CN111700873A - Plant-based soft capsule rubber, preparation method and application thereof - Google Patents
Plant-based soft capsule rubber, preparation method and application thereof Download PDFInfo
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- CN111700873A CN111700873A CN202010476242.3A CN202010476242A CN111700873A CN 111700873 A CN111700873 A CN 111700873A CN 202010476242 A CN202010476242 A CN 202010476242A CN 111700873 A CN111700873 A CN 111700873A
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- 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
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
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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
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Abstract
The invention relates to the technical field of soft capsule rubber materials, in particular to a plant-based soft capsule rubber, a preparation method and application thereof, wherein the plant-based soft capsule rubber comprises the following components: hydroxypropyl starch/lactic acid graft copolymer, cellulose/polylactic acid graft copolymer, plasticizer, gelling agent, edible pigment and water; wherein the substitution degree of the hydroxypropyl starch is not higher than 0.58, and the grafting ratio of lactic acid to the hydroxypropyl starch is 14-25%. The main material of the soft capsule rubber is derived from plants, the soft capsule rubber has extremely excellent disintegration time, is beneficial to the rapid release of the capsule in the organism, has excellent performances in the aspects of friability, disintegration time, tensile strength, elongation at break and the like, and is excellent in ageing resistance and remarkably prolonged in storage period.
Description
Technical Field
The invention relates to the technical field of soft capsule rubber materials, in particular to a plant-based soft capsule rubber, a preparation method and application thereof.
Background
The soft capsule is prepared by sealing a mixture of liquid or molten drugs containing a certain active ingredient, or a mixture of solution, suspension, emulsion or semisolid (paste) containing solid drugs dispersed and dissolved in the mixture, in a spherical or elliptical soft capsule shell. The soft capsule has the advantages that the embedded content is completely isolated from external factors such as air and the like, so that the active ingredients in the content are prevented from being damaged by the external factors; thus, 1) oily drugs, low melting point drugs; 2) drugs that are sensitive to light, unstable in heat and humidity, or easily oxidized; 3) drugs with unpleasant odor, and trace amounts of active drugs; 4) medicine with volatile components and easy to escape; 5) hydrophobic drugs with poor bioavailability such as cyclosporin can be encapsulated in soft capsules. Therefore, the soft capsule wall material, i.e. the capsule skin, of the soft capsule is generally prepared by singly or mixedly using gelatin, glycerin or other suitable pharmaceutical excipients for capsules.
The gelatin skin of the common soft capsule products at present takes gelatin as a main raw material, mainly comes from collagen parts in connective tissues such as animal skin, bones, sarcolemma and the like, and the gelatin commonly used in the food industry is from a large number of sources such as pigs and cattle. In recent years, the edible safety events of the capsule are frequently reported, and as industrial gelatin contains more heavy metal ions, the hazard is extremely high, and the low price of the industrial gelatin is often a way for the illegal trader to profit; the gelatin has the problem of cross-linking, so that the soft capsule is easy to become unstable, and the storage and transportation of the soft capsule product are influenced; meanwhile, due to the animal origin of gelatin, the soft capsule taking gelatin as the main component also does not meet the dietary habit and requirement of halal or vegetarian food connotation. For the above reasons, it is necessary to develop a novel vegetable rubber. In the capsule pharmaceutic adjuvant market, plant capsules are one of the fastest growing products, and the industry generally considers that only the replacement of gelatin capsules by plant-based capsules (Vegetable capsules) is the fundamental way to solve the chronic and stubborn problem of the capsules. Some hydrophilic high molecular food gums, such as gellan gum, carrageenan, xanthan gum, modified starch, etc., have been investigated as alternatives to preparing gelatin capsules. At present, the research on the vegetable soft capsule rubber is still relatively few, and although some patents have reported, the formulation still has the points of continuous improvement and perfection.
The above background disclosure is only for the purpose of assisting understanding of the inventive concept and technical solutions of the present invention, and does not necessarily belong to the prior art of the present patent application, and should not be used for evaluating the novelty and inventive step of the present application in the case that there is no clear evidence that the above content is disclosed at the filing date of the present patent application.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a plant-based soft capsule skin, which has a very excellent disintegration time limit, facilitates rapid release of the capsule in the body, has excellent performances in terms of friability, disintegration time, tensile strength, elongation at break, etc., and is excellent in aging resistance and significantly prolonged in storage life, and a main material of the soft capsule skin is derived from plants.
The invention also aims to provide a preparation method of the plant-based soft capsule rubber, which has the characteristics of simple process route, short production period, no pollution, low energy consumption, low cost and easy forming, the main material of the soft capsule rubber is derived from plants, and the soft capsule rubber has excellent performance and is suitable for large-scale popularization and production.
The invention also aims to provide the application of the plant-based soft capsule rubber in preparing the medical soft capsule.
