Compound Sarcandra glabra buccal tablet and preparation method thereof

Abstract

The application discloses a compound Sarcandra glabra buccal tablet and a preparation method thereof, and particularly relates to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: (1) inclusion: mint camphor and mint oil are subjected to melt treatment to obtain a mint camphor oil melt solution; the mint camphor oil melt solution is mixed with hydroxypropyl-beta-cyclodextrin and ardisia japonica infusion to prepare an inclusion compound through grinding; (2) granulation: the inclusion compound is mixed with sorbitol to prepare granules; and (3) tabletting: the granules are mixed with a lubricant, tabletted and coated to obtain the compound Sarcandra glabra buccal tablet. The compound Sarcandra glabra buccal tablet has a good cooling taste, and the uniformity and stability of the mint camphor and the mint oil are significantly improved. In the application, the hydroxypropyl-beta-cyclodextrin with high water solubility is dissolved in the ardisia japonica infusion to perform the inclusion of the mint camphor and the mint oil, and the ardisia japonica infusion is directly used for granulation and drying, so that the steps of refrigeration, filtration, drying and crushing of the traditional beta-cyclodextrin inclusion compound are not needed, and the method is simple and short in time.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a compound herbal lozenge and its preparation method. Background Technology

[0002] Compound Coral Gum Lozenges are recorded in Part I of the Chinese Pharmacopoeia (2020 edition). The prescription consists of 30g of *Hedyotis diffusa* extract, 0.5g of menthol, and 0.3mL of peppermint oil. The *Hedyotis diffusa* extract is prepared by decocting *Hedyotis diffusa* twice with water, the first time for 2 hours and the second time for 1.5 hours. The decoctions are combined, filtered, and the filtrate is concentrated to a relative density of 1.15 (80℃). Ethanol is added to a concentration of 65%, and the mixture is allowed to stand for 24 hours. After filtration, the ethanol is recovered under reduced pressure, and the filtrate is concentrated to a clear extract with a relative density of 1.24-1.26. The *Hedyotis diffusa* extract is granulated with appropriate excipients and dried. Menthol and peppermint oil are mixed and dissolved, then mixed with the granules and compressed into tablets or coated with a film. It has the effects of dispelling wind and clearing heat, reducing swelling and relieving pain, and clearing the throat. It is often used for sore throat caused by exogenous wind-heat, with symptoms such as sore throat, hoarseness, and loss of voice.

[0003] The raw material of Compound Herbal Coral Lozenges, menthol, is a saturated cyclic alcohol obtained by steam distillation, freezing, and recrystallization of the fresh stems and leaves of the mint plant (Lamiaceae family). It is a colorless needle-shaped or prismatic crystal or a white crystalline powder. Menthol oil is a volatile oil extracted from the fresh stems and leaves of the mint plant (Lamiaceae family) through steam distillation, freezing, and partial dementing. It is a colorless or pale yellow clear liquid. Both menthol and menthol oil have the effects of dispelling wind and clearing heat, and detoxifying. When applied to the skin or mucous membranes, they have a cooling and antipruritic effect. When taken internally, they can be used as a carminative for headaches and inflammation of the nose, pharynx, and throat. As a flavoring agent, they can be used in toothpaste, perfume, beverages, and candies. However, due to their unique chemical properties, they are highly volatile and unstable, which is not conducive to the taste and efficacy of the product. The compound herbal lozenges prepared using traditional methods have volatile menthol and peppermint oil, leading to unstable content during production and storage, which affects the product's refreshing taste and efficacy. Poor uniformity: Existing mixing methods result in extremely uneven formulation, affecting product quality.

[0004] Therefore, numerous studies have been conducted on methods for protecting menthol or peppermint oil. Chinese invention patent CN105664172A discloses a method for preparing menthol inclusion complexes. The method involves ultra-finely pulverizing menthol into ultrafine powder; then ultrasonically mixing hydroxypropyl-β-cyclodextrin and water to prepare a saturated aqueous solution of hydroxypropyl-β-cyclodextrin; finally, slowly adding the ultrafine menthol powder to the saturated aqueous solution of hydroxypropyl-β-cyclodextrin, continuously ultrasonically encapsulating the menthol, allowing it to stand, filtering, and vacuum drying to obtain the menthol hydroxypropyl-β-cyclodextrin inclusion complex. In this patented method, the ultrafine menthol powder with a particle size of less than 5 μm needs to account for more than 90% of the total content, and the saturation rate of menthol is approximately 82%, indicating significant room for improvement.

