Sugar-free isatis root granules and preparation method thereof

Abstract

The invention relates to sugar-free isatis root granules and a preparation method thereof, mannitol is adopted as a filling agent, and the sugar-free isatis root granules with smaller hygroscopicity and higher active ingredient content are obtained by combining a belt drying technology of premixing part of the filling agent. Wherein the isatis root granules comprise isatis root fluid extract and mannitol, and the ratio of the isatis root fluid extract to the mannitol is 1: 1-1: 1.2; premixing the isatis root fluid extract with 15-30% of mannitol, and carrying out vacuum belt drying to obtain mixed dry extract powder; and mixing the mixed dry paste powder with the residual mannitol, and carrying out dry granulation to obtain the sugar-free isatis root granules. The invention provides the sugar-free isatis root granules without monosaccharide and disaccharide, the isatis root granules are more suitable for diabetics to take, and the medication advantages of the isatis root granules as an OTC medicine in the patients are better exerted.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicines, and in particular to sugar-free Radix Isatidis granules and a preparation method thereof. Background Art

[0002] Isatis root is the dried root of the cruciferous plant Isatis indigotica, which has the effects of clearing away heat and detoxifying, cooling blood and relieving sore throat. It is used for epidemic diseases, fever and sore throat, fever and toxic spots, mumps, sore throat, big head plague, erysipelas, and carbuncle. The excipients of Isatis granules sold on the market contain monosaccharides and / or disaccharides, including sucrose, dextrin and other ingredients. Even sugar-free Isatis granules contain dextrin, which is not a true sugar-free type. Moreover, the instructions for Isatis granules currently sold on the market clearly stipulate that diabetic patients should take them under the guidance of a physician, and the advantages of Isatis granules as OTC drugs in such patients cannot be brought into play. Some preparation methods of sugar-free Isatis are also disclosed in the prior art.

[0003] "Preparation Process of Sugar-free Radix Isatidis Granules" (China Journal of Traditional Chinese Medicine, 1992, 17 (01): 33-34) adopts pretreatment of Radix Isatidis medicinal materials, directly extracts with water, eliminates the "alcohol precipitation" operation process, and obtains sugar-free Radix Isatidis Granules without adding sucrose. At present, the extraction method of Radix Isatidis is clearly recorded in the statutory standard of "Chinese Pharmacopoeia" (2020 edition), that is, the decoction alcohol extraction method, decocts Radix Isatidis with water twice, then filters the decoction, combines the filtrates, and concentrates to a relative density of 1.0 to 1.20 g / mL, then adds ethanol to make the alcohol content reach 60%, and takes the supernatant after standing and precipitating to remove polysaccharides, recovers ethanol and concentrates to an appropriate amount, adds auxiliary materials and sweeteners, and makes granules. Indigo, indirubin, tryptanthrin and adenosine are fat-soluble components with antibacterial activity, so the preparation in the existing standards needs to be decocted with water first, and then extracted with alcohol to enrich the above-mentioned active ingredients. The document eliminated the "alcohol precipitation" operation, which directly affected the content of ingredients in the finished granules. In addition, the document only stated that sucrose was not added, and it was not clear whether other monosaccharides or disaccharides were added.

[0004] CN102988451A "A method for preparing sugar-free Radix Isatidis granules" (publication date: 2013.03.27) uses Radix Isatidis water extraction and alcohol precipitation to prepare Radix Isatidis extract, adds soluble starch and stevioside, mixes, makes granules, and dries to obtain the finished product. The soluble starch added in this technical solution belongs to small molecule starch and disaccharides. Soluble starch is easily and quickly decomposed into glucose after entering the human digestive system. Its blood sugar rise rate is faster than that of insoluble starch, and it is not conducive to diabetic patients to take it. In addition, in this technical solution, the ratio of extract to soluble starch is 50:150-70:180, and the amount of auxiliary materials used is large.

[0005] CN111603494A "A process for producing sugar-free Radix Isatidis granules" (publication date: 2020.09.01) adopts step S1: pretreating the Radix Isatidis raw medicinal materials to obtain pretreated medicinal materials; step S2: decocting the pretreated medicinal materials to obtain Radix Isatidis solution; step S3: concentrating the Radix Isatidis solution through a concentration tank to obtain concentrated solution A; step S4: adding ethanol to the concentrated solution A to obtain a concentrated solution B with an ethanol concentration of 90%; step S5: The concentrated solution B is allowed to stand for more than 24 hours, and the supernatant is extracted; step S6: the supernatant is cooled to below 0°C, sucrose crystals in the supernatant are precipitated, and the sucrose crystals are filtered out to obtain concentrated solution C; step S7: the concentrated solution C is heated to 78°C, and ethanol is evaporated until a concentrated solution D with an ethanol content of 60% is obtained; step S8: the concentrated solution D is concentrated again to obtain a Radix Isatidis extract; step S9: the Radix Isatidis extract is prepared by a granulator to obtain Radix Isatidis granules. This technical solution precipitates the internal sucrose by refrigeration, and does not add sucrose externally, so as to obtain a sugar-free Radix Isatidis, but dextrin is added to the auxiliary material, which is also a sugar.