In order to achieve the above object, the present invention provides the following means.
The subject is a plant-based soft capsule rubber, and the components and the weight contents of the soft capsule rubber comprise:
the degree of substitution of the hydroxypropyl starch is not higher than 0.58, and
the grafting rate of lactic acid to hydroxypropyl starch is 14-25%.
The soft capsule rubber is prepared by taking the hydroxypropyl starch/lactic acid graft copolymer and the cellulose/polylactic acid graft copolymer as main materials, the defects that a pin needs to be preheated, the drying temperature is high and the like in the production process of the traditional hydroxypropyl methylcellulose (HPMC) capsule are overcome, the viscosity and the gel property of a glue solution at a low temperature can be improved by the introduction of a small amount of lactic acid graft, the film forming property is good, the processing energy consumption is reduced, and an unexpected synergistic effect is obtained between the hydroxypropyl starch/lactic acid graft copolymer and the cellulose/polylactic acid graft copolymer, so that the soft capsule rubber has excellent performances in the aspects of friability, disintegration time, tensile strength, elongation at break and the like.
In some embodiments, the aforementioned hydroxypropyl starch/lactic acid graft copolymer is prepared via a process comprising:
1) adding hydroxypropyl starch into a sodium carbonate solution, heating for gelatinization, adding lactic acid, reducing the system pressure to be not higher than 0.1MPa, heating to 75-85 ℃, and reacting for 0.5-2 h;
2) step 1), cooling the system to room temperature, adding acetone, and obtaining a crude product after settling, suction filtration and drying;
3) taking acetone as an extraction solvent, placing the crude product obtained in the step 2) in a Soxhlet extractor for reflux extraction for at least 36h to remove the generated lactic acid homopolymer, and drying to obtain the lactic acid homopolymer.
In other embodiments, in step 1) of preparing the hydroxypropyl starch/lactic acid graft copolymer, the hydroxypropyl starch is one of hydroxypropyl corn starch, hydroxypropyl potato starch, hydroxypropyl tapioca starch and hydroxypropyl wheat starch, and the substitution degree of the hydroxypropyl is not higher than 0.58, preferably 0.3-0.5, more preferably 0.4-0.5, and most preferably 0.4. The inventor surprisingly found that the copolymer prepared by grafting hydroxypropyl starch with the degree of substitution of not more than 0.58 and lactic acid is selected relative to the unsubstituted or over-substituted hydroxypropyl starch, and the final product soft capsule rubber can obtain unusual tensile strength and elongation at break, has excellent anti-aging capability and obviously prolongs the storage life.
In other embodiments, in the step 1) of preparing the hydroxypropyl starch/lactic acid graft copolymer, the concentration of the sodium carbonate solution is 0.2-0.4 mol/L.
In other embodiments, in the step 1) of preparing the hydroxypropyl starch/lactic acid graft copolymer, the weight ratio of the hydroxypropyl starch to the sodium carbonate solution to the lactic acid is 1: 4.0-8.0: 4.0-4.5.
In other embodiments, in the step 1) of preparing the hydroxypropyl starch/lactic acid graft copolymer, the heating rate is 3-5 ℃/min, the gelatinization temperature is 65-70 ℃, and the gelatinization time is 45-60 min.
In other examples, the drying temperature in step 2) of preparing the hydroxypropyl starch/lactic acid graft copolymer is not higher than 50 ℃.
In other embodiments, in the step 3) of preparing the hydroxypropyl starch/lactic acid graft copolymer, the drying is performed in a forced air drying oven at 65-80 ℃ for at least 12 hours.
The hydroxypropyl starch/lactic acid graft copolymer prepared by the method has the advantages that the glass transition temperature of the copolymer is reduced compared with that of hydroxypropyl starch, the forming and processing performance of the copolymer is improved to a certain extent, the solubility of the copolymer is improved, the reaction condition is controlled to ensure that the grafting rate of lactic acid to hydroxypropyl starch is 14-25%, the final product soft capsule rubber has extremely excellent disintegration time limit, the capsule can be rapidly released in an organism, and a certain synergistic effect is obtained after the copolymer is blended with the cellulose/polylactic acid graft copolymer, so that the soft capsule rubber has excellent performances in the aspects of friability, tensile strength, elongation at break and the like.
