Compound beta-hydroxybutyric acid traditional Chinese medicine solid preparation and preparation method thereof

Abstract

This invention discloses a compound β-hydroxybutyric acid (BHA) traditional Chinese medicine solid preparation and its preparation method. The steps include: water extraction of Polygonatum sibiricum, ginseng, peppermint, and wolfberry to obtain a filtrate; concentration; addition of BHA to obtain a compound mixed concentrate; addition of maltodextrin, spray drying, pulverization of the compound BHA traditional Chinese medicine solid extract and microcrystalline cellulose, and mixing the two evenly; addition of food-grade silica and magnesium stearate, grinding and mixing evenly to prepare a solid preparation. The advantages of this invention include: targeted improvement of mild neurodegenerative diseases and brain function damage; preparation based on medicinal and edible raw materials and novel food ingredients; safety and non-toxicity; stable properties; excellent product stability; no deterioration or abnormalities; strong production controllability; and high feasibility for mass production.

Description

Technical Field

[0001] This invention relates to the field of solid dosage form technology, particularly to solid dosage forms of β-hydroxybutyric acid and traditional Chinese medicine ingredients. Background Technology

[0002] Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are characterized by memory loss and speech delay. The disease progresses and is irreversible. Severe cases can induce serious cardiovascular and cerebrovascular complications, which seriously affect the physical and mental health and quality of life of the elderly.

[0003] Current routine clinical interventions have significant shortcomings. Modern Western medicine mainly uses donepezil and galantamine to improve symptoms, but these drugs have limited efficacy, and their efficacy is not positively correlated with dosage. Increasing the dosage can easily cause adverse reactions such as bradycardia and abnormal liver function, and long-term use has poor safety. Traditional Chinese medicine uses kidney-tonifying and qi-boosting herbs, compound preparations, and acupuncture to intervene. These methods can exert neuroprotective effects through anti-inflammatory, antioxidant, and circulation-improving pathways. However, Chinese medicine has poor taste, low patient compliance, and long-term use can easily cause gastrointestinal discomfort and has potential liver and kidney toxicity, making it difficult to meet the treatment principles of long-term, lifelong conditioning.

[0004] Existing clinical products struggle to balance efficacy and safety. Developing brain health improvement products based on food-grade medicinal materials and novel functional ingredients can effectively compensate for the shortcomings of existing technologies and has promising application prospects. Summary of the Invention

[0005] The purpose of this invention is to provide a compound β-hydroxybutyric acid traditional Chinese medicine solid preparation and its preparation method, so as to solve the problem that there is a lack of products that combine food and medicine raw materials with novel functional ingredients to effectively improve brain health in the existing technology.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for preparing a compound β-hydroxybutyric acid traditional Chinese medicine solid dosage form, comprising the following steps:

[0008] (1) Weigh out Polygonatum, ginseng, peppermint and wolfberry according to the prescription, add water to extract and obtain filtrate;

[0009] (2) Concentrate the filtrate obtained in (1);

[0010] (3) Add β-hydroxybutyric acid to the concentrated Chinese medicine solution obtained in (2) to obtain a compound mixed concentrated solution;

[0011] (4) Add maltodextrin to the compound mixed concentrate obtained in (3), mix well and spray dry to obtain compound β-hydroxybutyric acid Chinese medicine solid extract;

[0012] (5) Pulverize the compound β-hydroxybutyric acid traditional Chinese medicine solid extract and microcrystalline cellulose separately, and mix them evenly;

[0013] (6) Add food-grade silica and magnesium stearate to the powder obtained in step (5), grind and mix evenly to make a solid preparation.

[0014] Furthermore, by weight, the ratio of Polygonatum, ginseng, mint, and wolfberry is 9:3:3:6.

[0015] Furthermore, in step (3), if the total weight of Polygonatum, ginseng, mint, and wolfberry is 21g, then the amount of β-hydroxybutyric acid used is 2.5ml.

[0016] Further, in step (4), the compound mixed concentrate: maltodextrin = 20:10 by weight.

[0017] Furthermore, by weight, the ratio of compound β-hydroxybutyric acid traditional Chinese medicine solid extract: microcrystalline cellulose: food-grade silicon dioxide: magnesium stearate = 10:5:0.33:1.5.

[0018] Further, in step (1), the extraction parameters are: extraction temperature 100℃, extraction twice, 1.5h each time, and filtrate combined.

[0019] Furthermore, the concentration parameters in step (2) are 70°C and 0.7 kPa for 3 hours.

[0020] Furthermore, the parameters for spray drying in step (4) are an inlet air temperature of 120°C, an outlet air temperature of 60°C, and a flow rate of 1.5 ml / min.

[0021] Furthermore, the solid dosage form is a capsule or tablet.

[0022] The present invention also provides a compound β-hydroxybutyric acid traditional Chinese medicine solid preparation obtained by the method described above.

[0023] The advantages of this invention are:

[0024] 1. This product is specifically designed to improve mild neurodegenerative diseases and brain function damage, effectively making up for the shortcomings of existing technologies.