[0006] As mentioned above, the prior art lacks a truly sugar-free Radix Isatidis granule that retains the active ingredients in Radix Isatidis and solves the medication burden of diabetic patients. Summary of the invention

[0007] To solve the above problems, the present invention provides a sugar-free Radix Isatidis granules without monosaccharides or disaccharides and a preparation method thereof. Through the selection of fillers and preparation methods, the present invention increases the content of effective ingredients in the sugar-free Radix Isatidis granules, reduces the amount of auxiliary materials, and has a good yield and stability, making it more suitable for diabetic patients.

[0008] The present invention provides a sugar-free Radix Isatidis granules, which contain Radix Isatidis fluid extract and a filler, wherein the ratio of the Radix Isatidis fluid extract to the filler is 1:1 to 1:1.2, preferably, the ratio of the Radix Isatidis fluid extract to the filler is 1:1 to 1:1.1, and the filler comprises mannitol.

[0009] The preparation method of Isatis Radix Granules is as follows:

[0010] (1) Using Radix Isatidis as a raw material, add water and boil for 2 to 3 times, each time for 1 to 2 hours, filter the decoction, combine the filtrates, concentrate to a clear paste, add ethanol, let stand to precipitate, take the supernatant to recover ethanol, and concentrate to a Radix Isatidis fluid extract with a relative density of 1.25 to 1.28 at 60° C., continue to heat to 65° C. to 75° C., then add a filler in an amount of 15% to 30% of the amount of the fluid extract, and stir evenly to obtain a mixture 1.

[0011] Preferably, the relative density of the clear paste at 50° C. is 1.18 to 1.28, and the alcohol content of the clear paste after adding ethanol is 58 to 63%.

[0012] Furthermore, the relative density of the clear paste at 50° C. is 1.20, and the alcohol content of the clear paste after adding ethanol is 60%.

[0013] Preferably, the amount of filler added is 15-20%.

[0014] Furthermore, the amount of filler added is 20 to 30%.

[0015] (2) The mixture 1 is subjected to vacuum belt drying, with the temperature of zone 1 set at 105-115°C, the temperature of zone 2 set at 85-95°C, and the temperature of zone 3 set at 15-25°C. The material is crushed and 60-100 mesh particles are collected to obtain a mixed dry paste powder.

[0016] Preferably, the feed pump rate is 8 to 12 L / h, the vacuum degree is -95 to -100 KPa, and the conveyor belt frequency is 8 to 11 Hz.

[0017] Preferably, the temperature of zone 1 is set at 105-110°C, the temperature of zone 2 is set at 85-90°C, and the temperature of zone 3 is set at 15-20°C.

[0018] (3) Add the mixed dry paste powder and the remaining filler into a wet granulator, stir to make the two mixed evenly, dry granulate, dry, collect 10-70 mesh granules, and obtain sugar-free Radix Isatidis granules.

[0019] Preferably, the stirring speed of the wet granulator is 80-120 rpm, the cutting speed is 450-550 rpm, and 12-65 mesh granules are collected.

[0020] In the prior art, sucrose and dextrin are commonly used as sweeteners and fillers for Radix Isatidis granules. Even sucrose-free Radix Isatidis contains dextrin. The reason is that the adsorption of non-sugar fillers is worse than that of dextrin, and the drug loading is low; non-sugar fillers have high hygroscopicity, demanding production process, and poor stability of the finished product; moreover, the price of non-sugar fillers is higher than that of dextrin, and the production cost is higher when the drug loading is low. The present invention solves the problem of low drug loading of non-sugar fillers by establishing a specific preparation process, improves the stability of the finished product, and at the same time increases the content of the active ingredients uridine, guanosine, and adenosine.

[0021] Beneficial effects:

[0022] (1) The present invention uses mannitol as a filler and combines it with a belt drying technology in which part of the filler is premixed to obtain sugar-free Radix Isatidis granules with lower hygroscopicity and higher content of active ingredients.

[0023] The results of the hygroscopicity investigation of Example 17 show that the weight gain of granules 1 to 5 prepared by using mannitol as a filler combined with belt drying technology at 68% humidity is less than 3.8%, which is more than half of the weight gain of dry extract powder; the weight gain of Radix Isatidis granules 7 to 9 with other non-sugar fillers is 1.3 to 2.3 times that of granules 1 to 5, and the reduction in hygroscopicity is not obvious. In the example, granules 11 are also prepared by using a 1:1 composition of mannitol and xylitol. When the mannitol content is increased, the hygroscopicity of the granules can be reduced, but the effect is not as good as that of mannitol alone. It can be seen that only when mannitol is used as a filler, the hygroscopicity of the dry extract powder can be further reduced in combination with the premixing process.

[0024] In addition, the present invention compares the partially premixed granules 1 to 5 with the one-time feeding granules 6 and finds that the one-time feeding cannot effectively reduce the hygroscopicity of the granules. Moreover, after the proportion of mannitol premixing is limited in granules 1 to 3, the active ingredient content is increased by an average of 10% compared with granules 4 to 5. This shows that the present invention not only solves the hygroscopicity of the granules by limiting the content and proportion of the filler, but also increases the content of the active ingredient.

[0025] The present invention also studies the influence of different drying processes on the finished granules under the same formulation, and compares spray drying with belt drying. The experimental results are shown in Table 1. The corresponding weight gain rates of granules 12 and 13 obtained by spray drying at 68% humidity are 6.2% and 5.8%, respectively, which is about 1.7 times the weight gain rate of granule 3 by belt drying. The corresponding active ingredient contents of granules 12 and 13 are 3.60 mg / bag and 3.85 mg / bag, respectively, accounting for 88% of the content of granule 3. It can be seen that the belt drying method is specific in this formulation and preparation method, and the obtained Radix Isatidis granules are significantly better than spray drying in reducing hygroscopicity and increasing the content of active ingredients.