In some embodiments, the cellulose/polylactic acid graft copolymer is prepared by a method comprising:
1) adding 1 part by weight of crushed cellulose into 90-100 parts by weight of potassium tert-butoxide/urea aqueous solution, stirring at a high speed for at least 10min to obtain gelatinous transparent slurry, adding a large amount of distilled water, stirring and dispersing, performing suction filtration, repeatedly washing to neutrality, and drying to obtain alkali-treated cellulose;
2) adding 0.5-0.8 part by weight of stannous octoate into 80-100 parts by weight of dehydrated lactic acid, heating to 125-130 ℃ under stirring, preserving heat for at least 1h, then heating to 175-180 ℃, reducing the system pressure to be not higher than 0.1MPa, and keeping for at least 30min to remove condensation water to generate lactide;
3) adding the alkali-treated cellulose obtained in the step 1) into the system obtained in the step 3), cooling to 125-130 ℃, maintaining the low pressure of the system, and stirring for reaction for at least 5 hours;
4) and 3) carrying out suction filtration on the product obtained in the step 3) by using a large amount of dichloromethane to remove the homopolymerized lactic acid, repeatedly washing and carrying out suction filtration for not less than 3 times, and drying to obtain the cellulose/polylactic acid graft copolymer.
In other embodiments, in the step 1) of preparing the cellulose/polylactic acid graft copolymer, the mass fraction of the tert-butyl potassium in the potassium tert-butoxide/urea aqueous solution is 0.25-0.5%, and the mass fraction of the urea is 8-10%.
In other embodiments, in the step 1) of preparing the cellulose/polylactic acid graft copolymer, the rotation speed of high-speed stirring is not lower than 6000 r/min.
In other examples, in the step 1) of preparing the cellulose/polylactic acid graft copolymer, the rotation speed for stirring and dispersing is not lower than 600 r/min.
In other examples, the drying temperature in step 1) of preparing the cellulose/polylactic acid graft copolymer is not higher than 70 ℃.
In other examples, in the step 2) of preparing the cellulose/polylactic acid graft copolymer, the stirring speed is not lower than 600 r/min.
In other embodiments, in the step 2) of preparing the cellulose/polylactic acid graft copolymer, the temperature rise rate is 3-5 ℃/min.
In other examples, in the step 3) of preparing the cellulose/polylactic acid graft copolymer, the stirring rate is not less than 600 r/min.
In other examples, in step 4 of preparing the cellulose/polylactic acid graft copolymer, drying refers to drying at a temperature of not higher than 70 ℃ to a constant weight.
According to the invention, the alkali treatment is firstly carried out on the cellulose by using the potassium tert-butoxide/urea aqueous solution, so that the crystallinity of the cellulose is reduced, the cellulose fiber is effectively swelled, the subsequent graft modification is more favorable than that of common alkali liquor such as sodium hydroxide, and the final soft capsule rubber property is enhanced; in the grafting process, the number of hydroxyl groups in the cellulose is reduced, and new-C-O appears, which indicates that polylactic acid is grafted on cellulose molecules, and the main body ring-packaged structure of the cellulose is not damaged, the surface energy of the cellulose can be reduced by the grafting modification, the wettability of the cellulose and starch is improved, the interface compatibility of two phases is further improved, and the grafting modification method is beneficial to improving the mechanical strength and toughness of the soft capsule rubber, enhancing the ageing resistance of the soft capsule rubber, prolonging the storage life of the soft capsule rubber, reducing the friability of the soft capsule rubber and the like.
In some embodiments, the plasticizer is at least one of glycerin, sorbitol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 800, polyethylene glycol 1000, propylene glycol, mannitol, or xylitol, preferably glycerin, polyethylene glycol 400, mannitol, or a mixture thereof.
In some embodiments, the gelling agent is at least one of carrageenan, gellan gum, sodium alginate, cyclodextrin, pectin, agar, gum arabic, konjac gum, or xanthan gum.
In some embodiments, the edible color described above is at least one of red yeast, chlorophyll, curcumin, carotene, caramel color food grade color, capsanthin food grade color, or annatto food grade color.
In some embodiments, the aforementioned water is purified water.
When the cellulose/polylactic acid graft copolymer is prepared, the viscosity and the gelling property of a glue solution at a low temperature can be improved by the grafting introduction of a small amount of lactic acid, the defects that a contact pin needs to be preheated in the production process of the traditional hydroxypropyl methylcellulose (HPMC) capsule, the drying temperature is high and the like are overcome, the film forming property is good, and the processing energy consumption is reduced; in addition, lactic acid grafted hydroxypropyl starch with specific substitution degree is favorable for reducing the glass transition temperature, improving the forming processing performance and simultaneously improving the solubility performance, the subject is to prepare the soft capsule rubber by taking hydroxypropyl starch/lactic acid grafted copolymer and cellulose/polylactic acid grafted copolymer as main materials, and the obtained soft capsule rubber has excellent performances in the aspects of friability, disintegration time, tensile strength, elongation at break and the like, and is excellent in ageing resistance and storage life is remarkably prolonged.
