A type of orally disintegrating tablet containing Artemisia annua polypeptide, its preparation method and quality evaluation

Abstract

This invention relates to an orally disintegrating tablet containing Artemisia capillaris polypeptide and its preparation method, belonging to the field of pharmaceutical formulation technology. This tablet addresses the problems of traditional orally disintegrating tablets, such as the contradiction between disintegration rate and mechanical strength, rough taste, and complex processing, by optimizing the excipient combination and preparation process to achieve performance improvement. Using Artemisia capillaris polypeptide as the active ingredient, combined with a cross-linked povidone and microcrystalline cellulose-mannitol composite filler system, and supplemented with sucralose, sodium chloride, and peppermint flavoring agents, it is prepared using a direct powder compression method. The product provided by this invention is suitable for rapid administration to patients with dysphagia, providing an efficient delivery solution for the clinical application of Artemisia capillaris polypeptide.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an orally disintegrating tablet made from Artemisia annua polypeptide, its preparation method, and quality evaluation. Background Technology

[0002] Sargassum pallidum is an important medicinal species belonging to the Sargassum family of the Phaeophyte phylum. Its polypeptide components, extracted from algal proteins through enzymatic hydrolysis or chemical methods, possess antioxidant, antitumor, and glucose metabolism-regulating activities. Studies have shown that these polypeptides can scavenge free radicals, inhibit tumor cell proliferation, and enhance insulin sensitivity; however, the development of existing dosage forms lags behind, hindering their clinical application.

[0003] This invention addresses the aforementioned problems by proposing an orally disintegrating tablet made from Artemisia annua polypeptide and its preparation method. By screening highly swellable disintegrants and composite fillers, rapid disintegration within 20 seconds is achieved while maintaining tablet hardness. The use of flavoring agents and the synergistic effect of peppermint flavoring optimizes the taste and reduces any gritty sensation. This invention provides a novel, efficient, and safe delivery solution for polypeptide active ingredients. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing an orally disintegrating tablet of Artemisia annua polypeptide, its preparation method and quality evaluation.

[0005] To achieve the objectives of this invention, the following technical means are specifically employed:

[0006] A *Artemisia annua* polypeptide orally disintegrating tablet, characterized in that it comprises the following components by weight percentage (based on the total weight of the orally disintegrating tablet):

[0007] Active ingredient: 3.45% Artemisia annua polypeptide, with the following quality requirements: molecular weight ≤1000 Da, purity ≥99%, total heavy metals ≤10 ppm, total bacterial count ≤1000 cfu / g;

[0008] Disintegrant: 6.9%-10% crospovidone, the amount of which is adjusted by adjusting the proportion of the added filler to keep the total amount of the formulation 100%;

[0009] Internal filler: 3.1% mannitol;

[0010] Additional filler: selected from one of the following combinations:

[0011] (a) Microcrystalline cellulose (78.97%-82.07%), wherein microcrystalline cellulose accounts for 100% of the total amount of the added filler;

[0012] (b) Mannitol (78.97%-82.07%), wherein mannitol accounts for 100% of the total amount of the added filler;

[0013] (c) A combination of microcrystalline cellulose and mannitol, with a mass ratio of 1:3.76, and the proportions of microcrystalline cellulose being 16.59%-17.24% and mannitol being 62.38%-64.83%;

[0014] (d) A combination of microcrystalline cellulose and mannitol, with a mass ratio of 3.76:1, and the proportion of microcrystalline cellulose being 62.38%-64.83% and the proportion of mannitol being 16.59%-17.24%;

[0015] Flavoring agent: selected from a combination of sucralose (1.03%) and sodium chloride (1.38%), stevioside (2.41%), or aspartame (2.41%).

[0016] Lubricant: 1.38% magnesium stearate;

[0017] Flavoring: 0.28% peppermint flavoring;

[0018] Glide aid: 0.41% colloidal silica;

[0019] The disintegrating tablet has a disintegration time of ≤30 seconds in the oral cavity, a tablet hardness of 19.6-98N, and a tablet weight of 100±7.5mg.