[0026] Table 1 Comparison of the indexes of Isatis Root Granules 3 and 12-13

[0027] Particle number Weight gain at 68% humidity (%) Yield (%) Content (mg / bag) Isatis root granules 3 3.5 91.2 4.23 Isatis root granules 12 6.2 83.5 3.60 Isatis root granules 13 5.8 85.2 3.85

[0028] (2) The Radix Isatidis granules provided by the present invention adopt belt drying technology, and the finished product yield exceeds 90%. At the same time, the problem of high hygroscopicity of mannitol itself is solved, producing unexpected technical effects.

[0029] The prior art "Optimization of Dry Granulation Process of Radix Isatidis Granules by Response Surface Methodology" (Contemporary Chinese Medicine, 2017, 24 (24): 82-84) points out that the hygroscopicity of Radix Isatidis granules prepared with different excipients is different. In a glass dryer with a humidity of 75%, the Radix Isatidis granules with an addition amount of 20% excipients showed a difference in hygroscopicity in 45 minutes, and the order of hygroscopicity was: mannitol> sucrose> dextrin> soluble starch. The Radix Isatidis Granules 3 provided by the present invention use mannitol as an excipient, and the Radix Isatidis Granules 11 use dextrin as an excipient, and the amount of excipients used in both is the same. After being placed in different humidity environments for 24 hours, the weight gain rate of Radix Isatidis Granules 3 is similar to that of Radix Isatidis Granules 11. The present invention adopts a preparation process of partial premixing and drying, which better reduces the influence of the high hygroscopicity of the mannitol excipient itself on the Radix Isatidis granules, and obtains unexpected technical effects.

[0030] Table 2 Comparison of indicators of Isatis granules 1 to 3 and 11

[0031] Product Number Yield (%) Moisture (%) Weight gain at 68% humidity (%) Content (mg / bag) Isatis root granules 1 91.6 6.0 3.8 4.42 Isatis root granules 2 92.5 5.7 3.6 4.31 Isatis root granules 3 91.2 5.0 3.5 4.23 Isatis root granules 11 92.8 5.5 3.3 4.41

[0032] (3) The present invention uses mannitol as a filler and combines it with a belt drying technology in which part of the filler is premixed, thereby solving the problem of low drug loading of non-sugar fillers.

[0033] The Radix Isatidis Granules 1 to 3 provided by the present invention adopt the belt drying technology of mannitol combined with partial filler premixing, and the corresponding finished product yield is greater than 91%. Similarly, mannitol is used as an auxiliary material, and the granules 12 prepared by spray drying have a corresponding finished product yield of only 83.5%; increasing the amount of auxiliary material to 1.5 times that of the raw material, the finished product yield only rises to 85.2%. Content comparison analysis found that increasing the amount of mannitol can increase the finished product yield to a certain extent, but continuing to increase the amount of auxiliary materials will dilute the proportion of Radix Isatidis extract in the finished product. The present invention uses mannitol as an auxiliary material, combined with partial filler premixing + belt drying, which can fundamentally solve the problem of low drug loading of non-sugar fillers, reduce production costs, and increase the content of effective ingredients.

[0034] Table 3 Comparison of the indexes of Isatis granules 1-3 and 12-13

[0035] DETAILED DESCRIPTION

[0036] The present invention is further described below by way of examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0037] Example 1: Preparation of Radix Isatidis fluid extract 1

[0038] Take Radix Isatidis as raw material, add water and boil twice, each time for 1 hour, filter the decoction, combine the filtrates, and concentrate to a clear paste with a relative density of 1.18 at 50°C. After adding ethanol, the alcohol content is 58%. Let it stand to precipitate, take the supernatant to recover ethanol, and concentrate to a Radix Isatidis fluid extract 1 with a relative density of 1.25-1.28 at 60°C.

[0039] Example 2: Preparation of Radix Isatidis Fluid Extract 2

[0040] Take Radix Isatidis as raw material, add water and boil for 3 times, each time for 2 hours, filter the decoction, combine the filtrates, and concentrate to a clear paste with a relative density of 1.28 at 50°C. After adding ethanol, the alcohol content is 63%. Let it stand for precipitation, take the supernatant to recover ethanol, and concentrate to a Radix Isatidis fluid extract 2 with a relative density of 1.25-1.28 at 60°C.

[0041] Example 3: Preparation of Radix Isatidis Fluid Extract 3

[0042] Take Radix Isatidis as raw material, add water and boil for 3 times, each time for 2 hours, filter the decoction, combine the filtrates, and concentrate to a clear paste with a relative density of 1.20 at 50°C. After adding ethanol, the alcohol content is 60%, let it stand for precipitation, take the supernatant to recover ethanol, and concentrate to a Radix Isatidis fluid extract 3 with a relative density of 1.25-1.28 at 60°C.