In a second aspect, the present invention provides a method for preparing a plant-based soft capsule skin, comprising the steps of:
1) adding the hydroxypropyl starch/lactic acid graft copolymer into water to disperse uniformly to obtain a solution I;
2) adding the other components except the hydroxypropyl starch/lactic acid graft copolymer into water for uniform dispersion and/or complete dissolution to obtain a solution II;
3) uniformly mixing the solution I and the solution II, heating to 70-75 ℃, stirring, keeping the temperature for at least 1h, then cooling to 55-60 ℃, keeping the temperature, standing and defoaming to obtain a glue solution;
4) and (4) determining that the defoamed glue solution meets the viscosity requirement, and then preparing the soft capsule rubber by the conventional soft capsule production method.
In some embodiments, in the step 3) for preparing the plant-based soft capsule skin, the temperature rising rate is 5-10 ℃/min.
In some embodiments, in the step 3) for preparing the plant-based soft capsule skin, the stirring speed is 180-300 r/min.
In some embodiments, in the step 4) for preparing the plant-based soft capsule skin, the viscosity requirement may be 15000 to 30000mpa · s.
The preparation method of the plant-based soft capsule rubber has the characteristics of simple process route, short production period, no pollution, low energy consumption, low cost and easiness in forming, the main material of the soft capsule rubber is derived from plants, and the prepared soft capsule rubber has good toughness and is not easy to break, has excellent performances in the aspects of friability, disintegration time, tensile strength, elongation at break and the like, and meanwhile, the storage life of the soft capsule rubber is remarkably prolonged, so that the preparation method is suitable for large-scale popularization and production.
Subject three, subject one or subject two stated above based on the application of the soft capsule rubber of plant in preparing the medical soft capsule.
The invention has the beneficial effects that:
1) compared with the non-substituted or over-substituted hydroxypropyl starch, the hydroxypropyl starch with the substitution degree not higher than 0.58 is selected to be grafted with the lactic acid to prepare the copolymer, and the final product soft capsule rubber can obtain unusual tensile strength and elongation at break, has excellent anti-aging capability and obviously prolongs the storage life;
2) the hydroxypropyl starch/lactic acid graft copolymer prepared by the method has the advantages that the glass transition temperature of the copolymer is reduced compared with that of hydroxypropyl starch, the forming and processing performance of the copolymer is improved to a certain extent, meanwhile, the solubility of the copolymer is improved, the reaction conditions are controlled, so that the grafting rate of lactic acid to hydroxypropyl starch is 14-25%, the final product soft capsule rubber has extremely excellent disintegration time limit, and the capsule is favorably and rapidly released in an organism;
3) the alkali treatment is carried out on the cellulose by using the potassium tert-butoxide/urea aqueous solution, which is beneficial to reducing the crystallinity of the cellulose, effectively moistens the cellulose fiber, is more beneficial to subsequent graft modification than common alkali liquor such as sodium hydroxide and gains the property of the final soft capsule rubber;
4) polylactic acid is grafted on cellulose molecules, and a main body ring-packed structure of cellulose is not damaged, so that the surface energy of the cellulose can be reduced through the grafting modification, the wettability of the cellulose and starch is improved, the interface compatibility of two phases is further improved, and the soft capsule rubber has benefits on improving the mechanical strength and toughness of the soft capsule rubber, enhancing the ageing resistance of the soft capsule rubber, prolonging the storage life of the soft capsule rubber, reducing the crushing catalysis of the soft capsule rubber and the like;
5) the hydroxypropyl starch/lactic acid graft copolymer and the cellulose/polylactic acid graft copolymer are used as main materials to prepare the soft capsule rubber, and the obtained soft capsule rubber has excellent performances in the aspects of friability, disintegration time, tensile strength, elongation at break and the like, and is excellent in ageing resistance and remarkably prolonged in storage life.
The invention adopts the technical scheme for achieving the purpose, makes up the defects of the prior art, and has reasonable design and convenient operation.
Drawings
The foregoing and/or other objects, features, advantages and embodiments of the invention will be more readily understood from the following description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a schematic view of the structural formula of a hydroxypropyl starch/lactic acid graft copolymer of the present invention;
FIG. 2 is a hydrogen spectrum of a hydroxypropyl starch/lactic acid graft copolymer according to example 1 of the present invention;
FIG. 3 is a graph showing the data of the grafting ratio of the hydroxypropyl starch/lactic acid graft copolymer of the present invention.
Detailed Description
Those skilled in the art can appropriately substitute and/or modify the process parameters to implement the present disclosure, but it is specifically noted that all similar substitutes and/or modifications will be apparent to those skilled in the art and are deemed to be included in the present invention. While the products and methods of making described herein have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the products and methods of making described herein may be made and utilized without departing from the spirit and scope of the invention.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The present invention uses the methods and materials described herein; other suitable methods and materials known in the art may be used. The materials, methods, and examples described herein are illustrative only and are not intended to be limiting. All publications, patent applications, patents, provisional applications, database entries, and other references mentioned herein, and the like, are incorporated by reference herein in their entirety. In case of conflict, the present specification, including definitions, will control.
