US20200407763A1 - Method for the production of pullulan soft capsules - Google Patents
Method for the production of pullulan soft capsules Download PDFInfo
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- US20200407763A1 US20200407763A1 US16/453,111 US201916453111A US2020407763A1 US 20200407763 A1 US20200407763 A1 US 20200407763A1 US 201916453111 A US201916453111 A US 201916453111A US 2020407763 A1 US2020407763 A1 US 2020407763A1
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- US
- United States
- Prior art keywords
- pullulan
- fermentation liquor
- soft capsule
- gel
- production
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Links
- 229920001218 Pullulan Polymers 0.000 title claims abstract description 70
- 239000004373 Pullulan Substances 0.000 title claims abstract description 70
- 235000019423 pullulan Nutrition 0.000 title claims abstract description 70
- 239000007901 soft capsule Substances 0.000 title claims abstract description 60
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 32
- 238000000855 fermentation Methods 0.000 claims abstract description 59
- 230000004151 fermentation Effects 0.000 claims abstract description 59
- 239000000499 gel Substances 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000003860 storage Methods 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 10
- 239000004014 plasticizer Substances 0.000 claims description 10
- 241000223678 Aureobasidium pullulans Species 0.000 claims description 9
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- 239000002775 capsule Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000005086 pumping Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003230 hygroscopic agent Substances 0.000 claims description 5
- 238000005342 ion exchange Methods 0.000 claims description 5
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- 239000007787 solid Substances 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 4
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- RLMLFADXHJLPSQ-NPPFTVEMSA-N (3s,6s,9s,12s,15s,18s,21s,24r,27s)-3,6-dibenzyl-12,24-bis[(2r)-butan-2-yl]-15-(2-hydroxypropan-2-yl)-4,10,16,22-tetramethyl-18-(2-methylpropyl)-9,21-di(propan-2-yl)-13-oxa-1,4,7,10,16,19,22,25-octazabicyclo[25.3.0]triacontane-2,5,8,11,14,17,20,23,26-nonon Chemical compound C([C@H]1C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(N(C)[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@H](C(=O)O[C@H](C(=O)N(C)[C@@H](C(C)C)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N1C)[C@H](C)CC)C(C)(C)O)=O)[C@H](C)CC)C1=CC=CC=C1 RLMLFADXHJLPSQ-NPPFTVEMSA-N 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 108010008887 aureobasidin A Proteins 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds
- C12P19/10—Pullulan
-
- 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
-
- 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
- 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
- A61K9/4883—Capsule finishing, e.g. dyeing, aromatising, polishing
Definitions
- Embodiments of the invention relates generally to capsule production methods. More particularly, the invention relates to a method for the production of soft capsules formed from pullulan, from raw material to final product.
- Pullulan is a polysaccharide polymer of a maltotriose trimer made up of ⁇ -(1 ⁇ 6)-linked (1 ⁇ 4)- ⁇ -d-triglucosides, also known as ⁇ -1,4- ⁇ -1,6-glucan. Three glucose units in maltotriose are connected by an ⁇ -1,4 glycosidic bond, whereas consecutive maltotriose units are connected to each other by an ⁇ -1,6 glycosidic bond. Pullulan is produced from starch by the fungus Aureobasidium pullulans.
- Pullulan is a natural raw material of vegetable capsules with excellent film-forming property, water solubility, biological compatibility, and degradability.
- the production level of this product is low worldwide.
- the drying process has high requirements on equipment and the energy consumption is large. If the fermentation can't match with the drying production capacity, it can seriously restrict the pullulan production capacity, thus finally restrains the application of pullulan soft capsules.
- pullulan is produced by mesophilic fermentation of starch syrup by the selected non-toxigenic strain of Aureobasidium pullulans .
- the strain is selected by traditional techniques, i.e. the strain is not the product of genetic modification using recombinant technologies.
- the production strain has a high yield of pullulan, low production of melanin and does not produce aureobasidin A.
- the fungal cells are removed by microfiltration.
- the cell-free filtrate is heat-sterilized and treated with activated carbon to remove pigments and other impurities by adsorption.