[0025] 2. High safety profile, supporting lifelong intervention. Neurodegenerative diseases are progressive and irreversible, requiring long-term, lifelong management. However, conventional drugs have significant side effects and are not suitable for long-term use. This product is prepared based on medicinal and edible ingredients and novel food components, making it safe, non-toxic, and stable, perfectly aligning with the disease intervention principle of "active intervention and lifelong management."

[0026] 3. Innovative formulation, complementing the advantages of Chinese and Western medicine. The combination of traditional Chinese medicine compound with β-hydroxybutyric acid (BHA) relies on ingredients such as Polygonatum sibiricum, Lycium barbarum, and ginseng, which are both food and medicine, to achieve the effects of tonifying the kidneys and invigorating the brain, regulating immunity and cardiovascular function. Combined with the brain energy supply and nerve repair advantages of FDA-certified BHA, the formulation is scientifically novel and breaks through the traditional single intervention model.

[0027] 4. The product has proven efficacy and high reliability. It relies on clearly identified active ingredients such as polysaccharides and ginsenosides to improve brain damage and regulate bodily functions, resulting in stable and reliable efficacy.

[0028] 5. The process is mature and stable, suitable for large-scale production. The water extraction, concentration, and formulation process can prepare both tablets and capsules. The product has good flowability and high recovery rate, and the weight variation and active ingredient content meet the standards of the 2020 edition of the Chinese Pharmacopoeia. Accelerated high-temperature and high-humidity testing has verified that the product has excellent stability, with no deterioration or abnormalities, and the production is highly controllable and feasible for mass production. Attached Figure Description

[0029] The accompanying drawings, which are included to provide a further understanding of the invention and form part of this application, do not constitute an undue limitation of the invention. In the drawings:

[0030] Figure 1 These are photos of the compound solid extract and the capsules obtained by filling them with excipients;

[0031] Figure 2 These are photos of tablets obtained by compressing compound solid extracts and excipients;

[0032] Figure 3 These are photos of the contents of the capsules from the first month of the accelerated destruction experiment.

[0033] Figure 4 These are photos of the capsule contents from the second month of the accelerated destruction experiment.

[0034] Figure 5 These are photos of the capsule contents from the third month of the accelerated destruction experiment.

[0035] Figure 6 These are photos of the capsule contents from the sixth month of the accelerated destruction experiment.

[0036] Figure 7 These are photos of the tablets' appearance in the first month of the accelerated degradation experiment;

[0037] Figure 8 These are photos of the tablet's appearance from the second month of the accelerated degradation experiment;

[0038] Figure 9 These are photos of the tablets' appearance in the third month of the accelerated degradation experiment;

[0039] Figure 10This is a photograph of the tablet's appearance in the accelerated degradation experiment, taken in month 6. Detailed Implementation

[0040] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The illustrative embodiments and descriptions of the present invention are used to explain the present invention, but are not intended to limit the present invention.

[0041] 1. Screening of extraction methods for traditional Chinese medicine

[0042] Weigh out 4500g of Polygonatum sibiricum, 1500g of ginseng, 1500g of peppermint, and 3000g of wolfberry. Add 105L of pure water and place in a TD micro extraction and concentration unit for extraction. The extraction temperature is 100℃, and the extraction is performed twice, 1.5 hours each time. Combine the filtrates after extraction.

[0043] The combined filtrate was placed at room temperature for 48 hours, then divided into four equal portions, each weighing 20.00 g. Pure water, 50 ml of ethanol, 70 ml of ethanol, and 80 ml of ethanol were added to each portion, respectively. The volume was then adjusted to 100 ml with pure water, stirred thoroughly, and allowed to stand for 48 hours to obtain test solutions with 0%, 50%, 70%, and 80% ethanol concentrations. The content of solid extract in each test solution was determined, and the extraction process that retained the most solid extract and had the highest content was selected.

[0044] Experimental results: The 0% ethanol concentration solution yielded the highest solid extract content, significantly higher than other ethanol concentration solutions. The solid extract content of the 50% ethanol concentration solution decreased by 7.22% compared to the 0% ethanol concentration solution. The solid extract content of the 70% and 80% ethanol concentration solutions further decreased, by 11.58% and 18.82% respectively compared to the 0% ethanol concentration solution. Simultaneously, the 0% ethanol concentration solution showed no obvious precipitation of components or impurities, resulting in better flowability during subsequent spray drying. Considering the overall extract yield, the water solubility characteristics of Polygonatum sibiricum, Lycium barbarum, and Ginseng, and the requirements for industrial production, the results show that the 0% ethanol solution yielded the highest solid extract content. Therefore, the 0% ethanol concentration solution, i.e., water extraction, was selected as the extraction process to obtain the highest content of solid extracts from traditional Chinese medicine.

[0045] Table 1 Relationship between ethanol concentration and solid extract content

[0046] 2. Preparation of compound β-hydroxybutyric acid traditional Chinese medicine solid extract by spray drying method

[0047] The combined filtrate was placed in a concentration machine and concentrated at 70℃ and 0.7 kPa for 3 hours. Then, according to the prescription ratio, 1250 ml of β-hydroxybutyric acid solution was added to the Chinese herbal medicine concentrate and stirred evenly to obtain the compound mixed concentrate for later use.

