft capsule enteric coating.
  • the soft capsule is suitable for industrial production.
  • the application provides a soft capsule shell, which is prepared from a film-forming composition comprising 1.5-5wt% of the first gelling agent, 30-40wt% of starch, 10-25wt% of plasticizer agent and 35-55wt% water, wherein the first gelling agent is gellan gum having the following properties: according to the rotational viscometer, 1.5wt% gellan gum is dissolved in water at 90°C for 30 minutes to obtain gellan gum The solution has a viscosity in the range of 10-60mPa.s, wherein the soft capsule shell contains 0-3wt% starch granules, and the starch granules are starch granules with an average particle diameter of 10-50 microns.
  • the soft capsule shell is an enteric soft capsule shell.
  • the starch is one or more of hydroxypropyl starch, oxidized starch, or oxidized hydroxypropyl starch.
  • the starch is one or more of hydroxypropyl starch, oxidized starch or oxidized hydroxypropyl starch and no more than 2 wt% of acid-treated starch, acetate starch, hydroxypropyl distarch phosphate, One or more of starch phosphate, acetylated distarch phosphate, acetylated oxidized starch, acetylated distarch adipate or pregelatinized starch.
  • the weight ratio of gellan gum to starch is 0.03-0.2.
  • the plasticizer is selected from one or a combination of glycerin, sorbitol, maltitol, erythritol, xylitol, crystalline fructose, trehalose or glucose.
  • the film-forming composition also includes a second gelling agent, preferably, the second gelling agent is selected from carrageenan, agar, sodium alginate, pectin, pullulan, konjac gum, One or a combination of xanthan gum, locust bean gum, guar gum, linseed gum, curdlan gum or tamarind gum, preferably the second gum has a gel content of 0.2wt%-5wt%.
  • the second gelling agent is selected from carrageenan, agar, sodium alginate, pectin, pullulan, konjac gum, One or a combination of xanthan gum, locust bean gum, guar gum, linseed gum, curdlan gum or tamarind gum, preferably the second gum has a gel content of 0.2wt%-5wt%.
  • the soft capsule shell is prepared by the following method, which includes a) adding the first gelling agent to the plasticizer, stirring evenly, then adding it to water, and stirring the gelling agent at 60-98 heating and stirring at °C until the first gelling agent dissolves; b) adding the starch, and heating and stirring at 60-98 °C until the starch dissolves; c) removing air bubbles to obtain glue; and d) pelletizing and drying.
  • the a) also includes adding a second gelling agent, and the a) is adding the first gelling agent and the second gelling agent to the plasticizer, stirring evenly, Then add it into water, and heat and stir at 60-98° C. until the first gelling agent and the second gelling agent are dissolved.
  • the present invention provides a soft capsule comprising the soft capsule shell of the present application and a filling.
  • the soft capsule is an enteric-coated soft capsule.
  • the soft capsule is an enteric soft capsule without an enteric coating.
  • the present application provides the application of the soft capsule shell or soft capsule of the present application in food, nutraceutical food and medicine.
  • the application provides the use of a film-forming composition in the preparation of an enteric soft capsule shell, wherein the film-forming composition comprises 1.5-5wt% of the first gelling agent, 30-40wt% of starch, 10 - 25 wt% plasticizer and 35-55 wt% water, wherein the first gelling agent is gellan gum having the following properties: 1.5 wt% gellan gum is dissolved in water at 90°C for 30 minutes according to rotational viscometer The obtained gellan gum solution has a viscosity in the range of 10-60mPa.s, wherein the enteric soft capsule shell contains 0-3wt% starch granules, and the starch granules are starches with an average particle size of 10-50 microns particles.
  • the film-forming composition comprises 1.5-5wt% of the first gelling agent, 30-40wt% of starch, 10 - 25 wt% plasticizer and 35-55 wt% water
  • the first gelling agent is gellan gum having the following properties: 1.5
  • the soft capsule shell is prepared by the following method, which includes a) adding the first gelling agent to the plasticizer, stirring evenly, then adding it to water, and stirring the gelling agent at 60-98 heating and stirring at °C until the first gelling agent dissolves; b) adding the starch, and heating and stirring at 60-98 °C until the starch dissolves; c) removing air bubbles to obtain glue; and d) pelletizing and drying.
  • the a) also includes adding a second gelling agent, and the a) is adding the first gelling agent and the second gelling agent to the plasticizer, stirring evenly, Then add it into water, and heat and stir at 60-98° C. until the first gelling agent and the second gelling agent are dissolved.
  • the starch is one or more of hydroxypropyl starch, oxidized starch or oxidized hydroxypropyl starch, or the starch is one or more of hydroxypropyl starch, oxidized starch or oxidized hydroxypropyl starch Variety and not more than 2% by weight of acid-treated starch, acetate starch, hydroxypropyl distarch phosphate, starch phosphate, acetylated distarch phosphate, acetylated distarch adipate, acetylated oxidized starch or pre- One or more of gelatinized starches.
  • Embodiments of soft capsule shells may also be equally suitable for this aspect of use.
  • the present application also provides a film-forming composition for preparing soft capsule shells, which comprises 1.5-5wt% of the first gelling agent, 30-40wt% of starch, 10-25wt% of plasticizer and 35-55wt% of water, wherein the first A gelling agent is gellan gum having the following properties: as measured by a rotational viscometer, the gellan gum solution obtained by dissolving 1.5 wt% of gellan gum in water at 90°C for 30 minutes has a range of 10-60mPa.s viscosity.
  • the embodiment of the soft capsule shell may be equally applicable to this aspect of the film-forming composition.
  • the present invention provides a soft capsule comprising the soft capsule shell of the present application and a filling.
  • the soft capsule is an enteric-coated soft capsule.
  • the filler is an intestinal filler, such as a drug or nutritional supplement.
  • the preparation method of the soft capsule shell may not include the step of coating.
  • the present application provides the application of the film-forming composition, soft capsule shell or soft capsule of the present application in food, nutraceuticals and medicines.
  • the food, nutraceutical or drug is enterally absorbed or enterally applied.
  • the present application provides a method of enteral delivery using the soft capsule shell or soft capsule of the present application.
  • the present application also provides the use of the soft capsule shell or soft capsule of the present application in the preparation of intestinal medicine.
  • the film-forming composition or soft capsule shell of the present application does not comprise gelatin. In one embodiment, the film-forming composition or soft capsule shell of the present application does not contain pectin. That is to say, the soft capsule shell of the present application obtains excellent soft capsule performance indicators and realizes enteric-soluble effect without gelatin and/or pectin.
  • the soft capsule of the present application adopts the composition of gellan gum and starch of specific viscosity for the preparation of soft capsule, its film-forming strength, toughness and molding adhesion fully meet the requirements of soft capsule industrial production, and it is through a non-coating method
  • the soft capsule product with enteric-coated effect can be directly prepared, which can be used as an alternative to enteric-coated soft capsule technology and promoted and applied in the global market.