- the decolorized filtrate is cooled and deionized using cation and anion exchange resins.
- the deionized solution is concentrated to a solids content of about 12%, treated a second time with activated carbon, and filtered using diatomaceous earth as a filter aid.
- the filtrate is concentrated by evaporation to a solids content of about 30% and dried in a drum dryer.
- the dried pullulan is pulverized to a specified particle size and packed in sterilized polyethylene bags.
- the raw material of produced pullulan soft capsules is pullulan dried product, which is the purified fermentation fluid made in the drying process.
- pullulan dried product is the purified fermentation fluid made in the drying process.
- microwave drying would make the pullulan film distorted, while both the spray drying and microwave drying would both result in the browning of the raw pullulan material. Therefore, the drying process during the preparation of pullulan raw material reduces its quality and affects the pullulan soft capsules.
- one aspect is to reduce the impact of low raw material quality on soft capsule preparation of pullulan soft capsules by eliminating the separate drying process, which determines the quality of pullulan formed by conventional methods.
- another purpose is to reduce the equipment cost and energy consumption in the drying process by linking pullulan raw material production with soft capsule production.
- the purified pullulan fermentation fluid can be directly used in soft capsule preparation, thus removing the need for a separate melting process.
- these improvements may decrease material consumption, save the cost of equipment and labor, reduce production time and increase productivity.
- these improvements may reduce the fluctuating of raw material quality in the re-melting process and guarantee a more stable soft capsule production and quality.
- Embodiments of the present invention provide a method for the production of a pullulan soft capsule comprising fermenting cells to produce a pullulan fermentation liquor; filtering the fermentation liquor; concentrating the fermentation liquor; transferring the concentrated fermentation liquor into a gel storage tank having a temperature control function; pumping the concentrated fermentation liquor from the gel storage tank into a reaction tank; adding gelatin and plasticizer to the reaction tank with the concentrated fermentation liquor; and forming the pullulan soft capsule with a soft capsule making machine.
- Embodiments of the present invention further provide a method for the production of a pullulan soft capsule comprising fermenting Aureobasidium pullulans to produce a pullulan fermentation liquor; filtering the fermentation liquor through at least one of a plate and frame press filter and an ion exchange column; concentrating the fermentation liquor; transferring the concentrated fermentation liquor into a gel storage tank maintaining a temperature from about 50° C. to about 90° C.; pumping the concentrated fermentation liquor from the gel storage tank into a reaction tank; adding a gelatinizer and a plasticizer to the reaction tank to form a soft capsule gel liquid; and forming the pullulan soft capsule with a soft capsule making machine with the soft capsule gel liquid.
- Embodiments of the present invention also provide a pullulan soft capsule produced by a process comprising fermenting Aureobasidium pullulans to produce a pullulan fermentation liquor; filtering the fermentation liquor; concentrating the fermentation liquor; transferring the concentrated fermentation liquor into a gel storage tank having a temperature control function; pumping the concentrated fermentation liquor from the gel storage tank into a reaction tank; adding gelatin and plasticizer to the reaction tank with the concentrated fermentation liquor; and forming the pullulan soft capsule with a soft capsule making machine.
- FIG. illustrates a flow chart schematically showing a method for the production of pullulan soft capsules according to an exemplary embodiment of the present invention.
- a commercial implementation in accordance with the spirit and teachings of the present invention may be configured according to the needs of the particular application, whereby any aspect(s), feature(s), function(s), result(s), component(s), approach(es), or step(s) of the teachings related to any described embodiment of the present invention may be suitably omitted, included, adapted, mixed and matched, or improved and/or optimized by those skilled in the art, using their average skills and known techniques, to achieve the desired implementation that addresses the needs of the particular application.
- embodiments of the present invention provide methods for the production of pullulan soft capsules that eliminates the need to dry pullulan solid product, thereby reducing the equipment cost and energy consumption.
- the pullulan raw material production can be linked directly with the soft capsule production to provide a unique approach for soft capsule formation.
- the purified pullulan fermentation fluid can be directly used in soft capsule preparation, thus removing the need for a melting process.
- the method can decrease material consumption, save the cost of equipment and labor, reduce production time and increase productivity.
