A granule and an acidic food product comprising the granule

Abstract

The present invention relates to a granule and an acidic food containing the granule, particularly a granule containing an active substance, the granule comprising microcrystalline cellulose having a degree of polymerization of 200 to 300, and a filler. The stability of the active substance in the granule of the present invention is improved, or the yield of the granule is improved.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of pharmaceutical and food technology, in particular to a granule and an acidic food product comprising said granule. BACKGROUND

[0002] Microencapsulation is a new technology that uses natural or synthetic polymer materials as microcapsule wall materials to encapsulate solid or liquid pharmaceuticals, food and chemical raw materials as core materials to produce micron or nanometer particle products. It has been applied in many fields such as medicine, food, fine chemicals, etc. The prepared granules can be used in the field of food and medicine, especially in acidic food such as gummy candies (soft candies) etc. Vitamin soft candies are deeply recognized and loved by consumers for their pleasant taste and good appearance. However, the products containing heat-labile and acid-labile vitamins, such as vitamin B5 (calcium pantothenate), vitamin B9 (folic acid), vitamin B12, vitamin A, vitamin D, etc., have poor stability, especially in acidic food (pH 3 to pH 4). For example, for many vitamin soft candies (pH 3 to pH 4), after 40°C and 75% RH acceleration for three months, the retention rate of calcium pantothenate is about 16%, the retention rate of folic acid is about 33%, the retention rate of vitamin B12 is about 50%, the retention rate of vitamin A is about 50%, and the retention rate of vitamin D3 is about 30%.

[0003] In addition, the yield of vitamin granules with fine particle size (e.g. particle size 0.15 mm to 0.30 mm) is low, for example less than 45%.

[0004] There is still a need to improve the stability of granules containing unstable active substances. There is also a need to improve the yield of granules. SUMMARY

[0005] It is an object of the present invention to improve the yield of granules.

[0006] It is another object of the present invention to improve the stability of granules containing unstable active substances.

[0007] The present invention provides a granule comprising an active substance, said granule comprising microcrystalline cellulose having a degree of polymerization of 200 to 300, and a filler.

[0008] The present invention also provides an acidic food product comprising said granule, said acidic food product having a pH of preferably 3 to 4.

[0009] This invention produces the following advantageous effects: improved stability of active substances in the granules, or improved granule yield. For example, the yield of fine-sized granules (0.15 mm to 0.30 mm in diameter) can be greater than 90%. For example, the encapsulation efficiency of active substances is improved, such as the encapsulation efficiency of calcium pantothenate, which is improved from 28% to 98%. It also improves the retention rate of active substances (e.g., previously unstable vitamins) in acidic foods (pH 3 to pH 4). For example, after three months of accelerated treatment at 40°C and 75% RH, the retention rate of calcium pantothenate increased from 16% to 76%, folic acid from 33% to 85%, VB12 from 50% to 80%, vitamin A from 50% to 80%, and vitamin D3 from 30% to 85%. Detailed Implementation

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the definition herein shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used to practice or test the invention. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0011] All numerical ranges covered in this disclosure should be understood as disclosing all specific numerical values ​​within that range, as well as any sub-ranges defined by any two numerical values ​​within that range. For example, for 1-20, it should be understood as disclosing specific numerical values ​​such as 1, 2, 3, 3.5, 4.5, 10, 12, 15, and 20, as well as sub-ranges such as 1-5, 2-6, 3.5-7.5, and 15-20.

[0012] The term "parts" refers to "parts by weight". The percentage weight and parts by weight are calculated on a dry weight basis.

[0013] This invention relates to particles comprising an active substance (especially a heat- and / or acid-labile active substance, such as vitamins), said particles comprising microcrystalline cellulose with a degree of polymerization of 200 to 300, and a filler. The microcrystalline cellulose can be used as an excipient. For example, the yield of fine-sized particles (0.15 mm to 0.30 mm in diameter) can be greater than 90%.

[0014] In one aspect, the weight ratio of the microcrystalline cellulose to the filler is from 1.5:1 to 2.6:1.

[0015] In one aspect, the filler is selected from starch or dicalcium phosphate.

[0016] In one aspect, the particles are coated with a layer containing sodium alginate or a layer containing shellac.

[0017] Shellac, also known as lac, is a red substance secreted by lac insects that parasitize the branches of leguminous plants and suck sap. As a natural resin, shellac's main components are shellac resin, shellac wax, shellac pigments, sugars, and proteins.

[0018] Sodium alginate is a natural high-molecular-weight biomaterial extracted from brown algae such as kelp or Sargassum. It is also known as sodium alginate, alginate, and alginate gum. It can undergo cross-linking reactions with most polyvalent cations to form gels or precipitation reactions.

[0019] In one aspect, the particles are coated with at least one layer containing sodium alginate and at least one layer containing shellac.

[0020] In one aspect, the particles are sequentially coated with at least one layer containing sodium alginate, at least one layer containing shellac, and at least one layer containing sodium alginate. For example, the first layer, containing sodium alginate, has a coating thickness increase of ≥5%; the second layer, containing shellac, has a coating thickness increase of ≥15%; the third layer, containing sodium alginate, has a coating thickness increase of ≥5%; and the total coating thickness increase is ≤50%.