All percentages, parts, ratios, etc., are by weight unless otherwise indicated; additional instructions include, but are not limited to, "wt%" means weight percent, "mol%" means mole percent, "vol%" means volume percent.
When an amount, concentration, or other value or parameter is given as either a range, preferred range or a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when a range of "1 to 5(1 to 5)" is described, the described range is understood to include ranges of "1 to 4(1 to 4)", "1 to 3(1 to 3)", "1 to 2(1 to 2) and 4 to 5(4 to 5)", "1 to 3(1 to 3) and 5", and the like. Where numerical ranges are described herein, unless otherwise stated, the ranges are intended to include the endpoints of the ranges, and all integers and fractions within the ranges.
When the term "about" is used to describe a numerical value or an end point value of a range, the disclosure should be understood to include the specific value or end point referred to.
Furthermore, "or" means "or" unless expressly indicated to the contrary, rather than "or" exclusively. For example, condition a "or" B "applies to any of the following conditions: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), and both a and B are true (or present).
In addition, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to mean no limitation on the number of occurrences (i.e., occurrences) of the element or component. Thus, "a" or "an" should be understood to include one or at least one and the singular forms of an element or component also include the plural unless the singular is explicitly stated.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation. The use of the phrase "comprising one of the elements does not exclude the presence of other like elements in the process, method, article, or apparatus that comprises the element.
The materials, methods, and examples described herein are illustrative only and not intended to be limiting unless otherwise specified. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.
The present invention is described in detail below.
Example 1: a plant-based soft capsule shell:
the embodiment provides a plant-based soft capsule rubber, which comprises the following specific components in percentage by weight:
the degree of substitution of the hydroxypropyl starch is 0.4, and
the graft ratio of lactic acid to hydroxypropyl starch was 21%.
The soft capsule rubber is prepared by a method comprising the following steps:
1) preparation of hydroxypropyl starch/lactic acid graft copolymer:
1.1) adding 10g of hydroxypropyl corn starch into 75g of 0.25mol/L sodium carbonate solution, heating to 68 ℃ at a speed of 4 ℃/min, gelatinizing for 45min, adding 40g of lactic acid, reducing the system pressure to 0.1MPa, heating to 80 ℃, and reacting for 1 h;
1.2) cooling the system in the step 1.1) to room temperature, adding acetone, settling, filtering and drying at 50 ℃ to obtain a crude product;
1.3) taking acetone as an extraction solvent, placing the crude product obtained in the step 1.2) in a Soxhlet extractor for reflux extraction for 36h to remove the generated lactic acid homopolymer, and drying in a forced air drying oven at 70 ℃ for 12h to obtain the lactic acid homopolymer.
2) Preparation of cellulose/polylactic acid graft copolymer:
2.1) adding 1 part by weight of crushed cellulose into 99 parts by weight of potassium tert-butoxide/urea aqueous solution (the mass fraction of the tert-butyl potassium is 0.4 percent, and the mass fraction of the urea is 8.6 percent), stirring at a high speed of 7200r/min for 10min to obtain gelatinous transparent slurry, adding a large amount of distilled water, stirring and dispersing at 1200r/min, repeatedly washing to neutrality after suction filtration, and drying at 60 ℃ to obtain alkali-treated cellulose;
2.2) adding 0.5 weight part of stannous octoate into 85 weight parts of dehydrated lactic acid, heating to 125 ℃ at a speed of 5 ℃/min under stirring at 600r/min, preserving heat for 1h, then heating to 175 ℃, reducing the system pressure to 0.1MPa, and keeping for 30min to remove condensed water to generate lactide;
2.3) adding the alkali-treated cellulose obtained in the step 2.1) into the system obtained in the step 2.3), cooling to 125 ℃, maintaining the low pressure of the system, and stirring at 600r/min for reaction for 5 hours;
2.4) carrying out suction filtration on the product obtained in the step 2.3) by using a large amount of dichloromethane to remove the homopolymerized lactic acid, repeatedly washing, carrying out suction filtration for 5 times, and drying to obtain the cellulose/polylactic acid graft copolymer.
3) Preparing a soft capsule rubber:
3.1) adding the hydroxypropyl starch/lactic acid graft copolymer into water to disperse uniformly to obtain a solution I;
3.2) adding the other components except the hydroxypropyl starch/lactic acid graft copolymer into water for uniform dispersion and/or complete dissolution to obtain a solution II;
3.3) uniformly mixing the solution I and the solution II, heating to 70-75 ℃, stirring, keeping the temperature for at least 1h, then cooling to 55-60 ℃, keeping the temperature, standing and defoaming to obtain a glue solution;
3.4) determining that the defoamed glue solution meets the viscosity requirement, and then preparing the soft capsule rubber with the thickness of 0.1mm by the conventional soft capsule production method.