[0048] 20g of each compound concentrated solution was accurately weighed, and 0g, 6g, 10g, and 20g of maltodextrin were added respectively. The solution was then spray-dried and tested, and the following results were obtained.

[0049] Table 2. Relationship between maltodextrin addition ratio and flowability

[0050] Reference range for angle of repose for fluidity: θ < 30° is excellent fluidity, 30° ≤ θ < 40° is good fluidity, 40° ≤ θ < 50° is moderate fluidity, and θ ≥ 50° is poor fluidity (the formulation of this invention requires an angle of repose θ < 40°).

[0051] When 20g of the compound mixed concentrate was added with 10g of maltodextrin, the compound β-hydroxybutyric acid traditional Chinese medicine solid extract powder showed obvious powder and granule form, and the compound β-hydroxybutyric acid traditional Chinese medicine solid extract powder could be detached from the collection tube of the spray dryer.

[0052] Based on the results of maltodextrin addition and flowability, 3113g of the compound extract with added β-hydroxybutyric acid was taken, and the compound concentrate obtained after adding maltodextrin was placed in a spray dryer with the parameters set at an inlet air temperature of 120℃, an outlet air temperature of 60℃, and a flow rate of 1.5ml / min for spray drying, resulting in 2100.34g of compound β-hydroxybutyric acid traditional Chinese medicine solid extract.

[0053] The compound β-hydroxybutyric acid solid extract prepared by this process has good flowability and high recovery rate, and can be used for the subsequent preparation of capsules and tablets.

[0054] 3. Preparation of compound capsules

[0055] 3.1 Grinding, sieving, and flowability determination

[0056] The compound β-hydroxybutyric acid traditional Chinese medicine solid extract (hereinafter referred to as the compound solid extract) and microcrystalline cellulose were pulverized separately and passed through an 80-mesh sieve to remove impurities and large particles. Capsules and tablets were tested using a unified flowability test method and a microcrystalline cellulose addition ratio experiment.

[0057] Experiment on the proportion of microcrystalline cellulose added: Take 4 portions of 10g compound solid extract, add 0g, 3g, 5g and 10g of microcrystalline cellulose respectively and mix well. After pulverizing and sieving, the proportion of microcrystalline cellulose added to capsules and tablets is determined by the angle of repose measurement method using a uniform funnel.

[0058] Formal flowability testing equipment: funnel (upper diameter 10cm, lower diameter 2cm, height 15cm), ruler, electronic balance, and horizontal tabletop.

[0059] Fix the funnel above a horizontal table, ensuring the bottom of the funnel is 10cm above the table and that the funnel is vertical. Slowly pour the powders, containing different proportions of microcrystalline cellulose, into the funnel until the powder flows out naturally from the bottom, forming a cone-shaped accumulation. Avoid any artificial vibration. Measure the height (h) and base diameter (d) of the cone-shaped accumulation using a ruler, and then calculate the final value using the formula... Calculate the angle of repose θ; perform three parallel measurements, take the average value as the final angle of repose, and record the measurement data. The results are shown in Table 3:

[0060] Table 3. Test table on the relationship between different proportions of microcrystalline cellulose and flowability.

[0061] As shown in Table 3, when the amount of microcrystalline cellulose added to 10g of solid extract is 5g, the average angle of repose is 38°, the fluidity of the formulation meets the requirements (θ < 40°), and the fluidity is good. This ensures that the manual capsule filling and manual tableting processes are smooth, without jamming, sticking to the mold, uneven tablet weight, etc., thus guaranteeing the quality of preparation.

[0062] 3.2 Capsule Preparation Process

[0063] Based on the results of the process flowability and stability, and in accordance with the "Standard for Use of Food Additives" (GB2760) which stipulates that the maximum addition amount of silicon dioxide in each gram of food is 2% of the total mass, and that magnesium stearate should be added in appropriate amounts as needed, the following excipients were added to 10g of the compound solid extract: 5g microcrystalline cellulose, 0.33g silicon dioxide, and 1.5g magnesium stearate. These were placed in a clean mortar and pestle and slowly ground and mixed in the same direction for 15 minutes to ensure thorough mixing of the compound solid extract and excipients, avoiding powder clumping. After uniform grinding, the capsule contents were obtained. Figure 1 As shown in the left image. Capsules of size 0 were filled using a capsule mold. A total of 45 capsules were prepared. The finished capsules are shown below. Figure 1 As shown in the right figure, three batches were randomly selected and accurately weighed, and the average mass of the capsules was measured to be 0.3641g. The proportions of each component remained basically unchanged, and there were no problems such as powder clumping or capsule breakage.