- the method can reduce the fluctuating of raw material quality in the re-melting process and guarantee a more stable soft capsule production and quality.
- Aureobasidium pullulans can be fermented and produced at room temperature and atmospheric pressure.
- the fermentation of Aureobasidium pullulans may be performed by known techniques. Its raw materials include sucrose or glucose, some of which can be used for the growing consumption of microbial cells, and the rest can turn into polysaccharose.
- Raw material and water may be placed proportionally into the seed tank and provided with a sterilization treatment.
- the temperature can be controlled at about 26-30° C.
- Bacteria can be added to cultivate for 20-22 h, so as to provide sufficient quantity of liquid for the fermentation tank to produce bacteria.
- Raw material and nutritive material may be placed proportionally into the fermentation tank. Purified water may then be added. After sterilization, the fermentation liquor may then be added. The temperature is typically controlled at about 26-30° C. The resulting mixture is stirred and cultivated for about 65-75 h. After that, pullulan fermentation liquor will be obtained.
- the plate and frame press filter may then be used to filter and substantially remove the bacteria in the fermentation liquor.
- the resulting fermentation liquor may be poured into resin column for ion exchange, so as to substantially remove the small amount of small protein and salt content therefrom.
- the inlet valve of the filter system can maintain a working pressure of about 0.5 MPA.
- purified water can be used to backwash the filter system and the liquor may be concentrated.
- the mass fraction of the concentrated liquor can be controlled to about 6-58 (w/w) percent.
- the concentrated liquor may be transferred into a gel storage tank, which has a temperature control function, so that the liquor will be immersed in the tank at about 50-90° C.
- the concentrated liquor can then be pumped into the reaction tank.
- Gelatinizers, plasticizers, moisturizing agents and anti-hygroscopic agents may be added to the reaction tank at ambient pressure with an agitation speed of about 40-60 r/min.
- the gelatinizer may be various compounds known in the art.
- the genatinizer may be gelatin, gellan gum, high acyl gellan gum, or the like.
- the gelatin may be obtained from various sources, such as through a partial hydrolysis of collagen, derived, for example, from animal bones, skin or connective tissues.
- the gelatinizer may have a gelatin strength (bloom) between 150 and 200 and a viscosity range from about 25 to 45 milli poise, for example.
- the plasticizer may be present to make the soft capsule elastic and pliable.
- Some of the most common plasticizers include sorbitol and glycerin.
- the moisturizing agent can be any moisturizing agent known in the capsule formation arts, including, for example, methylglycine-proline.
- the anti-hygroscopic agent can be any anti-hygroscopic agent known in the capsule formation arts, including, for example, one or combination of stearic acid and lauric acid.
- the resulting mixture can be stirred until a first dispersion is formed, keeping the gel solution at a temperature of 70-90° C. for 2-8 h and vacuuming for 20-40 min.
- the gel solution can then be cooled to a temperature of about 35-75° C.
- the gel solution can be pelleted with a soft capsule making machine, to obtain a soft capsule formed with pullulan polysaccharide.
- the soft capsule making machine can produce a thin gelatin ribbon that can be used to with an encapsulation machine to create a soft capsule containing an appropriate fill material, such as a pharmaceutical preparation.
- the soft capsule making machine as described herein may take various forms, including those that are typically used in the art to make conventional soft capsules. The specifics for each of these machines may vary, where the present invention provides a concentrated pullulan liquor that can be used, with gelatinizers and plasticizers, for example, to create a desired soft capsule.
- Embodiments of the present invention provide a novel method for the production of pullulan capsules that does not require a drying or melting step, as is performed in conventional methods.
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Abstract
Description
- Embodiments of the invention relates generally to capsule production methods. More particularly, the invention relates to a method for the production of soft capsules formed from pullulan, from raw material to final product.
- The following background information may present examples of specific aspects of the prior art (e.g., without limitation, approaches, facts, or common wisdom) that, while expected to be helpful to further educate the reader as to additional aspects of the prior art, is not to be construed as limiting the present invention, or any embodiments thereof, to anything stated or implied therein or inferred thereupon.