Example 2: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin, which has substantially the same components, formulation and preparation method as example 1, except that cellulose is used to replace the cellulose/polylactic acid graft copolymer in the components of this example, i.e., the cellulose is used to prepare the soft capsule skin without polylactic acid graft modification.
Example 3: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin, which has substantially the same components, formulation, and preparation method as example 1, except that no cellulose/polylactic acid graft copolymer is added to the components of this example.
Example 4: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin having substantially the same composition, formulation, and preparation method as example 1, except that the hydroxypropyl starch/lactic acid graft copolymer was replaced with common corn starch.
Example 5: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin having substantially the same composition, formulation and preparation method as in example 1, except that hydroxypropyl corn starch having a degree of substitution of 0.4 was used in place of the hydroxypropyl starch/lactic acid graft copolymer in the composition of this example.
Example 6: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin having substantially the same composition, formulation and preparation method as in example 1, except that in this example, the substitution degree of hydroxypropyl starch is 0.3 when preparing the hydroxypropyl starch/lactic acid graft copolymer.
Example 7: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin having substantially the same composition, formulation and preparation method as in example 1, except that in this example, the substitution degree of hydroxypropyl starch is 0.7 when preparing a hydroxypropyl starch/lactic acid graft copolymer.
Example 8: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin having substantially the same composition, formulation and preparation method as in example 1, except that in this example, the substitution degree of hydroxypropyl starch is 1.5 when preparing a hydroxypropyl starch/lactic acid graft copolymer.
Example 9: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin having substantially the same composition, formulation and preparation method as in example 1, except that in this example, the sodium carbonate solution was replaced with 0.25mol/L sodium hydroxide solution when the hydroxypropyl starch/lactic acid graft copolymer was prepared.
Example 10: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin, which has substantially the same composition, formulation and preparation method as example 1, except that in this example, the amount of lactic acid added is 10g when preparing the hydroxypropyl starch/lactic acid graft copolymer.
Example 11: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin, which has substantially the same composition, formulation and preparation method as example 1, except that in this example, the amount of lactic acid added is 100g when preparing the hydroxypropyl starch/lactic acid graft copolymer.
Example 12: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin, which has substantially the same components, formulation and preparation method as example 1, except that in this example, sodium hydroxide was used instead of potassium tert-butoxide in the preparation of the cellulose/polylactic acid graft copolymer.
Example 13: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin, which has substantially the same components, formulation and preparation method as example 1, except that in this example, sodium carbonate was used instead of potassium tert-butoxide in the preparation of the cellulose/polylactic acid graft copolymer.
Example 14: another plant-based soft capsule shell:
this example provides another plant-based soft capsule skin, which has substantially the same components, formulation and preparation method as example 1, except that in this example, the step 2.3) is performed to prepare the cellulose/polylactic acid graft copolymer without removing the homopolylactic acid, i.e., the homopolylactic acid is used as the graft copolymer for preparing the cellulose/polylactic acid to prepare the soft capsule skin.
Experimental example 1: and (3) detecting the grafting rate of the hydroxypropyl starch/lactic acid graft copolymer:
the graft ratio of lactic acid to hydroxypropyl starch (GD/%) in the hydroxypropyl starch/lactic acid graft copolymer was calculated by the following formula (1),
in the formula (1), m1Is the mass (g), m of the purified hydroxypropyl starch/lactic acid graft copolymer0Is the mass (g) of the original hydroxypropyl starch. The statistical data according to the above-mentioned detection of the graft ratio of each hydroxypropyl starch/lactic acid graft copolymer in examples 1 and 6 to 11 are shown in FIG. 3.
As can be seen from fig. 3, the hydroxypropyl starch/lactic acid graft copolymers in examples 1 and 6 have a suitable graft ratio (14-25%) in the present application, while selecting high substitution hydroxypropyl starch, replacing sodium carbonate solution with sodium hydroxide solution, and increasing or decreasing the addition amount of lactic acid will change the graft ratio of lactic acid to different extents, and the too high or too low graft ratio will affect the performance of the final soft capsule shell.
Experimental example 2: and (3) mechanical property detection:
with each soft capsule rubber sample in examples 1 to 14 as a detection object, a test system of an Instron model 1122 is adopted, and a sample to be tested is placed in a constant temperature and humidity box (the temperature is 23 ℃, and the relative humidity is 50%) to be balanced for 5 hours and is tested according to the GB/T13735-1992. The test results are shown in table 1.