[0020] The orally disintegrating tablet is characterized in that the added filler is a combination of microcrystalline cellulose and mannitol, with a mass ratio of 1:3.76, and the proportion of microcrystalline cellulose is 16.59%-17.24% and the proportion of mannitol is 62.38%-64.83%.

[0021] The orally disintegrating tablet is characterized in that the added filler is a combination of microcrystalline cellulose and mannitol, with a mass ratio of 3.76:1, and the proportion of microcrystalline cellulose is 62.38%-64.83% and the proportion of mannitol is 16.59%-17.24%.

[0022] The orally disintegrating tablet, characterized in that the preparation method of the disintegrating tablet includes the following steps:

[0023] (1) Inner phase mixing: Mix the seaweed polypeptide, the selected flavoring agent, peppermint flavoring and inner phase mannitol evenly;

[0024] (2) External phase mixing: Cross-linked polyvinyl ketone, added filler, colloidal silica and magnesium stearate are mixed evenly;

[0025] (3) Total mixing and tableting: The internal and external phase materials are mixed by equal incremental addition and then compressed into tablets by direct powder compression. The die is a 6.0mm shallow concave die, the tablet weight is 100±7.5mg, and the tablet hardness is controlled at 19.6-98N.

[0026] The preparation method is characterized in that the tablet hardness is preferably 19.6-39.2N and the disintegration time is ≤12 seconds.

[0027] The application of the orally disintegrating tablets is characterized in that the disintegrating tablets are used in the fields of diabetes management, adjuvant anti-tumor therapy or antioxidant health care, and achieve efficient delivery of active ingredients based on the bioactivity of Artemisia capillaris polypeptides and their rapid oral disintegration characteristics.

[0028] The seaweed polypeptide described in this invention is an off-white powder with a particle size standard of 100% passing through an 80-mesh sieve, a peptide content (on a dry basis) ≥99%, a molecular weight ≤1000 Da, a loss on drying ≤5.0%, an ash content ≤5.0%, pesticide residues not detectable, total heavy metals ≤10 ppm, arsenic content ≤10 ppm, lead content ≤10 ppm, total bacterial count ≤1000 cfu / g, yeast and mold ≤100 cfu / g, Escherichia coli not detectable, Salmonella not detectable, and Staphylococcus not detectable.

[0029] Beneficial effects

[0030] The beneficial effects of this invention are:

[0031] 1. This invention utilizes crospovidone as a preferred disintegrant, combined with a specific ratio of microcrystalline cellulose to mannitol, to achieve rapid disintegration of orally disintegrating tablets within 20 seconds, significantly superior to the 60-second standard of the Chinese Pharmacopoeia. This characteristic avoids the swallowing difficulties associated with traditional tablets, making it particularly suitable for children, the elderly, and patients with swallowing disorders.

[0032] 2. Through the synergistic effect of flavoring agents and peppermint flavoring, the bitter taste of polypeptide components is significantly improved, enhancing patient compliance. Furthermore, the purity of Artemisia capillaris polypeptides is strictly limited to ≥99%, heavy metals ≤10ppm, and microbiological indicators meet pharmacopoeia requirements, ensuring medication safety. Detailed Implementation

[0033] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] The following is a description of the Artemisia annua polypeptide used in this invention: The manufacturer is Xi'an Muguo Biotechnology Co., Ltd., product batch number: MG-2024081502. It is an off-white powder with a particle size standard of 100% passing through an 80-mesh sieve. The peptide content (on a dry basis) is 99.07%, molecular weight ≤1000 Da, loss on drying is 0.79%, ash content is 1.42%, pesticide residues were not detected, total heavy metals ≤10 ppm, arsenic content ≤10 ppm, lead content ≤10 ppm, total bacterial count ≤1000 cfu / g, yeast and mold ≤100 cfu / g, Escherichia coli, Salmonella, and Staphylococcus were not detected.