[0005] Chinese invention patent CN116650486A discloses a cetirizine hydrochloride formulation containing menthol and its preparation method. The formulation describes a menthol inclusion complex process: β-cyclodextrin is added to an aqueous solution or dilute ethanol solution to prepare an inclusion solution; menthol is added to the inclusion solution to perform menthol inclusion; the included complex is filtered, washed, and dried to obtain the menthol inclusion complex. While inclusion of menthol can improve its stability, this formulation also contains excipients such as fillers, binders, disintegrants, and lubricants, which significantly affect stability, making it difficult to determine the specific inclusion effect.

[0006] Furthermore, the existing menthol inclusion technology involves complex preparation processes, long inclusion times, and low inclusion rates; the formulation also exhibits poor stability and uniformity. To address these technical issues, further research is needed on the preparation method of Compound Herba Sarcandrae Lozenges to obtain a method that offers product stability, high uniformity of active ingredients, short inclusion time, high inclusion rate, and a simple process. Summary of the Invention

[0007] This invention provides a compound herbal lozenge and its preparation method. The invention involves mixing and encapsulating molten menthol and peppermint oil with hydroxypropyl-β-cyclodextrin and *Hedyotis diffusa* extract, then granulating with sorbitol, and finally compressing with a lubricant to obtain a tablet. The resulting compound herbal lozenge has a refreshing taste, and the uniformity and stability of menthol and peppermint oil are significantly improved. This invention fully utilizes the spray granulation process of the inclusion complex prepared from *Hedyotis diffusa* extract. Highly water-soluble hydroxypropyl-β-cyclodextrin is dissolved in *Hedyotis diffusa* extract to encapsulate menthol and peppermint oil, and then directly granulated and dried together with the *Hedyotis diffusa* extract. This eliminates the need for separate refrigeration, filtration, drying, and pulverization steps required by traditional β-cyclodextrin inclusion complexes, resulting in a simple and quick preparation method.

[0008] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0009] On one hand, the present invention provides a method for preparing compound herbal lozenges, comprising the following steps:

[0010] (1) Inclusion: Menthol and peppermint oil were melted to obtain menthol oil melt; the menthol oil melt was mixed with hydroxypropyl-β-cyclodextrin and eugenol extract and ground to prepare inclusion complex;

[0011] (2) Granulation: The inclusion complex and sorbitol are mixed and granulated to obtain granules;

[0012] (3) Tablet preparation: Mix the granules with the lubricant and compress them into tablets to obtain compound herbal lozenges.

[0013] Preferably, in step (1), the melting process specifically involves mixing menthol and peppermint oil and heating to 40-60°C to prepare a menthol oil melt.

[0014] Preferably, in step (1), the ratio of the mass of menthol to the volume of peppermint oil is 0.5g:0.2-0.4mL; more preferably, it is 0.5g:0.3mL.

[0015] Preferably, in step (1), the amount of hydroxypropyl-β-cyclodextrin used is 8-12 times the weight of the menthol oil melt.

[0016] More preferably, in step (1), the amount of hydroxypropyl-β-cyclodextrin used is 10-12 times the weight of the menthol oil melt.

[0017] More preferably, in step (1), the amount of hydroxypropyl-β-cyclodextrin used is 10 times the weight of the menthol oil melt.

[0018] Preferably, in step (1), the mixing specifically involves mixing hydroxypropyl-β-cyclodextrin with *Hedyotis diffusa* extract to form a hydroxypropyl-β-cyclodextrin *Hedyotis diffusa* solution; then grinding it with molten menthol oil; more preferably, the grinding is carried out in a colloid mill.

[0019] Preferably, in step (1), the amount of the herb extract is 60 times the mass of menthol.