- Pullulan is a polysaccharide polymer of a maltotriose trimer made up of α-(1→6)-linked (1→4)-α-d-triglucosides, also known as α-1,4-α-1,6-glucan. Three glucose units in maltotriose are connected by an α-1,4 glycosidic bond, whereas consecutive maltotriose units are connected to each other by an α-1,6 glycosidic bond. Pullulan is produced from starch by the fungus Aureobasidium pullulans.
- Pullulan is a natural raw material of vegetable capsules with excellent film-forming property, water solubility, biological compatibility, and degradability. However, the production level of this product is low worldwide. In the production of pullulan, the drying process has high requirements on equipment and the energy consumption is large. If the fermentation can't match with the drying production capacity, it can seriously restrict the pullulan production capacity, thus finally restrains the application of pullulan soft capsules.
- Conventionally, pullulan is produced by mesophilic fermentation of starch syrup by the selected non-toxigenic strain of Aureobasidium pullulans. The strain is selected by traditional techniques, i.e. the strain is not the product of genetic modification using recombinant technologies. The production strain has a high yield of pullulan, low production of melanin and does not produce aureobasidin A.
- After completion of the fermentation, the fungal cells are removed by microfiltration. The cell-free filtrate is heat-sterilized and treated with activated carbon to remove pigments and other impurities by adsorption. The decolorized filtrate is cooled and deionized using cation and anion exchange resins. The deionized solution is concentrated to a solids content of about 12%, treated a second time with activated carbon, and filtered using diatomaceous earth as a filter aid. The filtrate is concentrated by evaporation to a solids content of about 30% and dried in a drum dryer. The dried pullulan is pulverized to a specified particle size and packed in sterilized polyethylene bags.
- Currently, the raw material of produced pullulan soft capsules is pullulan dried product, which is the purified fermentation fluid made in the drying process. A study found that microwave drying would make the pullulan film distorted, while both the spray drying and microwave drying would both result in the browning of the raw pullulan material. Therefore, the drying process during the preparation of pullulan raw material reduces its quality and affects the pullulan soft capsules.
- In view of the foregoing, there is a need for alternative processes for the production of pullulan soft capsules that addresses the problems outlines above in the conventional methods of pullulan drying.
- In some embodiments of the present invention, one aspect is to reduce the impact of low raw material quality on soft capsule preparation of pullulan soft capsules by eliminating the separate drying process, which determines the quality of pullulan formed by conventional methods.
- In some embodiments of the present invention, another purpose is to reduce the equipment cost and energy consumption in the drying process by linking pullulan raw material production with soft capsule production. At the same time, by process improvements, the purified pullulan fermentation fluid can be directly used in soft capsule preparation, thus removing the need for a separate melting process. On the one hand, these improvements may decrease material consumption, save the cost of equipment and labor, reduce production time and increase productivity. On the other hand, these improvements may reduce the fluctuating of raw material quality in the re-melting process and guarantee a more stable soft capsule production and quality.
- Embodiments of the present invention provide a method for the production of a pullulan soft capsule comprising fermenting cells to produce a pullulan fermentation liquor; filtering the fermentation liquor; concentrating the fermentation liquor; transferring the concentrated fermentation liquor into a gel storage tank having a temperature control function; pumping the concentrated fermentation liquor from the gel storage tank into a reaction tank; adding gelatin and plasticizer to the reaction tank with the concentrated fermentation liquor; and forming the pullulan soft capsule with a soft capsule making machine.
- Embodiments of the present invention further provide a method for the production of a pullulan soft capsule comprising fermenting Aureobasidium pullulans to produce a pullulan fermentation liquor; filtering the fermentation liquor through at least one of a plate and frame press filter and an ion exchange column; concentrating the fermentation liquor; transferring the concentrated fermentation liquor into a gel storage tank maintaining a temperature from about 50° C. to about 90° C.; pumping the concentrated fermentation liquor from the gel storage tank into a reaction tank; adding a gelatinizer and a plasticizer to the reaction tank to form a soft capsule gel liquid; and forming the pullulan soft capsule with a soft capsule making machine with the soft capsule gel liquid.