[0035] Example 1

[0036] 1. Preliminary prescription and preparation method

[0037] Taking into account the physicochemical properties of Artemisia annua polypeptides and the general formulation of orally disintegrating tablets, the preliminary formulation of this product is shown in Table 1 below.

[0038] Table 1 Preliminary prescription

[0039]

[0040] The preliminary proposed preparation method for this product is as follows: Weigh the materials according to the above-mentioned proposed formula, mix the internal and external phases separately, and mix the internal and external phases by adding them in equal increments. Compress the powder using the direct powder compression method, using a 6.0mm shallow concave die, with a target tablet weight of 100mg.

[0041] 2. The calculation and measurement methods for some evaluation indicators are as follows:

[0042] 2.1 Disintegration Time Limit

[0043] According to General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the disintegration time of orally disintegrating tablets shall be determined by a lift-type disintegrator. All six tablets shall completely disintegrate and pass through the sieve within 60 seconds. A small amount of light floating matter is allowed, but no hard core shall remain.

[0044] 2.2 Taste Evaluation

[0045] Sensory evaluation experiments were conducted, and 10 healthy volunteers were selected to taste the samples and evaluate the taste of the samples by classifying them as sour, sweet, bitter, etc.

[0046] Example 2: Screening of Prescription Composition

[0047] 1. Study on prescription composition

[0048] 1.1 Research on Disintegrant Varieties

[0049] Commonly used disintegrants in orally disintegrating tablets include croscarmellose sodium, croscarmellose, and carboxymethyl starch sodium. This experiment investigated the effects of these three disintegrants on the product. All materials except the disintegrants were weighed according to the proposed formula. Then, the disintegrants in the proposed formula were replaced with the three mentioned above. Tablets were prepared according to the proposed method, and the three samples were controlled within the same tablet hardness range and the same target tablet weight. The disintegration time of the three samples was compared. The results of the disintegrant selection experiment are shown in Table 2.

[0050] Table 2 Experimental data on the selection of disintegrant varieties

[0051] Disintegrant varieties Tablet weight (g) Hardness range Disintegration Time Cross-linked polyvinylpyrrolidone 0.1037±0.007778 20-50N 10 seconds Cross-linked carboxymethyl cellulose sodium 0.1068±0.00801 20-50N 1 minute 48 seconds Sodium carboxymethyl starch 0.1032±0.00774 20-50N 2 minutes and 36 seconds

[0052] Based on the above experimental results, only the crospovidone group sample had a disintegration time of less than 60 seconds, which meets the requirements of the 2020 edition of the Chinese Pharmacopoeia for the disintegration time limit of orally disintegrating tablets. Therefore, crospovidone was selected as the disintegrant for the product.

[0053] 1.2 Study on the dosage of disintegrant

[0054] The disintegrants identified in the above experiments were used at dosages of 4%, 6.9%, and 10%, respectively. The total dosage of the formulation was maintained at 100% by adjusting the amount of added mannitol, while other formulation parameters remained constant. Tablets were prepared according to the proposed method, ensuring that all samples maintained the same tablet hardness range and target tablet weight. The disintegration time of the three samples was compared. The disintegrant dosage screening experiment is shown in Table 3.

[0055] Table 3 Experimental data on the selection of disintegrant dosage

[0056] Disintegrant prescription dosage Tablet weight (g) Hardness range Disintegration Time 4％ 0.1029±0.007718 20-50N 1 minute 3 seconds 6.9％ 0.1015±0.007613 20-50N 10 seconds 10％ 0.1020±0.00765 20-50N 13 seconds

[0057] Based on the above experimental results, it can be seen that when the dosage of the disintegrant is 6.9% or 10%, the disintegration time of the prepared samples meets the requirements of the 2020 edition of the Chinese Pharmacopoeia. Therefore, the dosage of the disintegrant can be selected from 6.9% to 10%. Considering that the disintegration is faster when the dosage is 6.9%, a dosage of 6.9% disintegrant is temporarily selected for subsequent experimental investigation.