[0064] 3.3 Detection of β-hydroxybutyric acid and ginsenoside content in capsules

[0065] The contents of β-hydroxybutyric acid and saponins in capsules were determined by high performance liquid chromatography (HPLC), and the total amount and polysaccharide content of the traditional Chinese medicine extracts were determined by ultraviolet-visible spectrophotometry. The specific procedures are as follows:

[0066] (1) HPLC method for determining the content of β-hydroxybutyric acid (BHB)

[0067] Instruments and reagents: High performance liquid chromatograph, electronic balance of 0.01 g / L, ultrasonic cleaner, centrifuge (speed ≥ 5000 r / min), volumetric flasks (10 mL, 50 mL, 100 mL), pipettes (1 mL, 5 mL), filter membrane (0.22 μm, organic phase); β-hydroxybutyric acid reference standard (purity ≥ 99.5%), methanol (chromatographic grade), potassium dihydrogen phosphate (analytical grade), glacial acetic acid (analytical grade), ultrapure water.

[0068] Preparation of reference solution: Accurately weigh 10 mg of β-hydroxybutyric acid reference standard, place it in a 100 mL volumetric flask, add ultrapure water to dissolve and dilute to the mark, shake well to obtain a reference standard stock solution with a concentration of 0.1 mg / mL; accurately measure 5 mL of the stock solution, place it in a 50 mL volumetric flask, dilute to the mark with ultrapure water, shake well to obtain a reference standard working solution with a concentration of 0.01 mg / mL, and store at 4℃.

[0069] Preparation of test solution: Accurately weigh 50 mg of capsule contents powder, place it in a 50 mL volumetric flask, add 40 mL of ultrapure water, sonicate for 30 min (power 200 W, frequency 40 kHz), sonicate twice, cool to room temperature, dilute to the mark with ultrapure water, shake well, centrifuge for 10 min (5000 r / min), take the supernatant, filter through a 0.22 μm filter membrane to obtain the test solution.

[0070] Content determination: Accurately pipette 10 μL each of the reference working solution and the test solution into the high-performance liquid chromatograph, measure the peak area, and calculate the content of β-hydroxybutyric acid in the test sample using the external standard method. The mobile phase parameters for β-hydroxybutyric acid are shown in Table 4.

[0071] Table 4. Parameters of β-hydroxybutyric acid mobile phase

[0072] (2) The content of ginsenosides (Rg1, Rb, Re) was determined by HPLC. The content of ginsenosides was calculated by external standard method according to the mobile phase parameters in Table 5.

[0073] Table 5. Ginsenoside Mobile Phase Parameters

[0074] (3) Detection of total amount and active ingredients of Chinese herbal extracts

[0075] The total amount of traditional Chinese medicine extracts was determined by ultraviolet-visible spectrophotometry. Using a reference standard of traditional Chinese medicine extracts, the absorbance of the sample was measured at a wavelength of 482 nm, and the total amount of traditional Chinese medicine extracts was calculated. The content of polysaccharides was also determined by ultraviolet-visible spectrophotometry. After colorimetric treatment, the polysaccharide content was calculated.

[0076] Based on the above tests, and considering the capsule quality deviation (±10%) and process deviation (±2%), the content range of each ingredient in each capsule is determined as follows:

[0077] The content of β-hydroxybutyric acid (BHB) ranges from 0.0558g to 0.0581g per capsule, the content of traditional Chinese medicine extract ranges from 1.1705g to 1.2182g per capsule, the polysaccharide content is 9.638% to 12.343% of the content of the traditional Chinese medicine extract, the total amount of saponins Rg1 and Rb is 0.47% of the content of the traditional Chinese medicine extract, and the content of saponin Re is 0.22% of the content of the traditional Chinese medicine extract. The content meets the standards stipulated in the 2020 edition of the Chinese Pharmacopoeia.

[0078] 4. Preparation of compound tablets

[0079] 4.1 Compound Tablet Preparation Process

[0080] Mixing: Take 10g of the compound solid extract and add the following excipients: 5g microcrystalline cellulose, 0.33g food-grade silica and 1.5g magnesium stearate. Place them in a clean glass mortar and slowly grind and mix them in the same direction for 15 minutes to ensure that they are fully mixed.

[0081] Tableting: Use a round flat punch (8mm in diameter, suitable for tablet weight of 0.5g / tablet), manually control the tableting pressure (11-12.5MPa) and tableting speed, slowly compress the tablets, strictly control the tablet weight, ensure that the tablet weight difference is within ±5%, and ensure that the tablet surface is smooth, without pitting or cracks.

[0082] Tableting effect Figure 2 As shown, the total mass of the compound solid extract and excipients was 16.83g, and a total of 30 tablets were actually prepared. Ten tablets were randomly selected and the average tablet weight was initially measured to be 0.5709g. The tablets had a uniform appearance, moderate hardness, and no loose or cracked tablets.

[0083] 4.2 Content detection of compound tablets

[0084] Accurately weigh 50 mg of tablet powder and proceed with the preparation method for the capsule test solution. Subsequent determination steps are the same. In HPLC detection, the mobile phase parameters for β-hydroxybutyric acid and ginsenosides are the same as those in section 3.3 above.