- Embodiments of the present invention also provide a pullulan soft capsule produced by a process comprising fermenting Aureobasidium pullulans to produce a pullulan fermentation liquor; filtering the fermentation liquor; concentrating the fermentation liquor; transferring the concentrated fermentation liquor into a gel storage tank having a temperature control function; pumping the concentrated fermentation liquor from the gel storage tank into a reaction tank; adding gelatin and plasticizer to the reaction tank with the concentrated fermentation liquor; and forming the pullulan soft capsule with a soft capsule making machine.
- These and other features, aspects and advantages of the present invention will become better understood with reference to the following drawings, description and claims.
- Some embodiments of the present invention are illustrated as an example and are not limited by the figures of the accompanying drawings, in which like references may indicate similar elements.
- The FIG. illustrates a flow chart schematically showing a method for the production of pullulan soft capsules according to an exemplary embodiment of the present invention.
- Unless otherwise indicated illustrations in the figures are not necessarily drawn to scale.
- The invention and its various embodiments can now be better understood by turning to the following detailed description wherein illustrated embodiments are described. It is to be expressly understood that the illustrated embodiments are set forth as examples and not by way of limitations on the invention as ultimately defined in the claims.
- The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well as the singular forms, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof.
- Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one having ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
- In describing the invention, it will be understood that a number of techniques and steps are disclosed. Each of these has individual benefit and each can also be used in conjunction with one or more, or in some cases all, of the other disclosed techniques. Accordingly, for the sake of clarity, this description will refrain from repeating every possible combination of the individual steps in an unnecessary fashion. Nevertheless, the specification and claims should be read with the understanding that such combinations are entirely within the scope of the invention and the claims.
- In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be evident, however, to one skilled in the art that the present invention may be practiced without these specific details.
- The present disclosure is to be considered as an exemplification of the invention and is not intended to limit the invention to the specific embodiments illustrated by the figures or description below.
- As is well known to those skilled in the art, many careful considerations and compromises typically must be made when designing for the optimal configuration of a commercial implementation of any system, and in particular, the embodiments of the present invention. A commercial implementation in accordance with the spirit and teachings of the present invention may be configured according to the needs of the particular application, whereby any aspect(s), feature(s), function(s), result(s), component(s), approach(es), or step(s) of the teachings related to any described embodiment of the present invention may be suitably omitted, included, adapted, mixed and matched, or improved and/or optimized by those skilled in the art, using their average skills and known techniques, to achieve the desired implementation that addresses the needs of the particular application.
- Broadly, embodiments of the present invention provide methods for the production of pullulan soft capsules that eliminates the need to dry pullulan solid product, thereby reducing the equipment cost and energy consumption. The pullulan raw material production can be linked directly with the soft capsule production to provide a unique approach for soft capsule formation. The purified pullulan fermentation fluid can be directly used in soft capsule preparation, thus removing the need for a melting process. On the one hand, the method can decrease material consumption, save the cost of equipment and labor, reduce production time and increase productivity. On the other hand, the method can reduce the fluctuating of raw material quality in the re-melting process and guarantee a more stable soft capsule production and quality.
- Referring now to the FIG., Aureobasidium pullulans can be fermented and produced at room temperature and atmospheric pressure. The fermentation of Aureobasidium pullulans may be performed by known techniques. Its raw materials include sucrose or glucose, some of which can be used for the growing consumption of microbial cells, and the rest can turn into polysaccharose.
- Raw material and water may be placed proportionally into the seed tank and provided with a sterilization treatment. The temperature can be controlled at about 26-30° C. Bacteria can be added to cultivate for 20-22 h, so as to provide sufficient quantity of liquid for the fermentation tank to produce bacteria.
- Raw material and nutritive material may be placed proportionally into the fermentation tank. Purified water may then be added. After sterilization, the fermentation liquor may then be added. The temperature is typically controlled at about 26-30° C. The resulting mixture is stirred and cultivated for about 65-75 h. After that, pullulan fermentation liquor will be obtained.
- The plate and frame press filter may then be used to filter and substantially remove the bacteria in the fermentation liquor.