  • Figure 1 shows that the glue prepared in Example 11 is placed between two glass slides, the glue is heated and pressurized to form a film at 95°C, the formed capsule is cooled, and iodine solution is added dropwise on the film for staining Optical micrograph.
  • the magnification factor of the images is 600 (shown is a detailed view of a film with a width of 266.1 ⁇ m). Wherein the starch granules are separated by centrifugation, and the mass proportion in the soft capsule shell is 5%. It can be seen from the figure that there are more starch granules distributed in the capsule skin.
  • Figure 2 shows that the glue solution prepared in Example 4 is placed between two glass slides, the glue solution forms a thin film at 95°C by heating and pressing, and the formed capsule is cooled, and iodine solution is added dropwise on the film for staining Optical micrograph.
  • the magnification factor of the images is 600 (shown is a detailed view of a film with a width of 266.1 ⁇ m).
  • the starch granules are separated by centrifugation, and the mass proportion in the soft capsule shell is 3%. It can be seen from the figure that there are less starch granules distributed in the capsule skin.
  • Figure 3 shows that the glue solution prepared in Example 9 is placed between two glass slides, the glue solution forms a thin film at 95°C by heating and pressing, and the formed capsule skin is cooled, and iodine solution is added dropwise on the film for staining Optical micrograph.
  • the magnification factor of the images is 600 (shown is a detailed view of a film with a width of 266.1 ⁇ m).
  • the starch granules are separated by centrifugation, and the mass ratio in the soft capsule shell is 0%. It can be seen from the figure that there are no starch granules in the capsule skin.
  • the capsule skin exists in the form of granulated broken starch and gellan gum dispersed phase.
  • the present application provides a soft capsule shell, which is prepared from the film-forming composition of the present application.
  • the film-forming composition of the present application comprises a first gelling agent.
  • the content of the first gelling agent may be 1.5wt%-5wt%, such as 2wt%, 3wt%, 4wt% or 5wt%.
  • the content of the first gelling agent may be 2wt%-5wt%, such as 2.5-5wt%.
  • the first gelling agent may be gellan gum.
  • the first gelling agent can be gellan gum having the following properties: According to the rotational viscometer, the gellan gum solution obtained by dissolving 1.5 wt% gellan gum in water at 90°C for 30 minutes has a range of 10-60mPa.
  • a viscosity of s for example a viscosity of 12, 15, 20, 30, 35, 40, 45, 50 or 55 mPa.s.
  • the viscosity is 30-50 mPa.s.
  • the gellan gum is a single gel temperature gellan gum. Gellan gum with a suitable viscosity can show good film-forming performance during the film-forming process of the glue solution. When the viscosity of the gellan gum used is too low, the amount of gellan gum used to prepare a qualified film strength must be increased, and the rubber is condensed.
  • the inventors realized the application using 1.5-5wt% gellan gum in the starch film-forming composition, wherein 1.5wt% gellan gum was dissolved in water at 90°C for 30 minutes as measured by rotational viscometer
  • the resulting gellan gum solution has a viscosity in the range of 10-60 mPa.s.
  • the film-forming composition includes a plasticizer.
  • the content of the plasticizer may be 10-25 wt%, such as 13 wt%, 14 wt%, 15 wt%, 16 wt% or 20 wt%.
  • the plasticizer can be selected from one or a combination of glycerin, sorbitol, maltitol, erythritol, xylitol, crystalline fructose, trehalose or glucose.
  • the film forming composition comprises starch.
  • the content of starch may be 30-40 wt% starch, for example 30 wt%, 35 wt% or 40 wt%.
  • Starch can be one or a combination of native starch or modified starch.
  • Native starch can be selected from one or a combination of waxy corn starch, pea starch, corn starch, potato starch and tapioca starch.
  • the modified starch may be selected from acid treated starch, hydroxypropyl starch, oxidized starch, acetate starch, oxidized hydroxypropyl starch, hydroxypropyl distarch phosphate, starch phosphate, acetylated distarch phosphate, acetylated distarch One or a combination of starch adipate, pregelatinized starch, dextrin or maltodextrin.
  • the weight ratio of gellan gum to starch is 0.03-0.2.
  • the weight ratio of gellan gum to starch is 0.04-0.17.
  • the weight ratio of gellan gum to starch is 0.04, 0.09, 0.1, 0.13 or 0.17.
  • the starch is one or more of hydroxypropyl starch, oxidized starch or oxidized hydroxypropyl starch.
  • starches include readily gelatinizable starches and granular starches. Easily gelatinizable starches are starches whose granules are broken or dissolved after complete gelatinization, and are for example selected from waxy corn starch, tapioca starch, hydroxypropyl starch, oxidized starch, oxidized hydroxypropyl starch, dextrin and maltodextrin.
  • Granular starch is starch that is not completely gelatinized, and the granules are not broken after water swelling, selected from: natural starch: pea starch, corn starch, potato starch; modified starch: acid-treated starch, acetate starch, hydroxypropyl distarch Phosphate, Starch Phosphate, Acetylated Distarch Phosphate, Acetylated Distarch Adipate, Acetylated Oxidized Starch, Pregelatinized Starch.
  • the content of easily gelatinizable starch is 30-40wt% starch, such as 30wt%, 32wt%, 35wt% or 40wt%.
  • the amount of granular starch is no more than 2 wt%, such as 1 wt%, 1.5 wt% or 1.7 wt%.
  • the film-forming composition contains water.
  • the content of water may be 35wt%-55wt%, such as 40wt%, 45wt%, 50wt% or 55wt%.
  • the film-forming composition may also include a second gelling agent.
  • the content of the second gelling agent may be 0.2wt%-5wt%, such as 0.25wt%, 1wt%, 2wt%, 3wt% or 4wt%.
  • the second gelling agent is selected from carrageenan, agar, sodium alginate, pectin, pullulan, konjac gum, xanthan gum, locust bean gum, guar gum, linseed gum, curdlan gum or tamarind One or a combination of glues.
  • the application provides a soft capsule, which comprises the soft capsule shell and filler of the application.
  • Fillers can include various animal and vegetable oils, or suspensions, emulsions, semi-solids prepared from various solid functional ingredients and suitable auxiliary materials for soft capsules, or solid preparations (such as granules) made from solid functional ingredients and suitable auxiliary materials. , microcapsules, powder, plain tablets, capsules) or a combination.
  • the state of starch in the soft capsule shell can be starch granules (average size of starch granules ⁇ 10 ⁇ m), granulated starch (average size of starch granules ⁇ 10 ⁇ m) or chain segments after starch granules are broken, wherein the content of starch granules It is 0-3wt%, such as 1 or 2wt%, of the total amount of the soft capsule shell.
  • the present application also provides a method for preparing the soft capsule shell of the present application, which includes a) adding the first gelling agent to the plasticizer, stirring evenly, then adding it to water, and heating and stirring at 60-98°C until the first gelling agent is dissolved; b) adding the starch, and heating and stirring at 60-98° C. until the starch dissolves; c) removing air bubbles to obtain the glue; and d) pelletizing and drying.