[0085] Based on the tablet quality deviation (±5%) and process deviation (±2%), the content range of each component in each tablet is determined as follows:

[0086] β-hydroxybutyric acid (BHB) content range: 0.1387g-0.1442g / tablet; herbal extract content range: 2.9117g-3.0305g / tablet; based on an average weight of 0.5709g per tablet, polysaccharides account for 3.398%-5.062% / tablet, total saponins Rg1 and Rb account for 0.165%-0.193% / tablet, saponin Re account for 0.077%-0.089% / tablet, polysaccharides account for 9.661%-12.366% of the herbal extract, total saponins Rg1 and Rb account for 0.47% of the herbal extract, and saponin Re accounts for 0.22% of the herbal extract.

[0087] 5. Verify the stability of the two formulations

[0088] Referring to the stability evaluation methods for capsules and tablets in the 2020 edition of the Chinese Pharmacopoeia, the reference indicators for capsules were the difference in fill weight, water content, and disintegration time, while the reference indicators for tablets were the difference in tablet weight, water content, and disintegration time. The parameters of both dosage forms under accelerated degradation tests at 40±2.5℃ and 75±5% humidity were recorded at 1, 2, 3, and 6 months. The stability of the two dosage forms of compound traditional Chinese medicine solid preparations was comprehensively evaluated, and the optimal process for the two preparations was verified.

[0089] 5.1 Quality and stability evaluation of capsules

[0090] 5.1.1 Content Difference

[0091] According to the method for checking the weight variation of capsules in the Chinese Pharmacopoeia, the content of each capsule and the average content should be determined. No more than two capsules should exceed the content variation limit compared to the average content, and no single capsule should exceed the limit by more than 100%.

[0092] Prepare test capsules and label them 1 to 10. Accurately weigh the standard empty capsule shells and the total mass of the test capsules, calculate the mass of their contents, and obtain the average value of the 10 contents masses. Calculate the limit of content variation according to the Chinese Pharmacopoeia quality standards to confirm whether the content variation meets the pharmacopoeia quality requirements.

[0093] The mass of the empty capsule shell is 0.1025g. Subtracting the mass of the standard capsule from the mass of each of the 10 capsules yields the following mass of the test sample contents.

[0094] Table 6. Record Sheet of Contents Quality of Test Samples 1-10

[0095] The average mass of the content of the test product was calculated as 0.3641 g based on the mass of the above contents. As shown in Table 7, according to the provisions on content variation of *Chinese Pharmacopoeia*, the upper and lower floating range for traditional Chinese medicine capsules is 0.3641 ± 10%. Therefore, the range is obtained as 0.3275 to 0.4003. The minimum mass and maximum mass of the test capsules are 0.3302 g and 0.3922 g respectively, and all the above masses fall within the range. Therefore, the content variation limit meets the requirements specified in the 2020 edition of *Chinese Pharmacopoeia*.

[0096] Table 7 Content variation limit table of the 2020 edition of *Chinese Pharmacopoeia*

[0097] 5.1.2 Disintegration time limit of capsules

[0098] With reference to the disintegration time limit test method in *Chinese Pharmacopoeia*, a lifting-type disintegration tester is used, whose main structure consists of a liftable metal bracket, a hanging basket with a screen mesh inlaid at the lower end, and is equipped with a baffle.

[0099] The vertical movement distance of the liftable metal bracket is 55 mm ± 2 mm, and the round-trip frequency is 30 to 32 times per minute. The hanging basket is suspended on the bracket through the stainless steel shaft at the upper end and immersed in a 1000 mL beaker. The position of the hanging basket is adjusted so that the distance between the screen mesh and the bottom of the beaker is 25 mm when the hanging basket descends to the lowest point. The beaker contains water with a temperature of 37°C ± 1°C. The water level is adjusted so that the screen mesh is 15 mm below the water surface when the hanging basket ascends to the highest point, and the top of the hanging basket must not be immersed in the solution.

[0100] Take capsules of the test product, add a baffle on the liquid surface for the test. It is qualified if all capsules disintegrate completely within 30 minutes. If 1 capsule fails to completely disintegrate, another 6 capsules shall be taken for retest, and all shall meet the requirements.

[0101] In the present invention, a parallel determination method is adopted, and the measurement results of three consecutive batches are as follows:

[0102] Table 8 Determination of disintegration time limit of test capsules

[0103] After detection, the disintegration time limit of the test capsules meets the standard specified in *Chinese Pharmacopoeia*.

[0104] 5.1.3 Determination of water content

[0105] Preliminary capsule preparation work revealed that capsules containing only microcrystalline cellulose, food-grade silica, and a small amount (0.5g) of magnesium stearate exhibited moisture absorption within one week, exhibiting high water content and viscosity, which did not meet the stability requirements for capsules. Therefore, as shown in Table 9, different amounts of magnesium stearate were used for comparative screening. Finally, considering both stability requirements and excipient dosage, a product containing 10g of compound solid extract, 5g of microcrystalline cellulose, 0.33g of food-grade silica, and 1.5g of magnesium stearate was selected as the final product. Specific grouping, water content, and stability performance are detailed below.

[0106] Table 9. Statistical table of experimental groups with different doses of magnesium stearate.