- The resulting fermentation liquor may be poured into resin column for ion exchange, so as to substantially remove the small amount of small protein and salt content therefrom.
- The inlet valve of the filter system can maintain a working pressure of about 0.5 MPA. During the process, purified water can be used to backwash the filter system and the liquor may be concentrated. According to the setting, the mass fraction of the concentrated liquor can be controlled to about 6-58 (w/w) percent.
- The concentrated liquor may be transferred into a gel storage tank, which has a temperature control function, so that the liquor will be immersed in the tank at about 50-90° C.
- The concentrated liquor can then be pumped into the reaction tank. Gelatinizers, plasticizers, moisturizing agents and anti-hygroscopic agents may be added to the reaction tank at ambient pressure with an agitation speed of about 40-60 r/min.
- The gelatinizer may be various compounds known in the art. For example, the genatinizer may be gelatin, gellan gum, high acyl gellan gum, or the like. The gelatin may be obtained from various sources, such as through a partial hydrolysis of collagen, derived, for example, from animal bones, skin or connective tissues. In some embodiments, the gelatinizer may have a gelatin strength (bloom) between 150 and 200 and a viscosity range from about 25 to 45 milli poise, for example.
- The plasticizer may be present to make the soft capsule elastic and pliable. Some of the most common plasticizers include sorbitol and glycerin.
- The moisturizing agent can be any moisturizing agent known in the capsule formation arts, including, for example, methylglycine-proline.
- The anti-hygroscopic agent can be any anti-hygroscopic agent known in the capsule formation arts, including, for example, one or combination of stearic acid and lauric acid.
- The resulting mixture can be stirred until a first dispersion is formed, keeping the gel solution at a temperature of 70-90° C. for 2-8 h and vacuuming for 20-40 min.
- The gel solution can then be cooled to a temperature of about 35-75° C. The gel solution can be pelleted with a soft capsule making machine, to obtain a soft capsule formed with pullulan polysaccharide.
- In some embodiments, the soft capsule making machine can produce a thin gelatin ribbon that can be used to with an encapsulation machine to create a soft capsule containing an appropriate fill material, such as a pharmaceutical preparation. The soft capsule making machine as described herein may take various forms, including those that are typically used in the art to make conventional soft capsules. The specifics for each of these machines may vary, where the present invention provides a concentrated pullulan liquor that can be used, with gelatinizers and plasticizers, for example, to create a desired soft capsule.
- Many of the above described steps may be performed using equipment that is known in the art. For example, ion exchange resins and filtration devices for processing pullulan are known in the art. Embodiments of the present invention provide a novel method for the production of pullulan capsules that does not require a drying or melting step, as is performed in conventional methods.
- All the features disclosed in this specification, including any accompanying abstract and drawings, may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.
- Claim elements and steps herein may have been numbered and/or lettered solely as an aid in readability and understanding. Any such numbering and lettering in itself is not intended to and should not be taken to indicate the ordering of elements and/or steps in the claims.
- Many alterations and modifications may be made by those having ordinary skill in the art without departing from the spirit and scope of the invention. Therefore, it must be understood that the illustrated embodiments have been set forth only for the purposes of examples and that they should not be taken as limiting the invention as defined by the following claims. For example, notwithstanding the fact that the elements of a claim are set forth below in a certain combination, it must be expressly understood that the invention includes other combinations of fewer, more or different ones of the disclosed elements.
- The words used in this specification to describe the invention and its various embodiments are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification the generic structure, material or acts of which they represent a single species.
- The definitions of the words or elements of the following claims are, therefore, defined in this specification to not only include the combination of elements which are literally set forth. In this sense it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements in the claims below or that a single element may be substituted for two or more elements in a claim. Although elements may be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements from a claimed combination can in some cases be excised from the combination and that the claimed combination may be directed to a subcombination or variation of a sub combination.
- Insubstantial changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalently within the scope of the claims. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements.
- The claims are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted and also what incorporates the essential idea of the invention.
