Compound sarcandra glabra buccal tablet and preparation method thereof

Abstract

The invention discloses a compound sarcandra glabra lozenge and a preparation method thereof, and particularly relates to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: (1) clathration: melting menthol and dementholized peppermint oil to obtain menthol oil melt; mixing the menthol oil melt with hydroxypropyl-beta-cyclodextrin and the glabrous sarcandra herb extract, and grinding to prepare an inclusion compound; (2) granulating: mixing the clathrate compound with sorbitol, and granulating; and (3) tabletting: mixing the granules with a lubricant, tabletting, and coating to obtain the compound sarcandra glabra buccal tablet. The compound sarcandra glabra lozenge is cool and good in taste, and the uniformity and stability of menthol and dementholized peppermint oil are remarkably improved; according to the invention, hydroxypropyl-beta-cyclodextrin with high water solubility is dissolved in the glabrous sarcandra herb extract for clathration of menthol and dementholized peppermint oil, the menthol and dementholized peppermint oil are directly granulated and dried together with the glabrous sarcandra herb extract, the steps of refrigeration, filtration, drying and crushing of a traditional beta-cyclodextrin clathrate compound are not needed, the method is simple, and the used time is short.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a compound Sanguinaria officinalis Hance buccal tablet and a preparation method thereof. BACKGROUND

[0002] The compound Sanguinaria officinalis Hance buccal tablet is recorded in the Chinese Pharmacopoeia (2020 edition) Part I, and the prescription is 30 g of arisaema total alkaloid extract, 0.5 g of menthol, and 0.3 mL of peppermint essential oil. The arisaema total alkaloid extract is prepared by taking arisaema, adding water and decocting twice, 2 hours for the first time and 1.5 hours for the second time, combining the decoction, filtering, concentrating the filtrate to a relative density of 1.15 (80 DEG C), adding ethanol to a content of 65%, standing for 24 hours, filtering, recovering ethanol from the filtrate under reduced pressure, and concentrating to a clear extract with a relative density of 1.24-1.26. The arisaema total alkaloid extract is added with an appropriate amount of excipient to prepare granules, which are dried. The menthol and peppermint essential oil are mixed to dissolve, and then mixed with the above granules, compressed into tablets, or coated with a film, to obtain the compound Sanguinaria officinalis Hance buccal tablet. The compound Sanguinaria officinalis Hance buccal tablet has the effects of dispelling wind and clearing heat, relieving swelling and pain, and clearing and benefiting the throat, and is commonly used for laryngalgia caused by exogenous wind-heat, with symptoms of sore throat, hoarseness and loss of voice.

[0003] The raw material menthol of the compound Sanguinaria officinalis Hance buccal tablet is a saturated cyclic alcohol obtained by water vapor distillation, freezing and recrystallization of fresh stems and leaves of the plant Mentha haplocalyx Briq., which is a colorless needle-shaped or prismatic crystalline or white crystalline powder. The peppermint essential oil is a volatile oil extracted by water vapor distillation, freezing and partial brain removal processing of fresh stems and leaves of the plant Mentha haplocalyx Briq., which is a colorless or pale yellow clear liquid. Both menthol and peppermint essential oil have the effects of dispelling wind and clearing heat, and detoxification. They act on the skin or mucous membrane to have the effect of cooling and relieving itching. When taken orally, they can be used as a wind-dispelling drug for headache and inflammation of the nose, throat and larynx, and as a fragrance-imparting agent for toothpaste, perfume, beverage and candy, etc. However, due to its unique chemical properties, it has high volatility and instability, which is not conducive to the taste and effect of the product. The compound Sanguinaria officinalis Hance buccal tablet prepared by the traditional preparation process has unstable content of menthol and peppermint essential oil during production and storage, which affects the cooling taste and curative effect of the product. The existing mixing method is extremely uneven in the preparation, which affects the quality of the product.

[0004] For this reason, a large number of studies on the protection method of menthol or mint oil. Chinese invention patent CN105664172A discloses a preparation method of menthol inclusion complex, the menthol is ultra-finely pulverized into menthol ultra-fine powder; then hydroxypropyl-beta-cyclodextrin and water are uniformly mixed by ultrasonic to prepare a hydroxypropyl-beta-cyclodextrin saturated aqueous solution; finally, the menthol ultra-fine powder is slowly added into the hydroxypropyl-beta-cyclodextrin saturated aqueous solution, and the ultrasonic inclusion is continuously carried out, and then the mixture is left to stand, filtered, and dried under vacuum to obtain the menthol hydroxypropyl-beta-cyclodextrin inclusion complex. In the method of the patent, the menthol ultra-fine powder below 5 μm needs to account for more than 90% of the whole, and the saturation rate of menthol is about 82%, which still has a great space for improvement.