[0107] Weighing of test samples: Take 15g of each group of test samples prepared according to the formula in Table 9, and determine their moisture content under accelerated destructive testing conditions of 40±2℃ and 75±5% in January, February, March, and June. Grind the test samples into a fine powder, and quickly and accurately weigh approximately 0.3~0.4g, spread it evenly in a pre-weighed weighing bottle, and accurately weigh the total mass of the weighing bottle + the test sample (before drying). ).

[0108] Vacuum drying and constant weight: Place the weighing bottle containing the test sample in a vacuum drying oven with the mouth open, dry at 60℃ and reduced pressure to ≤2.56kPa until constant weight. After cooling for 30 minutes, accurately weigh the total mass of the weighing bottle and the dried test sample. ), calculate the net weight of the sample before and after drying ( , ).

[0109] Result calculation: Calculate the moisture content according to the formula, and take the average value as the final moisture content.

[0110] Moisture content = (net weight before drying - net weight after drying) / net weight before drying.

[0111] In the formula: The constant weight of the weighing bottle (g); The total mass (g) of the weighing bottle and the sample before drying is: The total mass (g) of the weighing bottle and the dried sample.

[0112] Since Group 1 completely bonded after one week of storage, failing to meet the quality requirements for capsule stability, moisture content testing was not conducted. The results for other dosage groups are described below.

[0113] Table 10. Observation table of water content stability in Group 2

[0114] Table 11 Observation Table of Moisture Content Stability in Group 3

[0115] Table 12 Observation Table of Moisture Content Stability in Group 4

[0116] Table 13 Observation Table of Moisture Content Stability in Group 5

[0117] Therefore, it can be concluded that Group 2 did not meet the requirement of ≤9.0% moisture content stipulated in the Chinese Pharmacopoeia in the 6th month, while Groups 3-5 all met the requirement of ≤9.0% moisture content stipulated in the Chinese Pharmacopoeia, which is within the prescribed limit.

[0118] 5.1.4 Stability observation of capsules

[0119] Grouped as in Table 9 of 5.1.3, the capsules and their contents were placed in an environment of 40±2℃ and 70±5% and photographed at 1, 2, 3 and 6 months to record whether their color changed, whether there was clumping or adhesion, deterioration or other phenomena.

[0120] like Figure 3 As shown, under accelerated destruction experimental conditions, in the first month, the contents of the capsules in groups 1 and 2 showed signs of clumping, while the contents of the capsules in groups 3-5 showed no obvious clumping or discoloration.

[0121] like Figure 4 As shown, under accelerated degradation experimental conditions, in the second month, the contents of the capsules in groups 1 and 2 had obvious agglomeration and could no longer exhibit fluid and particulate states. Groups 3-5 showed good stability and exhibited obvious color change patterns with increasing magnesium stearate dosage.

[0122] like Figure 5 As shown, under accelerated destruction experimental conditions in the third month, the contents of the first group of capsules were completely dark in color, the contents of the second group of capsules showed obvious large-area clumping, poor flowability, and irregular and intact particles, while the contents of the third to fifth groups of capsules had uniform particles and good flowability.

[0123] like Figure 6 As shown, the contents of the capsules in Group 1 had turned completely black and were highly viscous and difficult to decompose. Group 2 showed obvious clumping, poor flowability, and irregular, intact particles. Groups 3-5 had uniform particles and good flowability.

[0124] It is evident that the moisture content and stability tests in groups 3-5 all met the pharmacopoeia requirements. Considering stability, the process with the lowest excipient addition was selected as the optimal process. The formulation of this capsule consists of 10g of compound solid extract, 5g of microcrystalline cellulose, 1.5g of magnesium stearate, and 0.33g of food-grade silica. In the accelerated degradation test, the moisture content, disintegration time, and tablet weight variation of the capsule contents produced by this process all met the pharmacopoeia requirements, and the stability was good, with no obvious moisture absorption or discoloration issues.

[0125] 5.2 Evaluation of tablet quality and stability

[0126] 5.2.1 Tablet weight variation

[0127] According to the Chinese Pharmacopoeia, 20 compound tablets were randomly weighed and the average weight was calculated. The weight difference was required to be within ±5% of the average weight, as per the pharmacopoeia. The results are shown in Table 14.

[0128] Table 14 Tablet Weight Statistics

[0129] Calculations show that the average tablet weight is 0.5709g. Based on ±5%, the tablet weight variation range is 0.5424~0.5994g. The maximum values ​​in the table are 0.5429g and 0.5884g. Therefore, all values ​​fall within the tablet weight variation range, and the quality meets the standards of the Chinese Pharmacopoeia.

[0130] 5.2.2 Determination of tablet moisture content

[0131] The moisture content of tablets dried at 40±2℃ and 70±5% humidity was determined by vacuum drying. Two batches of samples were obtained in January, February, March, and June, and the average value was used to calculate the moisture content. The results are shown in Tables 15-18.

[0132] Instruments and test samples: electronic analytical balance (accuracy 0.1 mg), vacuum drying oven, flat weighing bottle, compound β-hydroxybutyric acid tablets, purified water.