[0043] Example 4: Preparation of Sugar-free Radix Isatidis Granules 1

[0044] (1) 1680 g of the Radix Isatidis fluid extract obtained in Example 1 was taken, and the mixture was heated to 65° C., and then 252 g of mannitol (15% of the amount of the fluid extract) was added, and the mixture was stirred to obtain a mixture 1;

[0045] (2) subjecting the mixture 1 to vacuum belt drying, with a feed pump rate of 8 L / h, a set temperature of 105° C. for zone 1, a set temperature of 85° C. for zone 2, a set temperature of 20° C. for zone 3, a conveyor belt frequency of 10 Hz, a vacuum degree of -100 KPa, crushing the material, collecting 60-mesh particles, and obtaining a mixed dry paste powder;

[0046] (4) Add the mixed dry paste powder and the remaining 1428 g of mannitol into a wet granulator, stir at a speed of 120 rpm, cut at a speed of 500 rpm, stir evenly, dry granulate, dry, collect 12 mesh granules, and obtain sugar-free Radix Isatidis Granules 1.

[0047] Example 5: Preparation of Sugar-free Radix Isatidis Granules 2

[0048] (1) 1680 g of the Radix Isatidis fluid extract obtained in Example 2 was taken, and the mixture was heated to 70° C., and then 504 g of mannitol (30% of the amount of the fluid extract) was added, and the mixture was stirred to obtain a mixture 1;

[0049] (2) Mixture 1 is subjected to vacuum belt drying, with a feed pump rate of 10 L / h, a set temperature of 110° C. in zone 1, a set temperature of 90° C. in zone 2, and a set temperature of 15° C. in zone 3, a conveyor belt frequency of 8 Hz, a vacuum degree of -95 KPa, and the material is crushed and 80 mesh particles are collected to obtain a mixed dry paste powder;

[0050] (4) Add the mixed dry paste powder and the remaining 1512 g of mannitol into a wet granulator, stir at a speed of 80 rpm, cut at a speed of 450 rpm, stir evenly, dry granulate, dry, collect 50 mesh granules, and obtain sugar-free Isatis Radix Granules 2.

[0051] Example 6: Preparation of Sugar-free Radix Isatidis Granules 3

[0052] (1) 1680 g of the Radix Isatidis fluid extract obtained in Example 3 was taken, and the mixture was heated to 75° C., and then 336 g of mannitol (20% of the amount of the fluid extract) was added, and the mixture was stirred to obtain a mixture 1;

[0053] (2) subjecting the mixture 1 to vacuum belt drying, with a feed pump rate of 12 L / h, a set temperature of 115° C. for zone 1, a set temperature of 95° C. for zone 2, a set temperature of 25° C. for zone 3, a conveyor belt frequency of 11 Hz, a vacuum degree of -100 KPa, crushing the material, collecting 100 mesh particles, and obtaining a mixed dry paste powder;

[0054] (4) Add the mixed dry paste powder and the remaining 1512 g of mannitol into a wet granulator, stir at a speed of 100 rpm, cut at a speed of 550 rpm, stir evenly, dry granulate, dry, and collect 65 mesh granules to obtain sugar-free Isatis Radix Granules 3.

[0055] Example 7: Preparation of Sugar-free Radix Isatidis Granules 4

[0056] (1) 1680 g of the Radix Isatidis fluid extract obtained in Example 3 was taken, and the mixture was heated to 75° C., and then 672 g of mannitol (40% of the amount of the fluid extract) was added, and the mixture was stirred to obtain a mixture 1;

[0057] (2) subjecting the mixture 1 to vacuum belt drying, with a feed pump rate of 12 L / h, a set temperature of 115° C. for zone 1, a set temperature of 95° C. for zone 2, and a set temperature of 25° C. for zone 3, a conveyor belt frequency of 11 Hz, a vacuum degree of -100 Kpa, and crushing the material to obtain 100 mesh particles to obtain a mixed dry paste powder;

[0058] (4) Add the mixed dry paste powder and the remaining 1176 g of mannitol into a wet granulator, stir at a speed of 100 rpm, cut at a speed of 550 rpm, stir evenly, dry granulate, dry, and collect 65 mesh granules to obtain sugar-free Isatis Radix Granules 4.

[0059] Example 8: Preparation of Sugar-free Radix Isatidis Granules 5

[0060] (1) 1680 g of the Radix Isatidis fluid extract obtained in Example 3 was taken, and the mixture was heated to 75° C., and then 168 g of mannitol (10% of the amount of the fluid extract) was added, and the mixture was stirred to obtain a mixture 1;

[0061] (2) subjecting the mixture 1 to vacuum belt drying, with a feed pump rate of 12 L / h, a set temperature of 115° C. for zone 1, a set temperature of 95° C. for zone 2, and a set temperature of 25° C. for zone 3, a conveyor belt frequency of 11 Hz, a vacuum degree of -100 Kpa, and crushing the material to obtain 100 mesh particles to obtain a mixed dry paste powder;

[0062] (4) Add the mixed dry paste powder and the remaining 1680 g of mannitol into a wet granulator, stir at a speed of 100 rpm, cut at a speed of 550 rpm, stir evenly, dry granulate, dry, and collect 65 mesh granules to obtain sugar-free Isatis Radix Granules 5.

[0063] Example 9: Control group 1

[0064] On the basis of Example 6, mannitol was added and mixed at one time.