TABLE 1 mechanical properties
| Examples | Tensile strength/MPa | Elongation at break/% | Examples | Tensile strength/MPa | Elongation at break/% |
| 1 | 3.22 | 126.81 | 8 | 1.82 | 105.51 |
| 2 | 1.81 | 99.28 | 9 | 2.68 | 115.14 |
| 3 | 1.05 | 76.62 | 10 | 1.95 | 108.30 |
| 4 | 1.37 | 89.85 | 11 | 1.93 | 102.05 |
| 5 | 1.26 | 92.07 | 12 | 2.82 | 116.39 |
| 6 | 3.48 | 125.04 | 13 | 2.79 | 118.08 |
| 7 | 2.09 | 102.69 | 14 | 2.85 | 118.48 |
As can be seen from table 1 above, the soft capsule shells of preferred examples 1 and 6 of the present application have excellent tensile strength and elongation at break, and it can be seen that the mechanical strength of the final soft capsule shell is not affected to a certain extent by not adding or modifying cellulose, replacing hydroxypropyl starch/lactic acid graft copolymer with hydroxypropyl substituted or unsubstituted corn starch, preparing graft copolymer with hydroxypropyl corn starch with higher degree of substitution, too little or too much grafting amount of lactic acid, and the like.
Experimental example 3: and (3) detecting the capsulicity:
the encapsulation test was carried out on each of the plant-based soft capsule shells of examples 1 to 14 according to the following methods, respectively:
a disintegration time: the disintegration time of the soft capsule rubber is tested by a method for checking the disintegration time limit of an empty capsule in 'Chinese pharmacopoeia' 2015 edition, which comprises the following steps: filling the soft capsule rubber with talcum powder to prepare the capsule, adding a baffle for inspection according to the method under the disintegration time limit inspection method capsule item, and measuring the disintegration time of the capsule;
b, loss on drying: the drying weight loss of the soft capsule rubber is tested by a drying weight loss inspection method of an empty capsule in 'Chinese pharmacopoeia' 2015 edition, which comprises the following steps: drying the soft capsule rubber at 105 ℃ for 6h, weighing, and calculating the water loss weight, wherein the water loss percentage is the drying weight loss;
c, friability: the friability rate of the soft capsule rubber is tested by a method for inspecting friability of empty capsules in 'Chinese pharmacopoeia' 2015 edition, and specifically comprises the following steps: taking 50 soft capsules, placing the soft capsules in a watch glass, placing the soft capsules in a dryer filled with a saturated solution of magnesium nitrate, keeping the temperature at 25 +/-1 ℃ for 24 hours, taking out the soft capsules, immediately placing the soft capsules one by one in a glass tube (the inner diameter is 24mm, the length is 200mm) erected on a wood plate (the thickness is 2cm), freely dropping cylindrical weights (the material is polytetrafluoroethylene, the diameter is 22mm, and the weight is 20g +/-0. lg) from the opening of the glass tube, and observing the number of broken capsules. The statistical results are shown in table 2.
TABLE 2 Encapsulated Properties
As can be seen from table 2, the soft capsules in preferred examples 1 and 6 of the present application have excellent dry weight loss and friability data, and have extremely rapid disintegration time limit, which is beneficial to rapid release of the capsules in the body, and it can be seen that the disintegration time, dry weight loss and friability of the soft capsules are significantly affected by not adding the cellulose/polylactic acid graft copolymer, replacing the hydroxypropyl starch/lactic acid graft copolymer with common corn starch, and if the graft ratio of the hydroxypropyl starch/lactic acid graft copolymer is too high or low, and it can be seen that the dry weight loss of the material is greatly affected by not removing the lactic acid homopolymerization in the cellulose/polylactic acid graft copolymer.
Experimental example 4: and (3) detecting the anti-aging capacity:
the soft capsules in the examples 1 to 14 are respectively stored in a heart-shaped bottle seal at normal temperature and normal humidity, the detection shows that the shelf life of each soft capsule in the examples 1 and 6 reaches more than 18 months, the shelf life of the soft capsules of examples 9-11 is also more than 12 months, while the shelf life of each of the capsules of examples 2-8 and examples 12-14 is between 6-12 months, the storage performance is not good, which shows that the hydroxypropyl starch/lactic acid graft copolymer and the cellulose/polylactic acid graft copolymer are taken as main materials to be beneficial to exerting the synergistic effect thereof to jointly improve the anti-aging capability of the soft capsule rubber, and the anti-aging performance of the final product soft capsule rubber can be influenced by changing the substitution degree of the hydroxypropyl starch and replacing potassium tert-butoxide with other inorganic salts or inorganic alkali liquids, and the excessive homopolymerized lactic acid in the cellulose/polylactic acid graft copolymer has no benefit on the anti-aging performance.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
In view of the numerous embodiments of the present invention, the experimental data of each embodiment is huge and is not suitable for being listed and explained herein one by one, but the contents to be verified and the final conclusions obtained by each embodiment are close. Therefore, the contents of the verification of the respective examples are not described herein, and the excellent points of the present invention will be described only by representative examples 1 to 14 and experimental examples 1 to 4.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
While the above detailed description has shown, described, and pointed out novel features as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the device or method illustrated may be made without departing from the spirit of the disclosure. In addition, the various features and methods described above may be used independently of one another, or may be combined in various ways. All possible combinations and sub-combinations are intended to fall within the scope of the present disclosure. Many of the embodiments described above include similar components, and thus, these similar components are interchangeable in different embodiments. While the invention has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and obvious modifications and equivalents thereof. Accordingly, the invention is not intended to be limited by the specific disclosure of preferred embodiments herein.