[0058] 1.3 Study on the proportion of added fillers

[0059] Using the disintegrant types and dosages screened in the above experiments, and keeping the total proportion of microcrystalline cellulose and mannitol in the added portion constant at 82.07%, the disintegration time of samples under four combinations were investigated: microcrystalline cellulose (82.07%), mannitol (82.07%), microcrystalline cellulose (17.24%) + mannitol (64.83%), and microcrystalline cellulose (64.83%) + mannitol (17.24%). The dosages of other materials were the same as the proposed formulation. Using the proposed preparation method, the four groups of samples maintained the same tablet hardness range and target tablet weight. The screening experiment for the proportion of added fillers is shown in Table 4.

[0060] Table 4. Experimental data on the screening of the proportion of added fillers

[0061] Filler ratio Tablet weight (g) hardness Disintegration time limit microcrystalline cellulose 0.1075±0.008063 20-50N 14 seconds Mannitol 0.1083±0.008123 20-50N 12 seconds Microcrystalline cellulose 17.24% + mannitol 64.83% 0.1044±0.00783 20-50N 12 seconds Microcrystalline cellulose 64.83% + mannitol 17.24% 0.1042±0.007815 20-50N 8 seconds

[0062] Based on the above findings, the disintegration time of samples prepared using the four filler combinations all met the standards of the 2020 edition of the Chinese Pharmacopoeia. All four filler combinations can be used as filler combinations for this product; for now, a microcrystalline cellulose of 17.24% + mannitol of 64.83% has been selected for further research.

[0063] 1.4 Study on Lubricant Dosage

[0064] Using the disintegrant types, dosages, and filler ratios selected in the above experiments, the dosage of magnesium stearate lubricant was set at 0.5%, 0.9%, and 1.38%, respectively. The total formulation amount was maintained at 100% by adjusting the amount of added mannitol. Other formulation dosages were based on the optimal results selected in the above experiments. Tablets were prepared according to the proposed method, and the flowability (angle of repose) and disintegration time after compression of the three combined samples were compared. The lubricant dosage screening experiment is shown in Table 5.

[0065] Table 5. Data from the Lubricant Dosage Screening Experiment

[0066] Lubricant dosage Tablet weight (g) Hardness range Angle of repose Disintegration time limit 0.5％ 0.1045±0.007838 20-50N 41.942° 11 seconds 0.9％ 0.1061±0.007958 20-50N 40.2576° 9 seconds 1.38％ 0.1065±0.007988 20-50N 29.091° 11 seconds

[0067] The results of the above investigation show that when the lubricant addition is 1.38%, the angle of repose of the total mixed material is <40°, and the disintegration time of the finished product meets the standard of the 2020 edition of the Chinese Pharmacopoeia. Therefore, the addition amount of magnesium stearate as lubricant is determined to be 1.38%.

[0068] 1.5 Study on Flavoring Agent Varieties

[0069] The following flavoring agents were used: 1.03% sucralose + 1.38% sodium chloride, 2.41% stevioside, and 2.41% aspartame. The taste and disintegration time of the samples prepared by the three flavoring agents were compared. The dosage and types of other prescriptions were based on the best results selected in the above experiments. The dosage and types of materials not investigated were based on the proposed prescriptions and the proposed preparation methods to prepare samples. The flavoring agent variety screening experiment is shown in Table 6.

[0070] Table 6. Experimental data on the screening of flavoring agents

[0071] Flavoring agent varieties Tablet weight (g) Hardness range taste Disintegration time limit Sucralose + Sodium Chloride 0.1065±0.007988 20-50N The sweetness is moderate and the taste is good. 8 seconds Stevia 0.1067±0.008003 20-50N Slightly sweet 10 seconds Aspartan 0.1069±0.008018 20-50N It has a strong sweetness 7 seconds

[0072] The above results show that the samples prepared by combining the three flavoring agents all have acceptable taste, and their disintegration times all meet the standards of the 2020 edition of the Chinese Pharmacopoeia. Therefore, the flavoring agents for this product can be selected as follows: 1.03% sucralose + 1.38% sodium chloride, 2.41% stevioside, and 2.41% aspartame.