[0005] Chinese invention patent CN116650486A discloses a cetirizine hydrochloride preparation containing menthol and a preparation method thereof. The preparation records a menthol inclusion complex inclusion process: β-cyclodextrin is added to an aqueous solution or a dilute ethanol solution to prepare an inclusion solution; menthol is added to the inclusion solution for menthol inclusion; the inclusion complex after inclusion is filtered, washed and dried to obtain the menthol inclusion complex. Although the inclusion of menthol can improve the stability of menthol, the preparation also contains filler, binder, disintegrant, lubricant and other auxiliary ingredients, which greatly affects the stability and cannot clearly determine the specific inclusion effect.

[0006] Moreover, the existing technology discloses a menthol inclusion technology with a complex preparation process, long inclusion time, low inclusion rate, poor preparation stability and uniformity. In order to solve the above technical problems, it is necessary to further study the preparation method of compound grass coral tablets, so as to obtain a method with stable product, high uniformity of active ingredients, short inclusion time, high inclusion rate and simple process. SUMMARY

[0007] The present application provides a kind of compound grass coral tablet and preparation method thereof, the menthol and mint oil melt liquid of the present application are mixed with hydroxypropyl-beta-cyclodextrin, ardisia japonica extract, then granulated with sorbitol, and mixed with lubricant to obtain the compound grass coral tablet, which has good cooling taste, and the uniformity and stability of menthol and mint oil are significantly improved; The present application fully utilizes the spray granulation process of the inclusion complex prepared by ardisia japonica extract, uses hydroxypropyl-beta-cyclodextrin with high water solubility to dissolve in ardisia japonica extract for inclusion of menthol and mint oil, and directly granulates and dries with ardisia japonica extract, without the need for traditional β-cyclodextrin inclusion complex to go through the steps of refrigeration, filtration, drying and crushing, so the method is simple and time-saving.

[0008] To achieve the above-mentioned purposes, the technical solutions of the present application are as follows: On the one hand, the present application provides a preparation method of compound grass coral tablet, comprising the following steps: (1) Inclusion: melt menthol and menthol oil to obtain menthol oil melt; the menthol oil melt is mixed with hydroxypropyl-β-cyclodextrin and Sanguisorba officinalis extract to prepare an inclusion compound by grinding; (2) Granulation: the inclusion compound is mixed with sorbitol to prepare granules. (3) Tabletting: the granules are mixed with a lubricant and tabletted to obtain the compound Sanguisorba officinalis lozenge.

[0009] Preferably, in step (1), the melting treatment is as follows: the menthol and menthol oil are mixed and heated to 40-60°C to prepare the menthol oil melt.

[0010] Preferably, in step (1), the ratio of the mass of menthol to the volume of menthol oil is 0.5g:0.2-0.4mL; further preferably, 0.5g:0.3mL.

[0011] Preferably, in step (1), the amount of hydroxypropyl-β-cyclodextrin is 8-12 times the weight of the menthol oil melt.

[0012] Further preferably, in step (1), the amount of hydroxypropyl-β-cyclodextrin is 10-12 times the weight of the menthol oil melt.

[0013] More preferably, in step (1), the amount of hydroxypropyl-β-cyclodextrin is 10 times the weight of the menthol oil melt.

[0014] Preferably, in step (1), the mixing is as follows: the hydroxypropyl-β-cyclodextrin is mixed with the Sanguisorba officinalis extract to form a hydroxypropyl-β-cyclodextrin Sanguisorba officinalis solution, which is then ground with the menthol oil melt; further preferably, the grinding is performed in a colloid mill.

[0015] Preferably, in step (1), the amount of Sanguisorba officinalis extract is 60 times the mass of menthol.

[0016] More preferably, in step (1), the amount of Sanguisorba officinalis extract is 60 times the mass of menthol.

[0017] Preferably, in step (1), the relative density of the Sanguisorba officinalis extract is 1.24-1.26.

[0018] In the present application, the preparation method of the Zhongjiefeng extract is a conventional method in the art, which is not limited to the method recorded in the first part of the Chinese Pharmacopoeia (2020 edition): taking Zhongjiefeng, adding water to decoct twice, the first time for 2 hours, the second time for 1.5 hours, combining the decoction, filtering, concentrating the filtrate to a relative density of 1.15 (80℃), adding ethanol to a content of 65%, standing for 24 hours, filtering, recovering ethanol from the filtrate under reduced pressure, and concentrating to a clear extract with a relative density of 1.24-1.26.