[0020] More preferably, in step (1), the amount of the herb extract is 60 times the mass of menthol.

[0021] Preferably, in step (1), the relative density of the extract of *Euphorbia helioscopia* is 1.24-1.26.

[0022] In this invention, the preparation method of the extract of *Hedyotis diffusa* is a conventional method in the art, and is not limited to the method recorded in Part I of the Chinese Pharmacopoeia (2020 edition): Take *Hedyotis diffusa*, add water and decoct twice, the first time for 2 hours and the second time for 1.5 hours, combine the decoctions, filter, concentrate the filtrate to a relative density of 1.15 (80℃), add ethanol to a content of 65%, let stand for 24 hours, filter, recover the ethanol from the filtrate under reduced pressure, and concentrate into a clear extract with a relative density of 1.24-1.26.

[0023] Preferably, in step (1), the grinding time is 30-60 min.

[0024] More preferably, in step (1), the grinding time is 45 min.

[0025] Preferably, in step (2), the inclusion compound is used as a binder and granulated in a granulator.

[0026] Preferably, in step (2), the amount of sorbitol added is 800-860 times the mass of menthol.

[0027] More preferably, in step (2), the amount of sorbitol added is 850 times the mass of menthol.

[0028] Preferably, in step (3), the lubricant is magnesium stearate.

[0029] More preferably, in step (3), the amount of lubricant added is 20-30 times the mass of menthol.

[0030] More preferably, in step (3), the amount of lubricant added is 28 times the mass of menthol.

[0031] Preferably, in step (3), the pressing force is 10-15 kN.

[0032] Preferably, step (3) may include a coating step after tableting: preparing a coating solution with a mass concentration of 18%-22% by preparing film coating powder and coating the uncoated tablets with film; the coating increases the weight by 2%-3%.

[0033] On the other hand, the present invention provides compound herbal lozenges prepared by the above preparation method.

[0034] The beneficial effects of this invention are as follows:

[0035] 1. In the preparation method of the present invention, menthol and peppermint oil melt are mixed and encapsulated with hydroxypropyl-β-cyclodextrin and eugenol extract, then granulated with sorbitol, and mixed with lubricant for tableting. This method can significantly reduce the encapsulation time, improve the encapsulation rate and uniformity, and ensure that the content of active ingredients such as menthol is stable with less loss.

[0036] 2. In the preparation method of the present invention, no additional fillers, additional binders, disintegrants or other components are used. Hydroxypropyl-β-cyclodextrin, which is highly water-soluble, is dissolved in the extract of *Hedyotis diffusa* for inclusion and is directly granulated and dried together with the extract of *Hedyotis diffusa*. It does not require the separate refrigeration, filtration, drying and pulverization steps of traditional β-cyclodextrin inclusion complexes. Under the premise of simple preparation process and simplified composition, the stability and uniformity of the product are significantly improved. Detailed Implementation

[0037] To make the technical means, creative features, and achieved objectives and effects of this invention easier to understand, the invention is further illustrated below with specific embodiments. However, the following embodiments are merely preferred embodiments of this invention and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the protection scope of this invention. Unless otherwise specified, the operating methods and equipment used in the following embodiments are conventional operating methods, and the materials and equipment used in each embodiment are the same.

[0038] In the specific embodiments of the present invention, the raw materials used are obtained through conventional commercial channels unless otherwise specified, and products from different manufacturers do not have a significant impact on the effect.

[0039] The hydroxypropyl-β-cyclodextrin was purchased from Shandong Binzhou Zhiyuan Biotechnology Co., Ltd., batch number HP23031027; the β-cyclodextrin was purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd., batch number TF53231001; and the film coating powder was purchased from Tianjin Bokelin Pharmaceutical Packaging Technology Co., Ltd., batch number BGP4061TT.

[0040] Basic Example 1

[0041] The preparation method of *Hedyotis diffusa* extract is as follows: Take *Hedyotis diffusa*, add water and decoct twice, the first time for 2 hours and the second time for 1.5 hours. Combine the decoctions, filter, concentrate the filtrate to a relative density of 1.15 (80℃), add ethanol to a content of 65%, let stand for 24 hours, filter, recover the ethanol from the filtrate under reduced pressure, and concentrate to a relative density of 1.24-1.26 for *Hedyotis diffusa* extract.