  • the a) also includes adding a second gelling agent, and the a) is adding the first gelling agent and the second gelling agent to the plasticizer, stirring evenly, Then add it into water, and heat and stir at 60-98° C. until the first gelling agent and the second gelling agent are dissolved.
  • Pill pressing can be carried out as follows: using a soft capsule production line, the glue is transported to the plastic box of the soft capsule filling machine, the glue is cooled on the surface of the drum to form a rubber skin, and the filling is compressed and molded, and can be further shaped in the tumbler . Drying can be carried out as follows: the shaped or shaped capsules are further dried, preferably until the water content of the capsule is 8-25%.
  • the application also provides the application of the starch film-forming composition, soft capsule shell or soft capsule in food, nutritional and health food, medicine and cosmetics.
  • the application selects the specific viscosity gellan gum suitable for preparing soft capsules by investigating the viscosity of gellan gum.
  • the film-forming composition of the present application through the use of gellan gum with a specific viscosity, is combined with starch within a certain range, and the film-forming has good mechanical strength and toughness, and is used for soft capsules in terms of rubber strength, toughness and molding adhesion. It is obviously superior to the prior art, fully meets the industrial production requirements of soft capsules, meets the disintegration time limit requirement of enteric-coated soft capsules, and can be used as an alternative to non-coated enteric-coated soft capsules technology.
  • a film-forming composition comprising a combination and amount of a particular starch type (e.g. readily gelatinizable starch and not more than 2% by weight of granular starch) compared to a film-forming composition containing a single
  • a particular starch type e.g. readily gelatinizable starch and not more than 2% by weight of granular starch
  • Starch granule content Dissolve 100 mg of dried soft capsule skin and 15 g of deionized water at 75°C for 30 minutes, stir several times during the period to completely dissolve the capsule skin, and then dissolve the dissolved soft capsule skin The turbid liquid is centrifuged at 4000rpm for 15 minutes. After centrifugation under these conditions, the starch granules are basically completely in the centrifugal sedimentation. After the upper liquid is removed and the bottom sediment is fully dried, the content of the starch granules is represented by the sediment content, and the starch granules are calculated. The proportion of the mass in the soft capsule skin.
  • Rubber strength (F) and toughness index (T) use a physical property tester, select the spherical probe and puncture mode, test the speed of 1.0mm/s, record the rubber breaking force, the greater the breaking force, the better the rubber strength; the rubber is broken The corresponding rupture distance (mm), the larger the rupture distance, the better the toughness of the rubber.
  • Gap bonding index cut open the capsule on the non-crack, squeeze to empty the contents, then keep perpendicular to the gap and cut a ring with two gaps in the middle, place the ring on the glass slide, Make the two gaps perpendicular to the glass slide, measure the thickness of the two gaps and the thickness of the capsule shell under a microscope, and calculate the ratio P (%) of the thickness of the thinnest gap to the thickness of the capsule shell.
  • the feasibility of soft capsule production and molding is comprehensively evaluated by rubber strength index (F), toughness index (T) and crack adhesion index (P). It accounts for 20%, and seam bonding accounts for 60%.
  • the three are added together, and the total score of the comprehensive evaluation is 5 points. The higher the score, the better the overall performance.
  • the rubber strength and toughness indicators are ⁇ 3 points respectively and the gap adhesion index is ⁇ 2 points, and the comprehensive evaluation must be ⁇ 2.4 to meet the industrial production of soft capsules.
  • the comprehensive evaluation of the three indicators has a total score of 5 points, and the higher the score, the overall performance the better.
  • the disintegration test was carried out on the sustained-release (enteric-coated) soft capsules. That is to say, in the simulated gastric juice, the soft capsule disintegrates without breaking in the gastric juice for at least 60 minutes, and then disintegrates in the simulated intestinal fluid within no more than 60 minutes.
  • Gellan gum is a kind of microbial metabolic glue. The rheological properties and gel properties of gellan gum produced under different process conditions are different. The inventor dissolved 1.5wt% gellan gum in water at 90° C. for 30 minutes to obtain a gellan gum solution, and studied the viscosity of commercially available gellan gum by using a rotational viscometer test:
  • the above-mentioned gellan gums are gellan gums with a single gel temperature.
  • the method for soft capsule preparation comprising:
  • the soft capsule production line is used to transport the glue liquid to the plastic box of the soft capsule filling machine.
  • the glue liquid is cooled on the surface of the drum to form a rubber skin, which is pressed and bonded by the packaged filler, and can be further shaped by the tumbler. .
  • Soft capsules were prepared with ingredients and contents as described in Table 2, and tested and scored. The measurement results are shown in Table 2.
  • Examples 1-8 use specific viscosity gellan gum and starch in combination, and the formed rubber has better strength, toughness and molding adhesion
  • Comparative Examples 1-2 use the same combination of the film-forming composition of the present invention.
  • content when comparative example 1 adopts gellan gum with higher viscosity and starch combination, the rubber skin strength formed is weaker, has certain toughness, but molding bonding is general;
  • comparative example 2 adopts gellan gum and starch with lower viscosity When combined, the rubber is basically viscous and has poor toughness, so it cannot be pressed and molded into soft capsules.
  • Soft capsules were prepared with ingredients and contents described in Table 3 and Table 4, and tested and scored. The measurement results are shown in Table 3 and Table 4.
  • the soft capsules prepared in Example 9, Example 10 and the above-mentioned Example 4 can all achieve the enteric-coating effect.
  • the comprehensive evaluation of the soft capsules made in Example 10 and the above-mentioned Example 4 becomes better, but when the granular starch is increased to 3%, the soft capsules made in the stomach All disintegrated. Therefore, the addition of less than 2% (such as 1.7%) of cross-linked starch, such as hydroxypropyl distarch phosphate, has achieved unexpected effects on the comprehensive evaluation and enteric solubility of soft capsules.
  • Examples 9-23 illustrate that gellan gum of specific viscosity is combined with various types of starch to prepare soft capsules, the technical effect is obviously better than that of the prior art, and the enteric coating effect can be achieved.
  • the size of the starch granules in the capsule skin of the soft capsule can be observed with a 600-fold magnification by a polarizing microscope.
  • the starch In the sol process of starch and gellan gum, after the starch is heated in the water medium, it first swells by absorbing water, and some starch granules are further dissolved, so that the swollen starch granules are broken and form smaller starch granules, which are further stirred and dissolved.
  • the starch Accompanied by the separation and dissolution of the starch molecular chain segments, the starch finally exists in the glue in a solution state. The glue is cooled first and then forms a rubber skin during the molding process of the pelletizing machine.
  • the starch in the glue consists of relatively free molecular segments, which are rapidly cooled during the temperature drop process to form broken starch or form interactions with gellan gum molecular segments. through the network structure. If during the sol process, after the starch granules absorb water and swell, due to the intermolecular force of the starch itself, the starch cannot be further swollen, broken, and finally dissolved, then the starch will exist in the form of swollen granules in the glue solution. The particles have no cross extinction phenomenon under the polarizing microscope.