[0021] In one aspect, the active substance is selected from vitamins, preferably vitamin B5, vitamin B9, vitamin B12, vitamin A, or vitamin D.

[0022] In one aspect, the particle size of the uncoated particles is from 0.15 mm to 0.30 mm.

[0023] In one aspect, the uncoated particles contain 35% to 65% microcrystalline cellulose, 10% to 40% active material, and 15% to 40% starch or dicalcium phosphate.

[0024] For example, the exemplary composition of the particles is as follows:

[0025] A. Granule formulation before coating

[0026] Microcrystalline cellulose 35%–65%

[0027] Vitamin B5 / Folic Acid / Vitamin B12 / Vitamin A / Vitamin D 10%–40%

[0028] Starch or dicalcium phosphate 15%–40%

[0029] Water appropriate amount

[0030] B. Granule Coating Formula

[0031]

[0032] The present invention also relates to an acidic food comprising the aforementioned granules, wherein the pH of the gummies is preferably 3 to 4, and the acidic food includes, for example, gummies, jellies, and beverages.

[0033] The granules and acidic foods of this invention can be prepared using conventional methods. For example, the components are added to a wet granulator and mixed, an appropriate amount of water is added to obtain a soft mass, and then the soft mass is subjected to one or more of the following steps: extrusion, spheroidization, drying, and sieving to obtain the target granules. Further, for example, the granules can be placed in a fluidized bed and bottom-spray coated sequentially with a layer containing sodium alginate, a layer containing shellac, and another layer containing sodium alginate, and then sieved to obtain coated granules. The coated granules can be used in the production of acidic foods.

[0034] Example

[0035] Degree of polymerization

[0036] Refer to the degree of polymerization (P) method in the Chinese Pharmacopoeia for microcrystalline cellulose.

[0037] Particle size

[0038] Please refer to the corresponding pharmacopoeia sieve aperture (compliant with national standard R40 / 3 series), i.e., particle size of 150μm to 300μm.

[0039] Method for measuring yield

[0040] The granules were sieved through a pharmacopoeia sieve (compliant with national standard R40 / 3 series) (using sieves with apertures of 300μm and 150μm respectively), and weighed to obtain the granule yield.

[0041] Method for measuring encapsulation efficiency and retention efficiency

[0042] I. Encapsulation rate

[0043] Methods for using Vitamin B5:

[0044] Principle: First, determine the total vitamin B5 content of the granules, then determine the amount of unencapsulated vitamin B5. This yields the amount of encapsulated vitamin B5.

[0045] (1) Determination of total content: Referring to the second method of GB 5009.210, after the particles are finely ground to remove the encapsulation, they are extracted with water under ultrasonic oscillation. After filtration through a 0.45μm microporous membrane, the filtrate is separated by a C18 reversed-phase chromatographic column and detected at a wavelength of 200nm. The qualitative analysis is based on the retention time of the chromatographic peak and the ultraviolet spectrum, and the quantitative analysis is based on the external standard method. The vitamin B5 content in the sample is calculated.

[0046] (2) Determination of unencapsulated amount: The particles were quantitatively added to water, vortexed for extraction, filtered through a 0.45μm microporous membrane, and the filtrate was tested according to the content method.

[0047] Methods for obtaining folic acid:

[0048] Principle: First, the total folic acid content of the granules is determined, and then the amount of unencapsulated folic acid is determined. The encapsulated folic acid content is then obtained.

[0049] (1) Determination of total content: Referring to the method of folic acid tablets in the Chinese Pharmacopoeia, after the granules were finely ground to remove the encapsulation, they were extracted by heating with alkaline solvent. After filtration through a 0.45μm microporous membrane, the filtrate was separated by a C18 reversed-phase chromatographic column and detected at a wavelength of 270nm. The retention time of the chromatographic peak was used for qualitative analysis, and the peak area was used for quantitative analysis. The folic acid content in the sample was calculated by the external standard method.

[0050] (2) Determination of unencapsulated amount: The particles were quantitatively added to water, vortexed for extraction, filtered through a 0.45μm microporous membrane, and the filtrate was tested according to the content method.

[0051] The formula for calculating the encapsulation ratio is as follows:

[0052] Encapsulation efficiency % = (Content of encapsulated active ingredient in microparticles) / (Content of encapsulated and unencapsulated active ingredient in microparticles) x 100%

[0053] II. Retention Rate

[0054] Methods for using Vitamin B5:

[0055] Referring to Method II of GB 5009.210, the gummies were treated by heating and grinding to break the encapsulation, extracted with hot water under ultrasonic oscillation, filtered through a 0.45μm microporous membrane, and the filtrate was separated by a C18 reversed-phase chromatographic column and detected at a wavelength of 200nm. The qualitative analysis was based on the retention time of the chromatographic peak and the ultraviolet spectrum, and the quantitative analysis was based on the external standard method. The vitamin B5 content in the sample was then calculated.