[0073] Example 3: Screening of Preparation Process

[0074] 1. Study on tablet hardness

[0075] Based on the formulation determined through the above experiments, the tablet hardness of the product was set to 19.6–39.2 N, 49–68.6 N, and 78.4–98 N, respectively. The disintegration time of samples in different tablet hardness ranges was compared. The tablet hardness screening experiments are shown in Table 7.

[0076] Table 7. Experimental data for screening tablet hardness

[0077] Tablet hardness range Tablet weight (g) Disintegration time limit 19.6～39.2N 0.1054±0.007905 12 seconds 49～68.6N 0.1054±0.007905 23 seconds 78.4～98N 0.1055±0.007913 29 seconds

[0078] The above experimental results show that the tablet hardness of this product is within the range of 19.6-98N, and the disintegration time of the prepared product meets the standards of the 2020 edition of the Chinese Pharmacopoeia. Therefore, the tablet hardness range of this product is determined to be 19.6-98N.

[0079] Based on the above experimental screening, the formulation composition of this product is determined as follows:

[0080]

[0081]

[0082] Note: The added filler can be selected as microcrystalline cellulose (82.07% of the formulation), or microcrystalline cellulose (17.24% of the formulation) + mannitol (64.83% of the formulation), or microcrystalline cellulose (64.83% of the formulation) + mannitol (17.24% of the formulation). The dosage of the disintegrant can be selected from 6.9% to 10%. The flavoring agent of this product can be selected as sucralose 1.03% + sodium chloride 1.38%, or stevioside 2.41%, or aspartame 2.41%.

[0083] Based on the above experiments, the preparation process of this product was determined as follows: Weigh the prescribed amount of material, mix the internal and external phases separately, and mix the internal and external phases by adding them in equal increments. The powder is directly compressed into tablets using a 6.0mm shallow concave die. The target tablet weight is 100mg, and the tablet hardness range is 19.6-98N.

[0084] Example 4 Quality Evaluation

[0085] 1. Appearance

[0086] The tablets are uniform, round, convex pieces approximately 6 mm in diameter and 2.5 mm in height. They have a smooth surface with a slight sheen, are predominantly white, have relatively sharp edges but no burrs, and are intact without cracks. They have no special odor, moderate hardness, and are not easily broken.

[0087] 2. Tablet weight difference

[0088] Referring to the determination method in the 2020 edition of the Chinese Pharmacopoeia, take 20 tablets of Artemisia annua polypeptide orally disintegrating tablets prepared according to the above-screened prescription and preparation process, accurately weigh the total weight, calculate the average tablet weight, and then accurately weigh each tablet separately. Compare the weight of each tablet with the average tablet weight. According to the provisions in the table, no more than 2 tablets shall exceed the weight difference limit, and no tablet shall exceed the limit by 1 time.

[0089] Average tablet weight or labeled tablet weight / g Quality variation limit / % Less than 0.30g ±7.5％ 0.30g and above ±5％

[0090] Following the above method, the following weights (in grams) of 20 tablets were weighed: 0.0982; 0.1038; 0.0981; 0.0931; 0.1063; 0.1070; 0.1041; 0.1056; 0.1008; 0.1054; 0.1058; 0.101; 0.1027; 0.1038; 0.1043; 0.1050; 0.1014; 0.1042; 0.1019; 0.1006. Calculations showed that only one tablet (0.0931g) exceeded the lower limit (0.0947g), but did not exceed the limit by more than 100%. The remaining 19 tablets were all within the allowable range. Based on the above judgment criteria, the tablet weight variation of this product is acceptable.

[0091] 3. Hardness Measurement

[0092] Referring to the General Chapter IV (0923 Tablet Friability Test Method) of the 2020 edition of the Chinese Pharmacopoeia, the hardness of the product was determined using a tablet hardness tester. Five consecutive samples were tested, and the hardness values ​​were 42N, 41.9N, 39N, 34.2N, and 29.8N, respectively.