  • the glue solution is cooled and finalized during the molding process of the pellet machine, and the starch in the glue solution still exists in the capsule skin of the soft capsule in the form of swollen granules.
  • gellan gum molecules cannot penetrate inside the starch granules, and Starch molecular segments form an interpenetrating network structure.
  • the reason why non-coated enteric-coated soft capsules can resist gastric acid erosion in artificial gastric juice is that the molecular chain segment of gellan gum is in the environment of artificial gastric juice, and the hydrogen ions and water molecules in hydrochloric acid can combine with the double helix molecular chain of gellan gum.
  • Carboxylate groups combine to form hydrogen bonds, so that the entire double helix molecule and the double helix molecule of gellan gum next door are crosslinked through hydrogen bonds to form a network structure.
  • the soft capsules prepared by gellan gum and starch will swell, and the volume will increase by 2-5 times, and the swollen soft capsules will become brittle along with the swelling.
  • the binding force of the gellan gum network structure is greater than the failure stress of the soft capsule swelling and becoming brittle, so that the soft capsule remains stable in the gastric juice. Does not break.
  • the soft capsule when the binding force produced by the cross-linking reaction of the double helix molecular chains of gellan gum is greater than the failure stress of swelling and becoming brittle, the soft capsule can remain unbroken in gastric juice; If the force is less than the destructive stress of swelling and becoming brittle, the soft capsule will rupture in the gastric juice, resulting in the inability of the soft capsule to achieve enteric coating effect.
  • Examples 25-31 use specific viscosity of gellan gum and hydroxypropyl starch respectively combined with agar, locust bean gum, guar gum, konjac gum, low-ester pectin, amide pectin, carrageenan, and xanthan gum to prepare soft
  • the effect of the capsule technology is better than that of the prior art, and the effect of enteric coating can be realized.
  • a gellan gum and starch composition with a specific viscosity of the present application is controlled within a certain range by using gellan gum with a specific viscosity and combining with starch, has good molding performance, has enteric coating effect, and fully meets the industrial production requirements of soft capsules , can be used as an alternative to soft capsule technology.

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Abstract

一种由成膜组合物制备的软胶囊囊壳和包含该软胶囊囊壳与填充物的软胶囊，其中成膜组合物包含1.5-5wt％第一胶凝剂、30-40wt％淀粉、10-25wt％增塑剂和35-55wt％水，第一胶凝剂是具有以下性质的结冷胶：根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度，其中该软胶囊囊壳包含0-3wt％的平均粒径在10微米-50微米的淀粉颗粒，该软胶囊囊壳具有肠溶性质。

Description

软胶囊囊壳及软胶囊
本申请要求2021年6月28日提交的，申请号为202110719246.4的，发明名称为“软胶囊囊壳及软胶囊”的中国发明专利申请的优先权。
技术领域
本申请涉及食品或药物领域，具体涉及一种软胶囊囊壳及软胶囊。
背景技术