[0056] Methods for obtaining folic acid:

[0057] Referring to the folic acid tablet method in the Chinese Pharmacopoeia, the gummies were treated by heating and grinding to break the encapsulation, and then extracted by heating after adding an alkaline solvent. After filtration through a 0.45μm microporous membrane, the filtrate was separated by a C18 reversed-phase chromatographic column and detected at a wavelength of 270nm. The chromatographic peak retention time was used for qualitative analysis, and the peak area was used for quantitative analysis. The folic acid content in the sample was calculated by the external standard method.

[0058] The formula for calculating the retention rate is as follows:

[0059] Retention rate % = (Active ingredient content of the gummies after 3 months of accelerated processing) / (Active ingredient content detected in the gummies at month 0) x 100%

[0060] Acceleration conditions:

[0061] The acceleration conditions for the gummy candy were 40℃±2℃ and relative humidity 75%±5%.

[0062] Example

[0063] Examples 1-22: Particle yield determination

[0064] Table 1

[0065]

[0066] Table 2

[0067]

[0068]

[0069] Table 3

[0070]

[0071] Table 4

[0072]

[0073] By using microcrystalline cellulose with a specific degree of polymerization of 200–300 and combining it with specific fillers such as starch or dicalcium phosphate within a specific ratio range (excipient:filler = 1.5:1–2.6:1), the yield of fine-grained vitamin B5 granules is higher compared to combinations outside this range. High yields are also achieved when using other vitamins such as folic acid.

[0074] Examples 23-47: Determination of Encapsulation and Retention Rates

[0075] The obtained vitamin granules were mixed with edible gum, white sugar, and starch syrup to prepare gel candies (soft candies), and the vitamin retention rate was determined. The process steps for preparing vitamin soft candies were: sol-gelling, sugar dissolving, boiling, mixing (adding vitamin granules), drying, and polishing. The vitamin encapsulation rate of the prepared granules and the vitamin retention rate of the soft candies after three months of accelerated processing (accelerated conditions: 40℃±2℃, relative humidity 75%±5%) were determined.

[0076] Table 5

[0077]

[0078] Even with a significant increase in the thickness of sodium alginate or shellac, the VB5 retention rate of single-layer granule coating did not improve significantly, and the retention rate of gummies was less than 25% after three months of accelerated treatment.

[0079] Table 6

[0080]

[0081] Double-layer granule coating and changing the order of coating materials have some effect, increasing VB5 retention to up to 45%, but it is still relatively low.

[0082] Table 7

[0083]

[0084]

[0085] Three layers of shellac coating can increase the retention rate of VB5 by about 55%; with the third layer of coating, after the shellac weight increases to 5%, the retention rate increases to 76.5%, but with further weight increase, the retention rate hardly changes.

[0086] Table 8

[0087]

[0088] The three-layer coating of the granules can significantly improve the retention rate of folic acid, accelerating the retention rate to approximately 85% by 3 months.

[0089] Table 9

[0090]

[0091] The three-layer granule coating significantly improves the retention rate of VB12, accelerating the retention rate to 81% in 3 months.

[0092] Table 10

[0093]

[0094] The three-layer granule coating significantly improves the retention rate of vitamin A, accelerating the retention rate to 82% in 3 months.

[0095] Table 11

[0096]

[0097] The three-layer granule coating significantly improves the retention rate of vitamin D, accelerating the retention rate to 85% in 3 months.

[0098] While certain features of the invention have been set forth and described herein, many modifications, substitutions, alterations, and equivalents will occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and alterations falling within the true spirit and scope of the invention.

Claims

1. A granule comprising an active substance, the granule comprising microcrystalline cellulose having a degree of polymerization of 200 to 300, and a filler, wherein the weight ratio of the microcrystalline cellulose to the filler is 1.5:1 to 2.6:1, the filler being selected from starch or calcium hydrogen phosphate, the granule being coated with a first layer, a second layer, and a third layer in this order, the first layer comprising sodium alginate, the coating weight gain thickness being > 5%; the second layer comprising shellac, the coating weight gain thickness being > 15%; the third layer comprising sodium alginate, the coating weight gain thickness being > 5%; and the total coating weight gain thickness being < 50%, wherein the granule, when uncoated, comprises 35% to 65% of the microcrystalline cellulose, 10% to 40% of the active substance, and 15% to 40% of the starch or calcium hydrogen phosphate.

2. The granule according to claim 1, wherein the active substance is selected from vitamins.

3. The granule according to claim 1, wherein the active substance is selected from vitamin B5, vitamin B9, vitamin B12, vitamin A, or vitamin D.

4. The granule according to claim 1, wherein the particle size of the granule, when uncoated, is 0.15 mm to 0.30 mm.

5. An acidic food product comprising the granule according to any one of claims 1 to 4.

6. The acidic food product according to claim 5, wherein the pH of the acidic food product is 3 to 4.

7. The acidic food product according to claim 5, wherein the acidic food product is a gummy, a jelly, or a drink.

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