Claims (10)
1. A plant-based soft capsule rubber is characterized in that the soft capsule rubber comprises the following components in parts by weight:
the degree of substitution of the hydroxypropyl starch is not higher than 0.58, and
the grafting rate of lactic acid to hydroxypropyl starch is 14-25%.
2. The soft capsule rubber of claim 1, characterized in that: the hydroxypropyl starch/lactic acid graft copolymer is prepared by a method comprising the following steps:
1) adding hydroxypropyl starch into a sodium carbonate solution, heating for gelatinization, adding lactic acid, reducing the system pressure to be not higher than 0.1MPa, heating to 75-85 ℃, and reacting for 0.5-2 h;
2) step 1), cooling the system to room temperature, adding acetone, and obtaining a crude product after settling, suction filtration and drying;
3) taking acetone as an extraction solvent, placing the crude product obtained in the step 2) in a Soxhlet extractor for reflux extraction for at least 36h to remove the generated lactic acid homopolymer, and drying to obtain the lactic acid homopolymer.
3. The soft capsule shell according to claim 1 or 2, characterized in that: the hydroxypropyl degree of substitution of the hydroxypropyl starch is not higher than 0.58, and the degree of substitution is preferably 0.3-0.5, more preferably 0.4-0.5, and most preferably 0.4.
4. The soft capsule rubber according to any one of claims 1 to 3, characterized in that: in the step 1) of preparing the hydroxypropyl starch/lactic acid graft copolymer, the weight ratio of the hydroxypropyl starch to the sodium carbonate solution to the lactic acid is 1: 4.0-8.0: 4.0-4.5.
5. The soft capsule rubber according to any one of claims 1 to 4, characterized in that: the cellulose/polylactic acid graft copolymer is prepared by a method comprising the following steps:
1) adding 1 part by weight of crushed cellulose into 90-100 parts by weight of potassium tert-butoxide/urea aqueous solution, stirring at a high speed for at least 10min to obtain gelatinous transparent slurry, adding a large amount of distilled water, stirring and dispersing, performing suction filtration, repeatedly washing to neutrality, and drying to obtain alkali-treated cellulose;
2) adding 0.5-0.8 part by weight of stannous octoate into 80-100 parts by weight of dehydrated lactic acid, heating to 125-130 ℃ under stirring, preserving heat for at least 1h, then heating to 175-180 ℃, reducing the system pressure to be not higher than 0.1MPa, and keeping for at least 30min to remove condensation water to generate lactide;
3) adding the alkali-treated cellulose obtained in the step 1) into the system obtained in the step 3), cooling to 125-130 ℃, maintaining the low pressure of the system, and stirring for reaction for at least 5 hours;
4) and 3) carrying out suction filtration on the product obtained in the step 3) by using a large amount of dichloromethane to remove the homopolymerized lactic acid, repeatedly washing and carrying out suction filtration for not less than 3 times, and drying to obtain the cellulose/polylactic acid graft copolymer.
6. The soft capsule rubber of claim 5, characterized in that: in the step 1) of preparing the cellulose/polylactic acid graft copolymer, the mass fraction of tert-butyl potassium in a potassium tert-butoxide/urea aqueous solution is 0.25-0.5%, and the mass fraction of urea is 8-10%.
7. The soft capsule rubber according to any one of claims 1 to 6, characterized in that: the plasticizer is at least one of glycerol, sorbitol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 800, polyethylene glycol 1000, propylene glycol, mannitol or xylitol, preferably glycerol, polyethylene glycol 400, mannitol or a mixture thereof.
8. The method for preparing the plant-based soft capsule rubber of any one of claims 1 to 7, characterized by comprising the following steps:
1) adding the hydroxypropyl starch/lactic acid graft copolymer into water to disperse uniformly to obtain a solution I;
2) adding the other components except the hydroxypropyl starch/lactic acid graft copolymer into water for uniform dispersion and/or complete dissolution to obtain a solution II;
3) uniformly mixing the solution I and the solution II, heating to 70-75 ℃, stirring, keeping the temperature for at least 1h, then cooling to 55-60 ℃, keeping the temperature, standing and defoaming to obtain a glue solution;
4) and (4) determining that the defoamed glue solution meets the viscosity requirement, and then preparing the soft capsule rubber by the conventional soft capsule production method.
9. The method of claim 8, wherein: the viscosity requirement can be 15000-30000 mpa · s.
10. Use of the plant-based softgel capsule skin according to any one of claims 1 to 9 for the preparation of soft medical capsules.
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