传统肠溶软胶囊，主要以包衣为主，先生产软胶囊，再进行包衣，从而获得肠溶的效果。而近年来的研究，主要采用一步成型进行肠溶软胶囊的制备，即在溶胶过程中添加肠溶材料，压丸成型，最后干燥。其采用不需要单独包衣的非包衣形式。这类非包衣肠溶软胶囊可改善包衣软胶囊的保存持久性，与传统的制备工艺相比其工艺简化，提高效率，降低成本。
非包衣肠溶软胶囊可采用明胶和果胶组合物、卡拉胶和丙烯酸树脂组合物、高低酰结冷胶和淀粉组合物制备。例如专利CN106456558A提出了明胶和低甲氧基果胶制备软胶囊，但一价、二价阳离子与果胶发生反应后使得软胶囊肠溶性变差，并且长时间的存放使得软胶囊的肠溶性进一步劣化，并且明胶由于老化或由于与诸如醛的化合物的反应而易于交联，虽在人工胃液中耐受酸液，但是在肠液中无法破裂崩解。再者，明胶主要来源于牛和猪，而素食主义者和某些宗教信徒不食用动物来源的明胶，这也进一步限制了明胶的应用。专利CN105263462A提出了由卡拉胶组合物、甲基丙烯酸共聚物、改性淀粉和增塑剂等组成的膜材料制备软胶囊。EP3010493A1提出了一种耐胃酸性软胶囊的膜组合物，通过混合高酰基结冷胶、低酰基结冷胶、淀粉和增塑剂得到，但这种高低酰结冷胶复配的胶体在制备软胶囊皮过程中容易预凝胶，使得胶皮粗糙不平整，成型性差，易漏油。
综上所述，目前明胶体系肠溶软胶囊存在应用受限，内容物适用范围小，卡拉胶体系中合成树脂在某些地区的不能添加用于软胶囊，结冷胶体系的成型性差，容易漏油等。本领域技术人员需要解决上述技术问题的肠溶软胶囊。
发明内容
本申请部分基于发明人长期工作中的以下发现：淀粉在软胶囊囊皮中的状态是颗粒淀粉或者颗粒淀粉破碎后的链段，其中淀粉颗粒的平均粒径大小在10微米-50微米。淀粉颗粒的含量占软胶囊囊皮的比值在0％-3％时，结冷胶在软胶囊的囊皮中的网络结构能支撑软胶囊在模拟人工胃液中变硬产生的机械作用力，从而保证在模拟人工胃液中不破裂，在人工肠液中破裂，最终达到软胶囊肠溶的效果。申请人发现当1.5wt％结冷胶在90℃状态下的粘度在10mPa.s-60Pa.s的结冷胶与淀粉组合可以制备愈合性好、耐受破裂力高、并且具备肠溶释放的软胶囊，适合工业化生产。
在一方面，本申请提供了软胶囊囊壳，其由成膜组合物制备，所述成膜组合物包含1.5-5wt％第一胶凝剂、30-40wt％淀粉、10-25wt％增塑剂和35-55wt％水，其中第一胶凝剂是具有以下性质的结冷胶：根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度，其中所述软胶囊囊壳包含0-3wt％淀粉颗粒，所述淀粉颗粒是平均粒径在10微米-50微米的淀粉颗粒。在本文中，软胶囊囊壳是肠溶性的软胶囊囊壳。
在一个实施方案中，淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种。
在一个实施方案中，淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种和不超过2wt％的酸处理淀粉、醋酸酯淀粉、羟丙基二淀粉磷酸酯、淀粉磷酸酯、乙酰化二淀粉磷酸酯、乙酰化氧化淀粉、乙酰化二淀粉己二酸酯或预胶化淀粉中的一种或多种。
在一个实施方案中，结冷胶与淀粉的重量比为0.03-0.2。
在一个实施方案中，增塑剂选自甘油、山梨糖醇、麦芽糖醇、赤藓糖醇、木糖醇、结晶果糖、海藻糖或葡萄糖中的一种或组合。
在一个实施方案中，成膜组合物还包含第二胶凝剂，优选地，所述第二胶凝剂选自卡拉胶、琼脂、海藻酸钠、果胶、普鲁兰多糖、魔芋胶、黄原胶、刺槐豆胶、瓜尔胶、亚麻籽胶、可得然胶或罗望子胶中的一种或组合，优选地第二胶凝胶含量为0.2wt％-5wt％。
在一个实施方案中，所述软胶囊囊壳通过如下的方法制备，所述方法包括a)将第一胶凝剂加入到增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至第一胶凝剂溶解；b)加入所述淀粉，并在60～98℃下加热搅拌 至淀粉溶解；c)除去气泡即得胶液；和d)压丸和干燥。
在一个实施方案中，所述a)还包括加入第二胶凝剂，所述a)为将所述第一胶凝剂和第二胶凝剂加入到所述增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至所述第一胶凝剂和第二胶凝剂溶解。
在另一个方面，本发明提供了软胶囊，其包含本申请的软胶囊囊壳和填充物。在一个实施方案中，软胶囊是肠溶软胶囊。在一个实施方案中，软胶囊是不含肠溶性包衣的肠溶软胶囊。
在另一个方面，本申请提供了本申请的软胶囊囊壳或软胶囊在食品、营养保健食品和药品中的应用。
在另一个方面，本申请提供了成膜组合物在制备肠溶性软胶囊囊壳中的用途，其中所述成膜组合物包含1.5-5wt％第一胶凝剂、30-40wt％淀粉、10-25wt％增塑剂和35-55wt％水，其中第一胶凝剂是具有以下性质的结冷胶：根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度，其中所述肠溶性软胶囊囊壳包含0-3wt％淀粉颗粒，所述淀粉颗粒是平均粒径在10微米-50微米的淀粉颗粒。
在一个实施方案中，所述软胶囊囊壳通过如下的方法制备，所述方法包括a)将第一胶凝剂加入到增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至第一胶凝剂溶解；b)加入所述淀粉，并在60～98℃下加热搅拌至淀粉溶解；c)除去气泡即得胶液；和d)压丸和干燥。
在一个实施方案中，所述a)还包括加入第二胶凝剂，所述a)为将所述第一胶凝剂和第二胶凝剂加入到所述增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至所述第一胶凝剂和第二胶凝剂溶解。
在一个实施方案中，淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种，或者淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种和不超过2wt％的酸处理淀粉、醋酸酯淀粉、羟丙基二淀粉磷酸酯、淀粉磷酸酯、乙酰化二淀粉磷酸酯、乙酰化二淀粉己二酸酯、乙酰化氧化淀粉或预胶化淀粉中的一种或多种。
软胶囊囊壳的实施方案也可以同样适用于该用途的方面。
本申请还提供了制备软胶囊囊壳的成膜组合物，其包含1.5-5wt％第一胶凝剂、30-40wt％淀粉、10-25wt％增塑剂和35-55wt％水，其中第一胶凝剂是具有以下性质的结冷胶：根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水 中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度。
软胶囊囊壳的实施方案也可以同样适用于该成膜组合物的方面。
在另一个方面，本发明提供了软胶囊，其包含本申请的软胶囊囊壳和填充物。在一个实施方案中，软胶囊是肠溶软胶囊。在一个实施方案中，填充物是肠部用的填充物，例如药物或营养补充剂。
在本申请中，软胶囊囊壳的制备方法可以不包括包衣的步骤。