[0065] (1) 1680 g of the Radix Isatidis fluid extract obtained in Example 3 was taken and vacuum belt dried, with a feed pump rate of 12 L / h, a set temperature of 115° C. for zone 1, a set temperature of 95° C. for zone 2, and a set temperature of 25° C. for zone 3, a conveyor belt frequency of 11 Hz, a vacuum degree of -100 Kpa, and the material was crushed and 100 mesh particles were collected to obtain a mixed dry paste powder;

[0066] (2) Add the dry paste powder and 1848 g of mannitol (110% of the amount of the extract in step (1)) into a wet granulator, stir at a speed of 100 rpm, cut at a speed of 550 rpm, stir evenly, dry granulate, dry, collect 65 mesh granules, and obtain sugar-free Isatis Radix Granules 6.

[0067] Example 10: Control group 2

[0068] On the basis of Example 6, an equal amount of maltitol was used to replace mannitol to prepare sugar-free Radix Isatidis Granules 7.

[0069] Example 11: Control group 3

[0070] On the basis of Example 6, an equal amount of sorbitol was used to replace mannitol to prepare sugar-free Isatis Radix Granules 8.

[0071] Example 12: Control group 4

[0072] On the basis of Example 6, an equal amount of xylitol was used to replace mannitol to prepare sugar-free Radix Isatidis Granules 9.

[0073] Example 13: Control group 5

[0074] On the basis of Example 6, an equal amount of mannitol was replaced by mannitol in a ratio of 1:1 as a filler to prepare sugar-free Radix Isatidis granules 10.

[0075] Example 14: Control group 6

[0076] On the basis of Example 6, an equal amount of dextrin was used to replace mannitol to prepare sugar-free Isatis Radix Granules 11.

[0077] Example 15: Control group 7

[0078] Based on Example 6, spray drying was used to replace belt drying.

[0079] (1) 1680 g of the Radix Isatidis fluid extract obtained in Example 3 was taken, and the mixture was heated to 75° C., and then 336 g of mannitol (20% of the amount of the fluid extract) was added, and the mixture was stirred to obtain a mixture 1;

[0080] (2) spray drying the mixture 1, with an air inlet temperature of 180° C. and an air outlet temperature of 80° C., collecting 100-mesh particles to obtain a mixed dry paste powder;

[0081] (4) Add the mixed dry paste powder and the remaining 1512 g of mannitol into a wet granulator, stir at a speed of 100 rpm, cut at a speed of 550 rpm, stir evenly, dry granulate, dry, and collect 65 mesh granules to obtain sugar-free Isatis Radix Granules 12.

[0082] Example 16: Control group 8

[0083] On the basis of Example 15, the amount of mannitol added is 150% of the amount of the Radix Isatidis extract, the proportion of premixed mannitol is 30% of the amount of the extract, and the mixed dry paste powder is mixed with the remaining mannitol to prepare the sugar-free Radix Isatidis granules 13.

[0084] Example 17: Hygroscopicity Study

[0085] 1.0 g of the dry extract powder obtained by drying the Radix Isatidis fluid extract 1 and 1.0 g of the Radix Isatidis granules prepared in Examples 4 to 16 were taken to carry out a drug hygroscopicity test.

[0086] 1. Test methods

[0087] Take a dry stoppered glass weighing bottle, place it in an artificial climate box (set temperature at 25°C ± 1°C, relative humidity at 43% ± 2%, 57% ± 2%, 68% ± 2%) one day before the test, and accurately weigh the weight (m1). Take 1.0g of the Isatis Radix Granules test sample of Examples 4 to 14, spread them flat in the above-mentioned weighing bottles respectively, the thickness of the test sample is about 1mm, and accurately weigh the weight (m2). Open the weighing bottle and place it with the bottle cap under the above-mentioned constant temperature and humidity conditions for 24 hours. Cover the weighing bottle lid and accurately weigh the weight (m3). Percentage of weight gain = (m3-m2) / (m2-m1)×100%.

[0088] Description of hygroscopic characteristics and definition of hygroscopic weight gain:

[0089] Deliquesce: Absorbs enough water to form a liquid;

[0090] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0091] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0092] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0093] No or almost no hygroscopicity: moisture gain is less than 0.2%.

[0094] 2. Test results

[0095] The results of the hygroscopicity of the dry extract powder and granules of Radix Isatidis are shown in Table 4. The dry extract powder has strong hygroscopicity, and the weight gain exceeds 9% at 68% humidity. Therefore, it is necessary to reduce the hygroscopicity of the dry extract powder of Radix Isatidis through auxiliary materials and preparation methods. Among them, the weight gain rate of Radix Isatidis granules 1 to 5 and 11 is less than 4%, which is more than half lower than the weight gain of the dry extract powder; the weight gain rate of other Radix Isatidis granules is between 5% and 9%, and the hygroscopicity is not significantly reduced.

[0096] Table 4 Hygroscopicity results of different Radix Isatidis granules (unit: %)

[0097]

[0098]

[0099] The difference between the preparation process of Radix Isatidis Granules 3 and 6 is that the granule 3 is prepared by premixing and drying the extract with 20% mannitol and then mixing it with the remaining mannitol, while the granule 6 is prepared by directly mixing the extract with mannitol after drying. The weight gain rates of the two at 68% humidity are 3.5% and 5.9% respectively, and the weight gain rate of Radix Isatidis Granules 3 is reduced by nearly half. Compared with Radix Isatidis Granules 6 directly mixed with raw and auxiliary materials, the extract of Radix Isatidis Granules 3 is premixed with part of mannitol and then dried to form an auxiliary material coated extract. After the auxiliary material is coated, it can partially prevent moisture from contacting with the dry extract powder with high hygroscopicity, slow down the moisture absorption rate, and reduce the moisture absorption amount. At the same time, the coated extract formed after premixing continues to mix with the remaining auxiliary materials, and the dry extract powder and the auxiliary materials are mixed with better uniformity. On the one hand, the specific surface area of ​​the coated extract is further reduced, the moisture contacts the dry extract less, and the hygroscopicity is lower; on the other hand, the finished product yield is improved, which is more suitable for industrial production.