[0042] The extract of *Hedyotis diffusa* prepared in Basic Example 1 was used in the preparation of the compound *Hedyotis diffusa* lozenges in the following Basic Example, Example, and Comparative Example.

[0043] Basic Implementation Example 2

[0044] A method for preparing compound herbal lozenges, comprising the following steps:

[0045] (1) Inclusion: Menthol and peppermint oil were melted to obtain menthol oil melt; the menthol oil melt was mixed with hydroxypropyl-β-cyclodextrin and eugenol extract and ground to prepare inclusion complex;

[0046] (2) Granulation: The inclusion complex and sorbitol are mixed and granulated to obtain granules;

[0047] (3) Tablet preparation: Mix the granules with the lubricant and compress them into tablets to obtain compound herbal lozenges.

[0048] Basic Example 3

[0049] A method for preparing compound herbal lozenges, comprising the following steps:

[0050] (1) Inclusion: Menthol and peppermint oil are melted at 40-60℃ to obtain menthol oil melt. The mass ratio of menthol to peppermint oil is 0.5g:0.2-0.4mL.

[0051] Hydroxypropyl-β-cyclodextrin and *Hedyotis diffusa* extract were mixed in 10-12 times their weight of molten menthol oil to form a hydroxypropyl-β-cyclodextrin *Hedyotis diffusa* solution, wherein the amount of *Hedyotis diffusa* extract was 60 times the weight of menthol; then the mixture was ground with molten menthol oil in a colloid mill for 30-60 minutes to prepare an inclusion complex.

[0052] (2) Granulation: The inclusion complex is mixed with sorbitol as a binder, granulated in a granulator, dried and granulated through a 2 mm sieve to obtain granules;

[0053] When the amount of menthol used is 0.5g, the amount of sorbitol added is 400-430g;

[0054] (3) Tableting: Mix the granules with the lubricant magnesium stearate and compress them at 10-15kN to obtain uncoated tablets; wherein, when the amount of menthol is 0.5g, the amount of magnesium stearate added is 10-15g;

[0055] The uncoated tablets were coated with a film (the film coating powder was prepared into a coating solution with a mass concentration of 18%-22%), and the coating weight increased by 2%-3%, thus obtaining compound herbal lozenges.

[0056] Example 1

[0057] A method for preparing compound herbal lozenges, comprising the following steps:

[0058] (1) Inclusion: 0.5g of menthol and 0.3mL of peppermint oil were heated in a water bath at a temperature not exceeding 60℃ to prepare a molten menthol oil solution;

[0059] Weigh 10 times the weight of molten menthol oil and add it to 30g of *Euphorbia humifusa* extract to prepare a hydroxypropyl-β-cyclodextrin *Euphorbia humifusa* solution. Grind the solution with molten menthol oil in a colloid mill for 45 minutes to obtain an inclusion complex for later use.

[0060] (2) Granulation: 425g of sorbitol was added to the granulator, and the inclusion complex was sprayed into the granulator as a binder for granulation, drying and granulation to obtain granules;

[0061] (3) Mixing: Mix the granules with 14g of lubricant magnesium stearate;

[0062] (4) Tableting: The mixed granules are compressed into tablets under a pressure of 10kN;

[0063] (5) Coating: The uncoated tablets are coated with a thin film. The film coating powder is prepared into a coating solution with a mass concentration of 20%, and the weight gain of the coating is 2%.

[0064] (6) Packaging: The coated sheets are packaged in aluminum-plastic packaging using an aluminum-plastic packaging machine.

[0065] Example 2

[0066] Unlike Example 1, in step (1), the amount of hydroxypropyl-β-cyclodextrin used is 8 times the weight of the menthol oil melt.

[0067] Everything else is the same as in Example 1.

[0068] Example 3

[0069] Unlike Example 1, in step (1), the amount of hydroxypropyl-β-cyclodextrin used is 12 times the weight of the menthol oil melt.