在另一个方面，本申请提供了本申请的成膜组合物、软胶囊囊壳或软胶囊在食品、营养保健品和药品中的应用。在一个实施方案中，食品、营养保健品或药品是肠部吸收的或肠用的。
在一个方面，本申请提供了使用本申请的软胶囊囊壳或软胶囊进行肠部递送的方法。本申请还提供了本申请的软胶囊囊壳或软胶囊在制备肠部用药中的用途。
在一个实施方案中，本申请的成膜组合物或软胶囊囊壳不包含明胶。在一个实施方案中，本申请的成膜组合物或软胶囊囊壳不包含果胶。也就是说，本申请的软胶囊囊壳在不含明胶和/或果胶的情况下获得优异的软胶囊性能指标并且实现肠溶性效果。
本申请的软胶囊采用特定粘度的结冷胶和淀粉的组合物用于制备软胶囊时其成膜强度、韧性和成型粘合方面完全满足软胶囊工业化生产要求，并且是通过非包衣的方式直接制备出具有肠溶效果的软胶囊产品，可以作为肠溶软胶囊技术的备选替代，在全球市场推广应用。
附图说明
图1是实施例11制备的胶液放置在两个载玻片中间，通过加热加压使得胶液在95℃下形成薄膜，冷却形成的囊皮，在此薄膜上滴加碘溶液进行染色的光学显微照片。影像的放大因子为600(图示宽度为266.1μm的膜的详细图)。其中淀粉颗粒通过离心分离出来，在软胶囊囊皮中的质量占比为5％。从图中可以看出在囊皮中分布着较多的淀粉颗粒。
图2是实施例4制备的胶液放置在两个载玻片中间，通过加热加压使得胶液在95℃下形成薄膜，冷却形成的囊皮，在此薄膜上滴加碘溶液进行染色的光学显微照片。影像的放大因子为600(图示宽度为266.1μm的膜的详细图)。淀粉颗粒通过离心分离出来，在软胶囊囊皮中的质量占比为3％。从图中可 以看出在囊皮中分布着较少的淀粉颗粒。
图3是实施例9制备的胶液放置在两个载玻片中间，通过加热加压使得胶液在95℃下形成薄膜，冷却形成的囊皮，在此薄膜上滴加碘溶液进行染色的光学显微照片。影像的放大因子为600(图示宽度为266.1μm的膜的详细图)。淀粉颗粒通过离心分离出来，在软胶囊囊皮中的质量占比为0％。从图中可以看出在囊皮不存在淀粉颗粒。囊皮中都是以颗粒破碎淀粉和结冷胶分散相形式存在。
具体实施方式
提供以下内容以进一步说明本申请。
本申请提供了软胶囊囊壳，其由本申请的成膜组合物制备。本申请的成膜组合物包含第一胶凝剂。第一胶凝剂的含量可以是1.5wt％-5wt％，例如2wt％、3wt％、4wt％或5wt％。优选地，第一胶凝剂的含量可以是2wt％-5wt％，例如2.5-5wt％。第一胶凝剂可以是结冷胶。第一胶凝剂可以是具有以下性质的结冷胶：根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度，例如12、15、20、30、35、40、45、50或55mPa.s的粘度。优选地，粘度为30-50mPa.s。在一个实施方案中，结冷胶为单凝胶温度的结冷胶。合适粘度的结冷胶能在胶液成膜过程中表现出良好成膜性能，当使用的结冷胶粘度过低时，制备合格膜强度的结冷胶使用量必须增大，并且胶皮凝结速度慢，成膜性能低，且黏性不足使得胶丸夹缝性能差，愈合性差，漏油严重；当使用的结冷胶粘度过高时，制备的胶液过稠，并且在过程中容易预凝胶，导致胶皮粗糙，成膜性能差，且膜的黏性差使得胶丸愈合不好，导致胶丸漏油；过高和过低粘度的结冷胶均无法在制备出合格的胶皮提供软胶囊的压制使用。在本文中，发明人在淀粉成膜组合物中使用1.5-5wt％的结冷胶实现了本申请，其中根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度。
成膜组合物包含增塑剂。增塑剂的含量可以是10-25wt％，例如13wt％、14wt％、15wt％、16wt％或20wt％。增塑剂可以选自甘油、山梨糖醇、麦芽糖醇、赤藓糖醇、木糖醇、结晶果糖、海藻糖或葡萄糖中的一种或组合。
成膜组合物包含淀粉。淀粉的含量可以是30-40wt％淀粉，例如30wt％、 35wt％或40wt％。淀粉可以是天然淀粉或改性淀粉中的一种或组合。天然淀粉可以选自蜡质玉米淀粉、豌豆淀粉、玉米淀粉、马铃薯淀粉、木薯淀粉中的一种或组合。改性淀粉可以选自酸处理淀粉、羟丙基淀粉、氧化淀粉、醋酸酯淀粉、氧化羟丙基淀粉、羟丙基二淀粉磷酸酯、淀粉磷酸酯、乙酰化二淀粉磷酸酯、乙酰化二淀粉己二酸酯、预胶化淀粉、糊精或麦芽糊精中的一种或组合。在一个实施方案中，结冷胶与淀粉的重量比为0.03-0.2。在一个实施方案中，结冷胶与淀粉的重量比为0.04-0.17。例如，结冷胶与淀粉的重量比为0.04、0.09、0.1、0.13或0.17。优选地，淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种。或者，淀粉包含易糊化淀粉和颗粒淀粉。易糊化淀粉是淀粉完全糊化后颗粒破碎或溶解的淀粉，例如选自蜡质玉米淀粉、木薯淀粉、羟丙基淀粉、氧化淀粉、氧化羟丙基淀粉、糊精和麦芽糊精。颗粒淀粉是淀粉未完全糊化，吸水膨胀后颗粒未破碎的淀粉，选自：天然淀粉：豌豆淀粉、玉米淀粉、马铃薯淀粉；改性淀粉：酸处理淀粉、醋酸酯淀粉、羟丙基二淀粉磷酸酯、淀粉磷酸酯、乙酰化二淀粉磷酸酯、乙酰化二淀粉己二酸酯、乙酰化氧化淀粉、预胶化淀粉。在一个实施方案中，易糊化淀粉的含量为30-40wt％淀粉，例如30wt％、32wt％、35wt％或40wt％。在一个实施方案中，颗粒淀粉的含量不超过2wt％，例如1wt％、1.5wt％或1.7wt％。
成膜组合物包含水。水的含量可以是35wt％-55wt％，例如40wt％、45wt％、50wt％或55wt％。
成膜组合物还可以包含第二胶凝剂。第二胶凝剂的含量可以是0.2wt％-5wt％，例如0.25wt％、1wt％、2wt％、3wt％或4wt％。第二胶凝剂选自卡拉胶、琼脂、海藻酸钠、果胶、普鲁兰多糖、魔芋胶、黄原胶、刺槐豆胶、瓜尔胶、亚麻籽胶、可得然胶或罗望子胶中的一种或组合。
本申请提供了软胶囊，其包含本申请的软胶囊囊壳和填充物。填充物可包括各种动、植物油脂，或各种固体功效成分与软胶囊适宜辅料制备而成的混悬液、乳液、半固体，或固体功效成分与适宜辅料制成的固体制剂(如颗粒、微囊、粉末、素片、胶囊)中的一种或组合。淀粉在软胶囊囊壳中的状态可以是淀粉颗粒(淀粉颗粒平均粒径大小≥10μm)、颗粒破碎淀粉(淀粉颗粒平均粒径大小<10μm)或者淀粉颗粒破碎后的链段，其中淀粉颗粒含量为软胶囊囊壳总量的0-3wt％，例如1或2wt％。
本申请还提供了制备本申请的软胶囊囊壳的方法，其包括a)将第一胶 凝剂加入到增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至第一胶凝剂溶解；b)加入所述淀粉，并在60～98℃下加热搅拌至淀粉溶解；c)除去气泡即得胶液；和d)压丸和干燥。在一个实施方案中，所述a)还包括加入第二胶凝剂，所述a)为将所述第一胶凝剂和第二胶凝剂加入到所述增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至所述第一胶凝剂和第二胶凝剂溶解。压丸可以如下进行：采用软胶囊生产线，将胶液输送至软胶囊填充机的胶盒中，胶液在转鼓表面上冷却形成胶皮，经封装填充物压制成型，可进一步在转笼中定型。干燥可以如下进行：将成型或定型后胶丸进一步干燥，优选干燥至囊皮水分8-25％。