[0100] Compared with Isatis Radix Granules 3 and 7-10, the difference lies in the different types of non-sugar fillers. Among them, Granule 3 is mannitol, and Granules 7-10 are maltitol, sorbitol, xylitol, and a mixture of mannitol and xylitol, respectively, and the corresponding weight gain rates are all greater than 5%. Maltitol, sorbitol, xylitol, and mannitol are all non-sugar fillers. The hygroscopicity obtained after premixing and drying is improved compared to the dry extract powder, but the weight gain rate is greater than Granule 3. A 1:1 composition of mannitol and xylitol is also used in the embodiment. The hygroscopicity of the particles can be reduced when the mannitol content is increased, but the effect is not as good as when mannitol is used alone. It can be seen that only mannitol as an excipient combined with a premixing process can reduce the hygroscopicity of the dry extract powder.

[0101] Compared with Radix Isatidis Granules 3 and 11, the difference lies in the type of filler. Granule 3 is mannitol, which is a non-sugar filler; Granule 11 is dextrin, which is a sugar filler. According to the prior art "Optimization of Dry Granulation Process of Radix Isatidis Granules by Response Surface Methodology" (Contemporary Chinese Medicine, 2017, 24 (24): 82-84), it is pointed out that the moisture absorption rate of Radix Isatidis granules prepared with different excipients is different. In a glass dryer with 75% humidity, Radix Isatidis granules with 20% excipient added showed different moisture absorption rates in 45 minutes, and the moisture absorption rate was in the order of mannitol> sucrose> dextrin> soluble starch. Radix Isatidis Granules 3 and 11 provided by the present invention use the same amount of excipients, and are placed in different humidity environments for 24 hours, but the weight gain rate of Radix Isatidis Granules 3 is similar to that of Radix Isatidis 11. The preparation process of partial premixing and drying is adopted to better reduce the influence of the hygroscopicity of the mannitol excipient itself on the Radix Isatidis granules, and obtain unexpected technical effects.

[0102] Compared with 12-13, the difference between Radix Isatidis Granules 3 and 12-13 is that the drying method of the fluid extract is different. Granule 3 adopts the belt drying method, and Granules 12-13 adopt the spray drying method. The particle size of the material obtained by spray drying is significantly smaller than that of the material obtained by belt drying. The smaller particle size has a larger specific surface area and stronger hygroscopicity. In addition, due to the light weight of the auxiliary materials in the spray drying process, there is a certain degree of auxiliary material loss during the premixing and drying process of the filler. Combined with the weight gain rate obtained by increasing the proportion of fillers in Granule 13, it can be seen that when the amount of auxiliary materials increases from 110% to 150% of the amount of extract and the proportion of premixed auxiliary materials increases from 20% to 30%, the weight gain rate at 68% humidity decreases from 6.2% to 5.8%. It can be seen that the use of spray drying cannot avoid the loss of auxiliary materials caused by mixing, and belt drying is more suitable for the premixing and drying of Radix Isatidis Granules and mannitol.

[0103] The hygroscopicity of the product mainly affects the operability of the product production process. Strong hygroscopicity requires controlling the ambient humidity at a lower level to ensure the feasibility of production. The hygroscopicity of Isatis Root Granules 1 to 5 is smaller than that of other control groups, which is suitable for industrial production.

[0104] Example 18: Product quality test results

[0105] 1. Test methods

[0106] 1.1 Yield Rate Statistical Method

[0107] The Radix Isatidis granules are made into a specification of 1.5g per bag, and the yield rate is calculated by comparing the actual number of finished products with the theoretical number of finished products.

[0108] Yield rate = actual number of finished products / theoretical number of finished products*100%.

[0109] 1.2 Content detection method

[0110] Determined by high performance liquid chromatography according to General Chapter 0512 of the 2020 edition of the "Chinese Pharmacopoeia".

[0111] Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel was used as filler; methanol was used as mobile phase A, water was used as mobile phase B, and gradient elution was performed according to the provisions in Table 5; the flow rate was 0.8 mL per minute; the column temperature was 30°C, and the detection wavelength was 254 nm. The theoretical plate number calculated based on the uridine peak should not be less than 10,000.

[0112] Table 5 Elution gradient

[0113]

[0114] Preparation of reference solution: Take appropriate amounts of uridine reference, guanosine reference and adenosine reference, weigh accurately, add 5% methanol to prepare a mixed solution containing 20 μg uridine, 20 μg guanosine and 25 μg adenosine per 1 mL.

[0115] Preparation of test solution: Take 0.3 g of the product, grind it into powder, weigh it accurately, put it in a stoppered conical flask, accurately add 10 mL of 5% methanol, stopper it tightly, weigh it, treat it with ultrasound (power 500 W, frequency 40 kHz) for 5 minutes, let it cool, weigh it again, make up the lost weight with 5% methanol, shake it well, filter it, and take the filtrate to obtain the solution.