Claims (18)
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US16/453,111 US10894971B1 (en) | 2019-06-26 | 2019-06-26 | Method for the production of pullulan soft capsules |
EP20832120.8A EP3989910A4 (en) | 2019-06-26 | 2020-06-03 | Method for the production of pullulan soft capsules |
CN202080019822.8A CN113543762A (en) | 2019-06-26 | 2020-06-03 | Method for producing soft pulullan capsule |
PCT/US2020/035909 WO2020263519A1 (en) | 2019-06-26 | 2020-06-03 | Method for the production of pullulan soft capsules |
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US16/453,111 US10894971B1 (en) | 2019-06-26 | 2019-06-26 | Method for the production of pullulan soft capsules |
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US20200407763A1 true US20200407763A1 (en) | 2020-12-31 |
US10894971B1 US10894971B1 (en) | 2021-01-19 |
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CN1106448C (en) | 1997-11-05 | 2003-04-23 | 中国科学院微生物研究所 | Tech. and process for extracting pullulan from fermentation liquor |
EP1398346B1 (en) * | 2001-04-26 | 2012-03-07 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Molded object having high pullulan content, process for producing the same |
JP4132767B2 (en) | 2001-07-19 | 2008-08-13 | 株式会社林原生物化学研究所 | Pullulan-containing powder, its production method and use |
FR2848473B1 (en) * | 2002-12-16 | 2008-04-11 | Laurence Paris | VISCOUS, AQUEOUS OR HYDRO ALCOHOLIC COMPOSITIONS, TAMPONED OR NOT, FOR THE MANUFACTURE OF SOFT CAPSULES, AND PROCESS FOR PRODUCING FILMS THEREFROM |
EP1593376A1 (en) * | 2004-05-04 | 2005-11-09 | Warner-Lambert Company LLC | Improved pullulan capsules |
EP1762232A1 (en) * | 2005-09-09 | 2007-03-14 | Warner-Lambert Company LLC | Liquid filled delivery system, preferably an HPMC capsule filled with glycerol |
CN100465191C (en) * | 2006-11-03 | 2009-03-04 | 天津市工业微生物研究所 | Drying method of bearing blue polysaccharide |
US8900629B2 (en) | 2007-04-05 | 2014-12-02 | University Of Kansas | Rapidly dissolving pharmaceutical compositions comprising pullulan |
JP5572086B2 (en) * | 2008-04-02 | 2014-08-13 | 株式会社林原 | Soft capsule film and soft capsule |
US20110171281A1 (en) * | 2010-01-14 | 2011-07-14 | Karl Wei Cao | Soft capsule composition and method of use |
KR20170001712A (en) * | 2010-06-17 | 2017-01-04 | 가부시기가이샤하야시바라 | Pullulan-containing powder, method for producing same and use thereof |
CN102813275B (en) * | 2011-06-10 | 2015-09-30 | 杭州养生堂保健品有限公司 | A kind of masticatory pattern soft capsule skin and masticatory pattern soft capsule |
CN102586088B (en) | 2011-09-18 | 2013-04-24 | 淮北市三和诺生物工程有限责任公司 | Sterile ultrafiltration concentration enzymic preparation fermentation liquid post-extraction production line |
CN103172757B (en) * | 2012-12-31 | 2015-01-14 | 天津北洋百川生物技术有限公司 | Extracting process of pulullan polysaccharide |
CN106109437B (en) * | 2016-07-13 | 2020-02-18 | 江苏力凡胶囊有限公司 | Film forming composition, soft and hard capsules prepared based on film forming composition and preparation method of soft and hard capsules |
US10350568B2 (en) | 2016-05-19 | 2019-07-16 | Jiangsu Lefan Capsule Co., Ltd. | Membrane-forming composition, soft and hard capsules prepared based on this composition and the preparation methods |
CN110678170A (en) | 2017-04-14 | 2020-01-10 | 比利时胶囊公司 | Pullulan polysaccharide capsule |
CN107890519A (en) * | 2017-10-17 | 2018-04-10 | 浙江济公缘药业有限公司 | A kind of dendrobium candidum soft capsule and preparation method thereof |
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WO2020263519A1 (en) | 2020-12-30 |
EP3989910A1 (en) | 2022-05-04 |
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