本申请还提供了本申请的淀粉成膜组合物、软胶囊囊壳或软胶囊在食品、营养保健食品、药品和化妆品中的应用。
本申请的优点包括：
1.本申请通过考察结冷胶的粘度，选择适合于制备软胶囊的特定粘度结冷胶。本申请的成膜组合物，通过采用特定粘度的结冷胶，与淀粉组合控制在一定范围内，成膜具有良好的机械强度和韧性，用于软胶囊在胶皮强度、韧性和成型粘合方面明显优于现有技术，完全满足软胶囊工业化生产要求，满足肠溶软胶囊崩解时限规定，可以作为非包衣的肠溶软胶囊技术的备选替代。
2.本申请通过观察囊壳中的淀粉颗粒，发现软胶囊在介质水中和人工胃液中的崩解破裂与该淀粉颗粒的粒径和含量有关。
3.本申请发现与含有单独的淀粉类型，例如羟丙基淀粉的成膜组合物相比，包含特定淀粉类型的组合和含量(例如易糊化淀粉和不超过2wt％的颗粒淀粉)的成膜组合物能够在软胶囊综合评价和肠溶性上实现了出乎意料的效果。
实施例
实施例中采用的方法
1.为了表征囊皮中的淀粉颗粒，采用以下的方法进行颗粒大小和含量的测定：
1)淀粉颗粒大小：成膜组合物通过混合加热制备的胶液放置在两个载玻片中间，通过加热加压使得胶液在95℃下形成薄膜，冷却后在此薄膜上滴 加碘溶液进行染色，采用偏光显微拍照。随机选取多个观察区域拍照，根据放大倍数校准标尺后，测量所拍摄区域内每颗淀粉颗粒的粒径，以其算术平均值表示淀粉颗粒大小。
2)淀粉颗粒含量：将100mg的干燥后的软胶囊囊皮与15g去离子水在75℃的条件下溶解30分钟，期间多次搅拌使得囊皮完全溶解后，将溶解后的软胶囊囊皮浑浊液进行4000rpm离心15min，经过此等条件的离心，淀粉颗粒基本完全处在离心沉淀中，将上层液体去除后，底层沉淀经过充分干燥后，以沉淀物含量表示淀粉颗粒含量，计算出淀粉颗粒在软胶囊囊皮中质量的占比。
为了更好说明本申请的效果，采用以下软胶囊性能指标进行评价说明：
(1)成型
1)胶皮强度(F)和韧性指标(T)：采用物性测试仪，选择球形探头与穿刺模式，测试速度1.0mm/s，记录胶皮破裂力，破裂力越大，胶皮强度越好；胶皮破裂时对应的破裂距离(mm)，破裂距离越大，胶皮的韧性越好。
2)夹缝粘合指标：从胶囊在非夹缝上剪开，挤压排空内容物，然后保持与夹缝垂直从中间剪取一个含有两条夹缝的环圈，使环圈置于载玻片上，并使两条夹缝垂直载玻片，在显微镜下测量两条夹缝处的厚度及囊壳的厚度，计算最薄夹缝厚度占囊壳厚度的比值P(％)。
表1软胶囊胶皮强度、韧性和夹缝粘合指标评价标准
Figure PCTCN2021142080-appb-000001
软胶囊生产成型可行性以胶皮强度指标(F)、韧性指标(T)和夹缝粘 合指标(P)进行综合评价软胶囊生产可行性，其中综合评价是由胶皮强度占比20％，韧性指标占比20％，夹缝粘合占比60％，三者相加得到，综合评价总分5分，分数越高表示综合性能越好。胶皮强度、韧性两个指标分别≥3分且夹缝粘合指标≥2分，且综合评价必须≥2.4，才能满足软胶囊工业生产，三个指标综合评价总分5分，分数越高表示综合性能越好。
2.肠溶软胶囊崩解时限测定
对于本申请而言，软胶囊必须符合
1)按照USP<2040>膳食补充剂的崩解和溶解的规定，对缓释(肠溶衣)软胶囊进行崩解试验。也就是说，在模拟胃液中，软胶囊在胃液中保持至少60分钟崩解不破裂，随后不超过60分钟内在模拟肠液中崩解。
2)用欧洲药典，软胶囊中定义的崩解试验EP 2.9.1，在模拟胃液中，软胶囊在胃液中保持至少120分钟不破裂。随后不超过60分钟内在pH 6.8的磷酸盐缓冲溶液中崩解。
3.粘度测定
结冷胶是一种微生物代谢胶，不同的工艺条件生产出来的结冷胶的流变性质和凝胶性质存在差异。发明人将1.5wt％的结冷胶在90℃的水中溶解30min得到结冷胶溶液，通过采用旋转粘度计测试研究市售结冷胶的粘度：
结冷胶A(粘度η＝12.2mPa.s)
结冷胶B(粘度η＝30.8mPa.s)
结冷胶C(粘度η＝20.4mPa.s)
结冷胶D(粘度η＝48.8mPa.s)
结冷胶E(粘度η＝43.7mPa.s)
结冷胶F(粘度η＝52.8mPa.s)
结冷胶G(粘度η＝65.2mPa.s)
结冷胶H(粘度η＝7.8mPa.s)。
上述结冷胶均为单凝胶温度的结冷胶。
4.软胶囊制备的方法，包括：
1)溶胶：A)先将结冷胶和增塑剂预混分散均匀，搅拌下加入到适量水中，在60～98℃下加热搅拌至结冷胶溶解；若含有除结冷胶外的食用胶，则先将结冷胶、食用胶和增塑剂预混并且分散均匀，搅拌下加入到水中，在60～98℃下加热搅拌至结冷胶和食品胶溶解；B)加入淀粉，继续在60～98℃ 下加热搅拌至淀粉溶解；C)除去气泡即得胶液；
2)压丸：采用软胶囊生产线，将胶液输送至软胶囊填充机的胶盒中，胶液在转鼓表面上冷却形成胶皮，经封装填充物压制粘合成型，可进一步通过转笼定型。
3)干燥：将成型或定型后胶丸进行干燥，直至胶皮水分为8-25％。
实施例1-8
如表2中所述的成分和含量制备软胶囊，并且进行测试和评分。测定结果如表2中所示。
根据表2可知，实施例1-8采用特定粘度结冷胶与淀粉组合，形成的胶皮强度、韧性和成型粘合较好，而对照例1-2采用本发明的成膜组合物相同的组分含量，对照例1采用的粘度较高的结冷胶和淀粉组合时，形成的胶皮强度较弱、有一定韧性，但成型粘合一般；对照例2采用粘度较低的结冷胶和淀粉组合时，胶皮基本粘性大，韧性差，无法压制成型制成软胶囊。
实施例9-23
表3和表4中所述的成分和含量制备软胶囊，并且进行测试和评分。测定结果如表3和表4中所示。实施例9、实施例10以及上述实施例4制成的软胶囊均能够实现肠溶性效果。与实施例9相比，由于颗粒淀粉的添加，实施例10以及上述实施例4制成的软胶囊综合评价变得更好，但是当颗粒淀粉增加到3％时，制成的软胶囊在胃部崩解。因此，小于2％(例如1.7％)的交联淀粉，例如羟丙基二淀粉磷酸酯的添加在软胶囊综合评价和肠溶性上实现了出乎意料的效果。
Figure PCTCN2021142080-appb-000002
Figure PCTCN2021142080-appb-000003
Figure PCTCN2021142080-appb-000004
Figure PCTCN2021142080-appb-000005
Figure PCTCN2021142080-appb-000006
实施例9-23举例说明特定粘度的结冷胶与各类淀粉组合制备软胶囊，技术效果明显优于现有技术，并且能实现肠溶效果。