[0116] The determination method is to accurately pipette 5 to 10 μL of the reference solution and the test solution respectively, inject them into the liquid chromatograph, and determine the result.

[0117] Each bag of this product (1.5g, equivalent to 7g of decoction pieces) contains uridine (C9H 12 N2O6), guanosine (C 10 H 13 N5O5), adenosine (C 10 H 13 The total amount of N5O4) shall not be less than 0.70 mg.

[0118] 2. Test results

[0119] The test results are shown in Table 6.

[0120] Table 6 Water content and content of different Radix Isatidis granules

[0121] Product Number Yield (%) Moisture (%) Content (mg / bag) Isatis root granules 1 91.6 6.0 4.42 Isatis root granules 2 92.5 5.7 4.31 Isatis root granules 3 91.2 5.0 4.23 Isatis root granules 4 90.2 5.8 3.90 Isatis root granules 5 89.9 5.2 3.95 Isatis root granules 7 90.6 6.5 3.94 Isatis root granules 8 91.8 6.1 4.16 Isatis root granules 9 92.0 6.2 4.08 Isatis root granules 10 91.0 6.0 4.37 Isatis root granules 11 92.8 5.5 4.41 Isatis root granules 12 83.5 6.8 3.60 Isatis root granules 13 85.2 5.7 3.85

[0122] The product yields of Radix Isatidis Granules 1-5, 7-11 are close to or exceed 90%, while the yields of Radix Isatidis Granules 12-13 are only 83%-85%, and Granule 13 requires 150% of the auxiliary material addition. Combined with the above hygroscopic results, it can be seen that belt drying has obvious advantages in the preparation process of light auxiliary material premixed extracts, which can reduce the amount of auxiliary materials, increase the product yield, reduce the hygroscopicity of the product, and is more suitable for industrial production.

[0123] Comparison of Radix Isatidis Granules 1 to 5 revealed that the content of active ingredients in Granules 1 to 3, measured in terms of the total amount of uridine, guanosine and adenosine, increased by an average of 10% compared to Granules 4 to 5. The reason is that the amount of auxiliary materials added during the premixing process affects the loss rate of active ingredients in belt drying. Granule 4 added 40% mannitol, and excessive addition of auxiliary materials affected the fluidity of the fluid extract during belt drying, resulting in easy accumulation of materials during the drying process, and a large loss of materials obtained by drying, so the content of active ingredients in the finished granules was significantly reduced. Granule 5 added 10% mannitol, and the amount of auxiliary materials added was too little, the fluidity of the fluid extract was too good, and there was overflow and adhesion of the extract during the belt drying process, which also increased the loss of materials obtained by drying, and also resulted in a decrease in the content of active ingredients in the finished granules. It can be seen that the amount of auxiliary materials added in Granules 1 to 3 provided by the present invention is highly compatible with the belt drying method, and a higher yield can be obtained, while retaining a higher amount of active ingredients.

[0124] Comparison of Isatis Radix Granules 3 with 7-10 revealed that replacing other non-sugar fillers with mannitol had greater hygroscopicity, and there were varying degrees of material loss during the belt drying process, which also reduced the effective ingredients in the finished granules to varying degrees.

[0125] Comparison between Radix Isatidis Granules 3 and 11 revealed that the yield and effective ingredient content of the two granules were similar. However, dextrin is a carbohydrate filler and is not suitable for diabetic patients. As described above, the Radix Isatidis Granules 3 provided by the present invention changes the high hygroscopicity of mannitol itself in the preparation process of the extract premixed with some light auxiliary materials, and obtains sugar-free Radix Isatidis Granules with low hygroscopicity, high yield, high effective ingredient content and meeting the needs of diabetic patients.

[0126] Example 19: Solubility and Clarity

[0127] Solubility and clarity experiments were conducted on Isatis Radix Granules 1-5 and 7-13 to determine the relevant properties of the above granules.

[0128] 1. Test methods

[0129] 1.1 Solubility test method

[0130] Take 1.5g of Isatis Radix Granules, add 200mL of hot water, stir for 5 minutes, and observe immediately. The soluble granules should be completely dissolved or slightly turbid.

[0131] 1.2 Clarity test method

[0132] Check according to the first method (visual method) of the Clarity Inspection Method of the Chinese Pharmacopoeia. "Clear" under the category means that the clarity of the test solution is the same as that of the solvent used, or does not exceed the turbidity of the No. 0.5 turbidity standard solution. "Almost clear" means that the turbidity of the test solution is between the turbidity of the No. 0.5 and No. 1 turbidity standard solutions.

[0133] According to the concentration requirements specified under each item, at room temperature, the test sample solution diluted with water to a certain concentration and an equal amount of turbidity standard solution are placed in paired turbidity glass tubes (15-16mm inner diameter, flat bottom, with stopper, made of colorless, transparent, neutral hard glass). 5 minutes after the turbidity standard solution is prepared, place them vertically under an umbrella shed light in a dark room with an illumination of 1000lx, and observe and compare from the horizontal direction. Unless otherwise specified, the test sample should be inspected immediately after dissolution.