[0093] 4. Disintegration time limit

[0094] Take 6 tablets of Artemisia annua polypeptide orally disintegrating tablets prepared according to the above-selected prescription and preparation process, and use a lift-type disintegration apparatus to examine the disintegration time limit of the samples in accordance with the "disintegration time limit test method" of the 2020 edition of the Chinese Pharmacopoeia.

[0095] The disintegration times were measured to be 8 seconds, 8 seconds, 9 seconds, 10 seconds, 10 seconds, and 11 seconds, which meet the requirements.

[0096] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A kind of Artemisia annua polypeptide orally disintegrating tablet, characterized in that, The product contains the following components by weight percentage (based on the total weight of the orally disintegrating tablet): Active ingredient: 3.45% Artemisia annua polypeptide, with the following quality requirements: molecular weight ≤1000 Da, purity ≥99%, total heavy metals ≤10 ppm, total bacterial count ≤1000 cfu / g; Disintegrant: 6.9%-10% crospovidone, the amount of which is adjusted by adjusting the proportion of the added filler to keep the total amount of the formulation 100%; Internal filler: 3.1% mannitol; Additional filler: selected from one of the following combinations: (a) Microcrystalline cellulose (78.97%-82.07%), wherein microcrystalline cellulose accounts for 100% of the total amount of the added filler; (b) Mannitol (78.97%-82.07%), wherein mannitol accounts for 100% of the total amount of the added filler; (c) A combination of microcrystalline cellulose and mannitol, with a mass ratio of 1:3.76, and the proportion of microcrystalline cellulose being 16.59%-17.24% and the proportion of mannitol being 62.38%-64.83%; (d) A combination of microcrystalline cellulose and mannitol, with a mass ratio of 3.76:1, and the proportion of microcrystalline cellulose being 62.38%-64.83% and the proportion of mannitol being 16.59%-17.24%; Flavoring agent: selected from a combination of sucralose (1.03%) and sodium chloride (1.38%), stevioside (2.41%), or aspartame (2.41%); Lubricant: 1.38% magnesium stearate; Flavoring: 0.28% peppermint flavoring; Glide aid: 0.41% colloidal silica; The disintegrating tablet has a disintegration time of ≤30 seconds in the oral cavity, a tablet hardness of 19.6-98N, and a tablet weight of 100±7.5mg.

2. The orally disintegrating tablet according to claim 1, characterized in that, The added filler is a combination of microcrystalline cellulose and mannitol. The mass ratio of the two is 1:3.76, and the proportion of microcrystalline cellulose is 16.59%-17.24% and the proportion of mannitol is 62.38%-64.83%.

3. The orally disintegrating tablet according to claim 1, characterized in that, The added filler is a combination of microcrystalline cellulose and mannitol, with a mass ratio of 3.76:1, and the proportion of microcrystalline cellulose is 62.38%-64.83% and the proportion of mannitol is 16.59%-17.24%.

4. The orally disintegrating tablet according to claim 1, characterized in that, The method for preparing the disintegrating tablets includes the following steps: (1) Inner phase mixing: Mix the seaweed polypeptide, the selected flavoring agent, peppermint flavoring and inner phase mannitol evenly; (2) External phase mixing: Cross-linked polyvinyl ketone, added filler, colloidal silica and magnesium stearate are mixed evenly; (3) Total mixing and tableting: The internal and external phase materials are mixed by equal incremental addition and then compressed into tablets by direct powder compression. The die is a 6.0mm shallow concave die, the tablet weight is 100±7.5mg, and the tablet hardness is controlled at 19.6-98N.

5. The preparation method according to claim 4, characterized in that, The tablet hardness is preferably 19.6-39.2N, and the disintegration time is ≤12 seconds.

6. The application of an orally disintegrating tablet according to any one of claims 1-5, characterized in that, The disintegrating tablets are used in diabetes management, adjuvant anti-tumor therapy, or antioxidant health care. Based on the bioactivity of Artemisia capillaris polypeptides and their rapid oral disintegration characteristics, they achieve efficient delivery of active ingredients.

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