[0133] Constant weight of weighing bottle: Take two clean flat weighing bottles, place them in a vacuum drying oven, dry them at 60℃ and reduced pressure to ≤2.67kPa until constant weight (the difference in mass between the two drying cycles is ≤0.3mg), take them out and quickly put them into a desiccator to cool for 30min, weigh them accurately, and record the constant weight of the weighing bottle as m1.

[0134] Sample preparation and weighing: Take the sample, prepare it into a fine powder, quickly and accurately weigh about 1-2g of the fine powder, spread it evenly in the weighing bottle, accurately weigh the total mass of the weighing bottle and the sample, record it as m2, and calculate the sample quantity (m2-m1).

[0135] Vacuum drying and constant weight determination: Place the weighing bottle containing the test sample open in a vacuum drying oven at 60℃ with reduced pressure to ≤2.67 kPa. After the first drying for 2 hours, remove the bottle, quickly tighten the cap, and place it in a desiccator to cool for 30 minutes. Weigh accurately. Dry again for 1 hour, cool, and weigh until constant weight is achieved. Record the total mass (m3) of the weighing bottle and the dried test sample. The calculation formula is: Moisture content

[0136] In the formula: m1 is the constant weight mass of the weighing bottle (g); m2 is the initial total mass of the weighing bottle and the test sample (g); m3 is the constant weight mass of the weighing bottle and the test sample after drying (g).

[0137] Table 15. Moisture Content Determination of Compound Tablets in Month 1

[0138] Table 16. Moisture Content Determination of Compound Tablets in February

[0139] Table 17. Moisture Content Measurement of Compound Tablets in March

[0140] Table 18. Moisture Content Determination of Compound Tablets in June

[0141] In summary, the tablets maintained a moisture content below 9.0% in the accelerated destructive testing, which meets the requirement of ≤9.0% moisture content in the Chinese Pharmacopoeia for tablets, and thus maintained relatively good stability.

[0142] 5.2.3 Tablet disintegration determination

[0143] Referencing the 2020 edition of the Chinese Pharmacopoeia for the disintegration time test method, the specific operating procedure is the same as that for capsule disintegration time test method 5.1.2.

[0144] Take 6 tablets of the test sample and test them using a disintegration apparatus. All Chinese herbal powder tablets should disintegrate completely within 30 minutes. If one tablet fails to disintegrate completely, take another 6 tablets for retesting, and all should meet the requirements. This invention adopts a parallel determination method, and the measurement results of three consecutive batches are shown in Table 19.

[0145] Table 19 Statistical Table of Tablet Disintegration Time Test Results

[0146] The tablet disintegration time was determined to be in accordance with the time standard stipulated in the Chinese Pharmacopoeia.

[0147] 5.2.4 Tablet stability observation

[0148] The test tablets were divided into three batches and placed in an environment of 40±2℃ and 70±5% humidity for accelerated degradation experiments. The appearance and color changes, whether there was clumping or adhesion, and whether there were cracked, loose or deteriorated phenomena were recorded in January, February, March and June.

[0149] like Figure 7-10 As shown, in the accelerated degradation experiments at 1, 2, 3, and 6 months, the tablets did not show obvious signs of loosening or cracking, and the tablet color did not change significantly. The tablets maintained relatively good stability in the accelerated degradation experiments.

[0150] This invention evaluates the stability of tablets. Tablet weight variations all conform to the Chinese Pharmacopoeia standards. Moisture content in different months is below the specified standard, and the tablets completely disintegrate within a specified 30 minutes. Under accelerated degradation test conditions of high temperature and humidity for 6 months, the tablets showed no abnormalities such as loosening or cracking, and no significant color change. The overall stability of the tablets was good, and the measured indicators met the standards specified in the 2020 edition of the Chinese Pharmacopoeia.

[0151] Observation on the effect of 6 tablets in improving mild neurodegenerative diseases

[0152] This invention targets middle-aged and elderly individuals in the surrounding community who meet the criteria for neurodegenerative diseases. A total of 36 subjects were included in the study, comprising 17 males and 19 females, with a mean age of (62.24±5.18) years and a mean disease duration of (2.26±0.57) years. Clinical observation forms were collected from the subjects 8 weeks after they began taking the tablets prepared in section 4.1 to report their improvement. Specific evaluation indicators and feedback results are detailed below.

[0153] Inclusion criteria for study participants:

[0154] (1) Meets the diagnostic criteria for neurodegenerative diseases such as AD.

[0155] (2) Can swallow tablets normally and has normal digestive ability.

[0156] (3) Able to cooperate with research and have regular companionship.

[0157] (4) Be able to take the tablet products on time, accept the observation required by the research institute and provide feedback regularly.

[0158] (5) Sign the informed consent form.

[0159] Exclusion criteria for study subjects:

[0160] (1) The patient had taken psychotropic drugs within one week prior to enrollment.

[0161] (2) Severe AD, or mental symptoms caused by stroke, depression or other diseases.

[0162] (3) Poor control of underlying diseases, with large fluctuations in blood sugar, blood pressure, blood lipids, etc.

[0163] (4) Major diseases such as malignant tumors, heart failure, renal failure, and autoimmune diseases.

[0164] (5) Allergic to any of the ingredients involved in the research.