[0134] Preparation of turbidity standard stock solution Weigh 1.00 g of hydrazine sulfate dried to constant weight at 105°C, place in a 100 mL volumetric flask, add appropriate amount of water to dissolve, if necessary, warm in a 40°C water bath to dissolve, dilute to scale with water, shake well, and leave for 4 to 6 hours. Mix this solution with an equal volume of 10% urotropine solution, shake well, and leave at 25°C away from light for 24 hours. The solution is stored in a cold place away from light and can be used within 2 months. Shake well before use.

[0135] Preparation of turbidity standard stock solution Take 15.0mL of turbidity standard stock solution, place it in a 1000mL volumetric flask, add water to dilute to the mark, shake well, take an appropriate amount and place it in a 1cm absorption cell, and measure at a wavelength of 550nm according to the UV-Vis spectrophotometry (General Rule 0401). Its absorbance should be within the range of 0.12 to 0.15. The solution should be used within 48 hours and shake well before use.

[0136] Preparation of turbidity standard solution Take the turbidity standard stock solution and water and prepare it according to Table 7. The turbidity standard solution should be prepared just before use and shaken thoroughly before use.

[0137] Table 7 Turbidity standard solution list

[0138] Level 0.5 1 2 3 4 Turbidity standard stock solution / mL 2.50 5.0 10.0 30.0 50.0 Water / mL 97.50 95.0 90.0 70.0 50.0

[0139] 2. Test results

[0140] The test results are shown in Table 8.

[0141] Table 8 Solubility and clarity results of different Radix Isatidis granules

[0142] Product Number Solubility Melting time(s) Clarity Isatis root granules 1 All melted ＜10 clarify Isatis root granules 2 All melted ＜10 clarify Isatis root granules 3 All melted ＜10 clarify Isatis root granules 4 All melted ＜10 clarify Isatis root granules 5 All melted ＜10 clarify Isatis root granules 7 All melted ＜10 clarify Isatis root granules 8 All melted ＜10 clarify Isatis root granules 9 All melted ＜10 clarify Isatis root granules 10 All melted ＜10 clarify Isatis root granules 11 Slightly turbid ＞30 Not clarifying Isatis root granules 12 All melted ＜10 clarify Isatis root granules 13 All melted ＜10 clarify

[0143] The solubility and clarity experimental results of Isatis Radix Granules 1-5 and 7-13 showed that except for Granule 11 which became slightly turbid and unclear after dissolution, the remaining granules were completely dissolved within 10 seconds and the solutions became clear.

Claims

1. A sugar-free Radix Isatidis granules, characterized in that: The Radix Isatidis granules include Radix Isatidis fluid extract and mannitol, the ratio of the Radix Isatidis fluid extract to mannitol is 1:1 to 1:1.2, and the preparation method of the Radix Isatidis granules is as follows: (1) Using Radix Isatidis as a raw material, adding water and boiling for 2 to 3 times, each time for 1 to 2 hours, filtering the decoction, combining the filtrates, concentrating to a clear paste, adding ethanol, standing to precipitate, taking the supernatant to recover the ethanol, concentrating to a Radix Isatidis fluid extract having a relative density of 1.25 to 1.28 at 60° C., continuing to heat to 65° C. to 75° C., adding mannitol in an amount of 15% to 30% of the fluid extract, and stirring to obtain a mixture 1; (2) subjecting the mixture 1 to vacuum belt drying, with the temperature of the first zone set at 105-115° C., the temperature of the second zone set at 85-95° C., and the temperature of the third zone set at 15-25° C., crushing the material, collecting 60-100 mesh particles, and obtaining a mixed dry paste powder; (3) Add the mixed dry paste powder and the remaining mannitol into a wet granulator, stir to make the two mixed evenly, dry granulate, dry, collect 10-70 mesh granules, and obtain sugar-free Radix Isatidis granules.

2. The Radix Isatidis granules according to claim 1, characterized in that The ratio of the Radix Isatidis fluid extract to mannitol is 1:1 to 1:1.

1.

3. The Radix Isatidis granules according to claim 1, characterized in that The relative density of the clear paste in step (1) of the preparation method at 50° C. is 1.18 to 1.

28.

4. The Radix Isatidis granules according to claim 1, characterized in that In step (1) of the preparation method, the alcohol content of the clear paste after adding ethanol is 58-63%.

5. The Radix Isatidis granules according to claim 4, characterized in that After adding ethanol, the alcohol content of the clear paste is 60%.

6. The Radix Isatidis granules according to claim 1, characterized in that The amount of mannitol added in step (1) of the preparation method is 15% to 20%.

7. The Radix Isatidis granules according to claim 1, characterized in that The amount of mannitol added in step (1) of the preparation method is 20% to 30%.

8. The Radix Isatidis granules according to claim 1, characterized in that In step (2) of the preparation method, the feed pump rate is 8 to 12 L / h, the vacuum degree is -95 to -100 KPa, and the conveyor belt frequency is 8 to 11 Hz.

9. The Radix Isatidis granules according to claim 1, characterized in that In step (2) of the preparation method, the temperature of zone 1 is set at 105°C to 110°C, the temperature of zone 2 is set at 85°C to 90°C, and the temperature of zone 3 is set at 15°C to 20°C.

10. The Radix Isatidis granules according to claim 1, characterized in that In step (3) of the preparation method, the stirring speed of the wet granulator is 80-120 rpm, the cutting speed is 450-550 rpm, and 12-65 mesh granules are collected.

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