软胶囊囊皮中的淀粉颗粒大小可以通过偏光显微镜放大600倍观察得到。淀粉和结冷胶在溶胶过程中，淀粉在水介质中加热后，先通过吸水膨胀，某些淀粉颗粒进一步溶解，使得溶胀后的淀粉颗粒破碎后，形成更小的淀粉颗粒，进一步搅拌溶解，伴随着淀粉分子链段的分离和溶解，最终使得淀粉以溶液状态存在于胶液中。胶液在压丸机成型过程中先冷却后形成胶皮，其中淀粉在胶液中由相对自由的分子链段，在温度下降过程中迅速冷却，形成破碎淀粉或者与结冷胶分子链段形成互穿网络结构。如果在溶胶过程中，淀粉颗粒吸水溶胀后，由于淀粉自身的分子间作用力，使得淀粉无法进一步被溶胀、破碎，最后溶解，那么淀粉在胶液中将以溶胀的颗粒形式存在，此时淀粉颗粒在偏光显微镜下是无十字消光现象。此时的胶液在压丸机成型过程中冷却定型，淀粉在胶液中仍然以溶胀的颗粒形式存在于软胶囊的囊皮中，此时，结冷胶分子无法在淀粉颗粒内部贯穿，与淀粉分子链段形成互穿网络的结构。非包衣肠溶软胶囊在人工胃液中可以抵抗胃酸侵蚀的原因是：结冷胶分子链段在人工胃液环境中，盐酸中的氢离子、水分子可以与结冷胶双螺旋分子链上的羧酸根结合，形成氢键作用，使得整个双螺旋分子与隔壁的结冷胶双螺旋分子通过氢键作用交联起来形成网络结构。但是结冷胶和淀粉制备的软胶囊在水或者胃液崩解过程中，其会发生溶胀现象，体积增大2-5倍，并且，伴随着溶胀，溶胀后的软胶囊会变脆。淀粉颗粒在软胶囊囊皮的占比越小，结冷胶网络结构的强度越大，最终，结冷胶网络结构的结合力大于软胶囊溶胀变脆的破坏应力，使得软胶囊在胃液中保持不破裂。因此，当结冷胶双螺旋分子链交联反应产生的结合力大于溶胀变脆的破坏应力，则软胶囊在胃液中可以保持不破裂；当结冷胶双螺旋分子链交联反应产生的结合力小于溶胀变脆的破坏应力，则软胶囊在胃液中将会发生破裂，导致软胶囊无法实现肠溶效果。
实施例24-31
表5中所述的成分和含量制备软胶囊，并且进行测试和评分。测定结果如表5中所示。
Figure PCTCN2021142080-appb-000007
Figure PCTCN2021142080-appb-000008
实施例25-31采用特定粘度的结冷胶和羟丙基淀粉分别与琼脂、刺槐豆胶、瓜尔胶、魔芋胶、低酯果胶、酰胺果胶、卡拉胶、黄原胶组合制备软胶囊技术效果优于现有技术，并且能实现肠溶效果。
本申请的一种具有特定粘度的结冷胶和淀粉组合物，通过采用粘度的结冷胶，与淀粉组合控制在一定范围内，成型性能好，具有肠溶效果，完全满足软胶囊工业化生产要求，可以作为软胶囊技术的备选替代。
上述实施例为本申请较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本申请的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本申请的保护范围之内。

Claims (10)

  1. 软胶囊囊壳，其由成膜组合物制备，所述成膜组合物包含1.5-5wt％第一胶凝剂、30-40wt％淀粉、10-25wt％增塑剂和35-55wt％水，其中第一胶凝剂是具有以下性质的结冷胶：根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度，其中所述软胶囊囊壳包含0-3wt％淀粉颗粒，所述淀粉颗粒是平均粒径大小在10微米-50微米的淀粉颗粒；所述软胶囊囊壳是肠溶性的。
  2. 权利要求1的软胶囊囊壳，其中淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种，或者淀粉是(1)羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种和(2)不超过2wt％的酸处理淀粉、醋酸酯淀粉、羟丙基二淀粉磷酸酯、淀粉磷酸酯、乙酰化二淀粉磷酸酯、乙酰化氧化淀粉、乙酰化二淀粉己二酸酯或预胶化淀粉中的一种或多种。
  3. 权利要求1或2的软胶囊囊壳，其中结冷胶与淀粉的重量比为0.03-0.2。
  4. 权利要求1-3中任一项的软胶囊囊壳，其中增塑剂选自甘油、山梨糖醇、麦芽糖醇、赤藓糖醇、木糖醇、结晶果糖、海藻糖或葡萄糖中的一种或组合。
  5. 权利要求1-4中任一项的软胶囊囊壳，其中成膜组合物还包含第二胶凝剂，优选地，所述第二胶凝剂选自卡拉胶、琼脂、海藻酸钠、果胶、普鲁兰多糖、魔芋胶、黄原胶、刺槐豆胶、瓜尔胶、亚麻籽胶、可得然胶或罗望子胶中的一种或组合，优选地第二胶凝胶含量为0.2wt％-5wt％。
  6. 权利要求1-5中任一项的软胶囊囊壳，其中所述软胶囊囊壳通过如下的方法制备，所述方法包括a)将第一胶凝剂加入到增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至第一胶凝剂溶解；b)加入所述淀粉，并在60～98℃下加热搅拌至淀粉溶解；c)除去气泡即得胶液；和d)压丸和干燥。
  7. 权利要求6的软胶囊囊壳，其中所述a)还包括加入第二胶凝剂，所述a)为将所述第一胶凝剂和第二胶凝剂加入到所述增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至所述第一胶凝剂和第二胶凝剂溶解。
  8. 软胶囊，其包含权利要求1-7中任一项的软胶囊囊壳和填充物，优选地其中软胶囊是肠溶软胶囊，优选是不含肠溶性包衣的肠溶软胶囊。
  9. 根据权利要求1-7任一项所述的软胶囊囊壳或权利要求8的软胶囊在 食品、营养保健品和药品中的应用。
  10. 成膜组合物在制备肠溶性软胶囊囊壳中的用途，其中所述成膜组合物包含1.5-5wt％第一胶凝剂、30-40wt％淀粉、10-25wt％增塑剂和35-55wt％水，其中第一胶凝剂是具有以下性质的结冷胶：根据旋转粘度计测得，1.5wt％的结冷胶在90℃的水中溶解30分钟得到的结冷胶溶液具有范围为10-60mPa.s的粘度，其中所述肠溶性软胶囊囊壳包含0-3wt％淀粉颗粒，所述淀粉颗粒是平均粒径在10微米-50微米的淀粉颗粒；
    优选地其中淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种，或者淀粉是羟丙基淀粉、氧化淀粉或氧化羟丙基淀粉中的一种或多种和不超过2wt％的酸处理淀粉、醋酸酯淀粉、羟丙基二淀粉磷酸酯、淀粉磷酸酯、乙酰化二淀粉磷酸酯、乙酰化二淀粉己二酸酯、乙酰化氧化淀粉或预胶化淀粉中的一种或多种；
    优选地其中结冷胶与淀粉的重量比为0.03-0.2；
    优选地其中增塑剂选自甘油、山梨糖醇、麦芽糖醇、赤藓糖醇、木糖醇、结晶果糖、海藻糖或葡萄糖中的一种或组合；
    优选地其中成膜组合物还包含第二胶凝剂，优选地，所述第二胶凝剂选自卡拉胶、琼脂、海藻酸钠、果胶、普鲁兰多糖、魔芋胶、黄原胶、刺槐豆胶、瓜尔胶、亚麻籽胶、可得然胶或罗望子胶中的一种或组合，优选地第二胶凝胶含量为0.2wt％-5wt％；
    优选地其中所述软胶囊囊壳通过如下的方法制备，所述方法包括a)将第一胶凝剂加入到增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至第一胶凝剂溶解；b)加入所述淀粉，并在60～98℃下加热搅拌至淀粉溶解；c)除去气泡即得胶液；和d)压丸和干燥；
    优选地其中所述a)还包括加入第二胶凝剂，所述a)为将所述第一胶凝剂和第二胶凝剂加入到所述增塑剂中，搅拌均匀，再加入到水中，并在60～98℃下加热搅拌至所述第一胶凝剂和第二胶凝剂溶解。
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