[0070] Everything else is the same as in Example 1.

[0071] Example 4

[0072] Unlike Example 1, in step (1), the grinding time is 30 minutes. Everything else is the same as in Example 1.

[0073] Example 5

[0074] Unlike Example 1, in step (1), the grinding time is 60 minutes. Everything else is the same as in Example 1.

[0075] Comparative Example 1

[0076] A method for preparing compound herbal lozenges, comprising the following steps:

[0077] (1) Inclusion: 0.5g of menthol and 0.3mL of peppermint oil were heated in a water bath at a temperature not exceeding 60℃ to prepare a molten menthol oil solution;

[0078] Weigh 10 times the weight of β-cyclodextrin in the molten menthol oil, add 140g of water to prepare a β-cyclodextrin solution, and grind it with the molten menthol oil in a colloid mill for 45min to obtain an inclusion complex for later use.

[0079] (2) Granulation: Add 425g of sorbitol and 30g of *Hypericum perforatum* extract to the granulator. The inclusion complex is sprayed into the granulator as a binder for granulation, drying and granulation to obtain granules.

[0080] Steps (3)-(6) are the same as in Example 1.

[0081] Comparative Example 2

[0082] Unlike Example 1, the extract of *Hypericum striatum* was added during granulation in step (2).

[0083] A method for preparing compound herbal lozenges, comprising the following steps:

[0084] (1) Inclusion: 0.5g of menthol and 0.3mL of peppermint oil were heated in a water bath at a temperature not exceeding 60℃ to prepare a molten menthol oil solution;

[0085] Weigh 10 times the weight of molten menthol oil of hydroxypropyl-β-cyclodextrin, add it to 30g of purified water to prepare a hydroxypropyl-β-cyclodextrin solution, and grind it with molten menthol oil in a colloid mill for 45min to obtain an inclusion complex for later use.

[0086] (2) Granulation: Add 425g of sorbitol and 30g of *Hypericum perforatum* extract to the granulator. The inclusion complex is sprayed into the granulator as a binder for granulation, drying and granulation to obtain granules.

[0087] Steps (3)-(6) are the same as in Example 1.

[0088] Comparative Example 3

[0089] The preparation method of compound herbal lozenges was adopted according to Part I of the Chinese Pharmacopoeia (2020 edition).

[0090] Comparative Example 4

[0091] Unlike Example 1, the amount of hydroxypropyl-β-cyclodextrin used was 4 times the weight of the menthol oil melt.

[0092] Everything else is the same as in Example 1.

[0093] I. Effect Detection

[0094] For all examples and comparative examples, the preparation time of the compound herbal lozenges was recorded, the inclusion effect was tested, the stability of the tablets was tested, and the menthol content (stability) of the compound herbal lozenges was tested.

[0095] Methods for detecting menthol content:

[0096] Gas chromatography

[0097] Chromatographic conditions and system usability test: Capillary column with cross-linked polyethylene glycol as stationary phase; column temperature 120℃; injection port temperature 250℃, detector temperature 250℃; split injection, split ratio 10:1. The theoretical plate number, calculated based on the menthol peak, should not be less than 10,000.

[0098] Assay: Accurately weigh approximately 1 g of this product and place it in a 25 mL volumetric flask. Dissolve and dilute to the mark with anhydrous ethanol, shake well, and use this as the test solution. Accurately inject 1 μL into the gas chromatograph and record the chromatogram. Separately, accurately weigh an appropriate amount of menthol reference standard, add anhydrous ethanol to prepare a solution containing approximately 0.05 mg per mL, and determine using the same method. Calculate the result by peak area using the external standard method.

[0099] Inclusion rate calculation method: Inclusion rate (%) = Total menthol content of inclusion complex / Total menthol content in molten menthol oil × 100%.

[0100] Uniformity detection method: 10 samples were taken from each of the examples and comparative examples, and the menthol content was detected by gas chromatography as described above. The relative standard deviation (RSD) of each group of data was calculated. The result of the relative standard deviation is the uniformity result.