[0165] The study participants took 4 tablets (0.5g / tablet) three times a day for 8 weeks and completed a clinical observation form to collect feedback.

[0166] The observation indicators are examined from multiple perspectives and are mainly divided into four major sections: mental and behavioral symptoms, cognitive function, traditional Chinese medicine syndromes, and other comprehensive indicators of motor function.

[0167] Mental and behavioral symptoms: Mental and behavioral symptoms are assessed using the NPI scale. The severity of each symptom in the NPI is divided into 3 levels and the frequency is divided into 4 levels. The assessment is based on the sum of the product of the severity and frequency of each mental disorder before and after treatment. The higher the score, the worse the mental symptoms.

[0168] Cognitive function: Cognitive function is assessed using the MMSE. The total score for the MMSE is 30 points, with lower scores indicating poorer cognitive function.

[0169] Traditional Chinese Medicine Syndrome Score Scale: The TCM syndrome score is assessed using five items: poor memory, palpitations, poor sleep with many dreams, hot flashes and sweating, and five-center heat. Each item is scored from 0 to 4 points, for a total of 20 points. The higher the score, the more severe the symptoms.

[0170] Other comprehensive evaluation indicators were assessed across six dimensions: limb muscle tone, limb muscle strength and voluntary movement ability, involuntary movement signs, gait balance and coordination function, and fine motor skills and body coordination ability. Each dimension was further divided into six sub-dimensions, with the first three scored out of 20 points, the middle two out of 15 points, and the last out of 10 points. These sub-dimensions were then assessed using four levels, resulting in a detailed evaluation table. See Tables 20-26 for details.

[0171] Table 20 Feedback Form on Improvement Effects During Weeks 0-8

[0172] Table 21 Comparison of MMSE Scores (n=35) Scoring Quantification Table

[0173] Table 22 Evaluation of NPI (n=35) in Weeks 0-8

[0174] The higher the level, the worse the effect.

[0175] Table 23 Quantification Table of TCM Syndrome Scores (n=35)

[0176] Table 24 Comprehensive Evaluation Table for Athletic Ability

[0177]

[0178] Table 25 Observation of the effect of tablets on improving mild neurodegenerative diseases Table 1

[0179]

[0180] Table 26 Observation of the effect of tablets on improving mild neurodegenerative diseases (evaluation of movement disorders)

[0181]

[0182]

[0183] The feedback above indicates that no adverse reactions were found, and the tablet is safe and effective.

[0184] The technical solutions provided by the embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the embodiments of the present invention. The descriptions of the embodiments above are only for helping to understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the embodiments of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A method for preparing a compound β-hydroxybutyric acid traditional Chinese medicine solid dosage form, characterized in that the steps include... include: (1) Weigh out Polygonatum, ginseng, peppermint and wolfberry according to the prescription, add water to extract and obtain filtrate; (2) Concentrate the filtrate obtained in (1); (3) Add β-hydroxybutyric acid to the concentrated Chinese medicine solution obtained in (2) to obtain a compound mixed concentrated solution; (4) Add maltodextrin to the compound mixed concentrate obtained in (3), mix well and spray dry to obtain compound β-hydroxybutyric acid Chinese medicine solid extract; (5) Pulverize the compound β-hydroxybutyric acid traditional Chinese medicine solid extract and microcrystalline cellulose separately, and mix them evenly; (6) Add food-grade silica and magnesium stearate to the powder obtained in step (5), grind and mix evenly to make a solid preparation.

2. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine solid dosage form according to claim 1, characterized in that, The ratio of Polygonatum, ginseng, mint, and wolfberry by weight is 9:3:3:

6.

3. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine preparation according to claim 2, characterized in that, In step (3), if the total weight of Polygonatum, ginseng, mint, and wolfberry is 21g, then the amount of β-hydroxybutyric acid used is 2.5ml.

4. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine solid dosage form according to claim 2, characterized in that, In step (4), the compound mixed concentrate and maltodextrin are 20:10 by weight.

5. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine preparation according to claim 2, characterized in that, By weight, the ratio of compound β-hydroxybutyric acid traditional Chinese medicine solid extract: microcrystalline cellulose: food-grade silicon dioxide: magnesium stearate = 10:5:0.33:1.

5.

6. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine solid dosage form according to claim 2, characterized in that, The extraction parameters in step (1) are: extraction temperature 100℃, extraction twice, 1.5h each time, and filtrate combined.

7. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine solid dosage form according to claim 2, characterized in that, In step (2), the concentration parameters are 70°C and 0.7 kPa for 3 hours.

8. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine preparation according to claim 2, characterized in that, In step (4), the parameters for spray drying are: inlet air temperature 120°C, outlet air temperature 60°C, and flow rate 1.5 ml / min.

9. The method for preparing the compound β-hydroxybutyric acid traditional Chinese medicine solid dosage form according to claim 1, characterized in that, The solid dosage form is a capsule or tablet.

10. A compound β-hydroxybutyric acid traditional Chinese medicine solid preparation prepared by the method described in any one of claims 1-9.

Images