[0101] 1. Preparation process time

[0102] The process time for preparing 10,000 pieces of the product is shown in Table 1.

[0103] Table 1

[0104]

[0105] As can be seen from Table 1, the preparation method described in this invention can significantly reduce the preparation time compared to Comparative Example 1. The process is simple, convenient, and saves time.

[0106] 2. Encapsulation effect

[0107] Table 2 shows the inclusion rate, menthol content, and uniformity results of each embodiment and comparative example in the preparation of compound herbal lozenges.

[0108] Table 2

[0109]

[0110] As can be seen from Table 2, the preparation method of the present invention can significantly improve the inclusion rate and menthol content; compared with the comparative method, the uniformity is significantly improved.

[0111] 3. Stability of coated sheets

[0112] In the preparation of compound herbal lozenges in each embodiment and comparative example, the menthol content (mg / g) of the coated tablets (without aluminum-plastic packaging and stored open at room temperature) was tested to represent the stability of the coated tablets. The test results are shown in Table 3.

[0113] Table 3

[0114]

[0115] As can be seen from Table 3, the preparation method of the present invention can significantly improve the stability of menthol content in the coated tablets; compared with the comparative method, the stability of menthol is significantly improved.

[0116] 4. Stability Study of Compound Herba Sarcandrae Lozenges

[0117] After the compound herbal lozenges obtained from each embodiment and comparative example were packaged in aluminum-plastic packaging, the finished products were placed in a constant temperature and humidity chamber with high temperature (40°C) and high humidity (75% relative humidity) for 3 months for accelerated testing. The menthol content was tested at 0 days, 1 month and 3 months.

[0118] The results of menthol content are shown in Table 4.

[0119] Table 4

[0120]

[0121] As can be seen from Table 4, the preparation method of the present invention can significantly improve the stability of compound herbal lozenges, and the content of menthol changes little after the specific encapsulation process.

[0122] In summary, compared with traditional preparation methods and comparative examples, the preparation method of the present invention can significantly shorten the preparation time and improve the inclusion rate, uniformity and stability of compound herbal lozenges.

[0123] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing compound herbal lozenges, characterized in that, Including the following steps: (1) Inclusion: Menthol and peppermint oil are melted to obtain menthol oil melt; the menthol oil melt is mixed with hydroxypropyl-β-cyclodextrin and Hedyotis diffusa extract, and ground to prepare inclusion complex; the amount of hydroxypropyl-β-cyclodextrin is 8-12 times the weight of menthol oil melt; the amount of Hedyotis diffusa extract is 60 times the weight of menthol; (2) Granulation: The inclusion complex and sorbitol are mixed and granulated to obtain granules; (3) Tablet preparation: Mix the granules with the lubricant and compress them into tablets to obtain compound herbal lozenges.

2. The preparation method according to claim 1, characterized in that, In step (1), the melting process specifically involves mixing menthol and peppermint oil and heating the mixture to 40-60°C to prepare a menthol oil melt.

3. The preparation method according to claim 1, characterized in that, In step (1), the ratio of the mass of menthol to the volume of peppermint oil is 0.5g:0.2-0.4mL.

4. The preparation method according to claim 1, characterized in that, In step (1), the amount of hydroxypropyl-β-cyclodextrin used is 10-12 times the weight of the menthol oil melt.

5. The preparation method according to claim 1, characterized in that, In step (1), the mixing specifically involves mixing hydroxypropyl-β-cyclodextrin with *Hedyotis diffusa* extract to form a hydroxypropyl-β-cyclodextrin *Hedyotis diffusa* solution; then grinding it with molten menthol oil.

6. The preparation method according to claim 1, characterized in that, In step (1), the grinding time is 30-60 minutes.

7. The preparation method according to claim 1, characterized in that, In step (2), the inclusion complex is used as a binder and granulated in a granulator; In step (2), the amount of sorbitol added is 800-860 times the mass of menthol; In step (3), the lubricant is magnesium stearate, and the amount added is 20-30 times the mass of menthol.

8. The compound herbal lozenges prepared by the preparation method according to any one of claims 1-7.

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