[0019] Preferably, in step (1), the grinding time is 30-60 min.

[0020] Further preferably, in step (1), the grinding time is 45 min.

[0021] Preferably, in step (2), the inclusion compound is used as a binder for granulation in a granulator.

[0022] Preferably, in step (2), the amount of sorbitol added is 800-860 times the mass of menthol.

[0023] Further preferably, in step (2), the amount of sorbitol added is 850 times the mass of menthol.

[0024] Preferably, in step (3), the lubricant is magnesium stearate.

[0025] Further preferably, in step (3), the amount of lubricant added is 20-30 times the mass of menthol.

[0026] More preferably, in step (3), the amount of lubricant added is 28 times the mass of menthol.

[0027] Preferably, in step (3), the force for tabletting is 10-15 kN.

[0028] Preferably, in step (3), after tabletting, a coating step can be included: preparing a film coating powder into a coating liquid with a mass concentration of 18%-22%, and coating the film on the substrate tablet; the coating weight gain is 2%-3%.

[0029] In another aspect, the present application provides a compound Sanguo coral lozenge prepared by the above preparation method.

[0030] The present application has the following advantages: 1. In the preparation method of the present application, the menthol and menthol oil melt are mixed with hydroxypropyl-beta-cyclodextrin and Zhongjiefeng extract for inclusion, then granulated with sorbitol, and mixed with a lubricant for tabletting, which can significantly reduce the inclusion time, improve the inclusion rate and uniformity, stabilize the content of active ingredients such as menthol, and reduce the loss.

[0031] 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

[0032] 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.

[0033] 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.

[0034] 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.

[0035] Basic Example 1 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.

[0036] 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.

[0037] Basic Implementation Example 2 A method for preparing compound herbal lozenges, comprising the following steps: (1) Inclusion: melt menthol and peppermint oil to obtain a menthol oil melt; the menthol oil melt is mixed with hydroxypropyl-β-cyclodextrin and a lung- node wind extract to obtain an inclusion compound by grinding; (2) Granulation: the inclusion compound is mixed with sorbitol to obtain granules by granulation; (3) Tabletting: the granules are mixed with a lubricant and tabletted to obtain compound Sanguisorba officinalis-containing tablets.

[0038] Basic Example 3 A method for preparing compound Sanguisorba officinalis-containing tablets, comprising the following steps: (1) Inclusion: melt menthol and peppermint oil at 40-60°C to obtain a menthol oil melt, wherein the mass ratio of menthol to peppermint oil is 0.5g:0.2-0.4mL; Mix 10-12 times the weight of the menthol oil melt with hydroxypropyl-β-cyclodextrin and a lung-node wind extract to form a hydroxypropyl-β-cyclodextrin lung-node wind solution, wherein the lung-node wind extract is used in an amount of 60 times the mass of the menthol; then grind the mixture in a colloid mill for 30-60min to obtain an inclusion compound; (2) Granulation: mix the inclusion compound as a binder with sorbitol in a granulator, dry and sieve through a 2mm mesh to obtain granules; When the amount of menthol is 0.5g, the amount of sorbitol added is 400-430g; (3) Tabletting: mix the granules with a lubricant, magnesium stearate, and tabletted at 10-15kN to obtain a base tablet; wherein when the amount of menthol is 0.5g, the amount of magnesium stearate added is 10-15g; Film coat the base tablet (film coating powder is prepared into a coating solution with a mass concentration of 18%-22%), with a coating weight gain of 2%-3% to obtain compound Sanguisorba officinalis-containing tablets.

[0039] Example 1 A method for preparing compound Sanguisorba officinalis-containing tablets, comprising the following steps: (1) Inclusion: melt 0.5g of menthol and 0.3mL of peppermint oil using a water bath, with a water bath temperature not exceeding 60°C, to prepare a menthol oil melt; Weigh 10 times the weight of the menthol oil melt of hydroxypropyl-β-cyclodextrin, add 30g of a lung-node wind extract to prepare a hydroxypropyl-β-cyclodextrin lung-node wind solution, and grind the solution with the menthol oil melt in a colloid mill for 45min to obtain an inclusion compound for standby use; (2) Granulation: add 425g of sorbitol to a granulator, and spray the inclusion compound as a binder into the granulator to granulate, dry and sieve to obtain granules; (3) Mixing: mix the granules with 14g of a lubricant, magnesium stearate. (4) tabletting: total mixed granules were compressed into tablets under 10 kN pressure; (5) coating: film coating was performed on the tablets, and a film coating powder was prepared into a coating liquid with a mass concentration of 20%, and the coating weight was increased by 2%; (6) packaging: the coated tablets were packaged using an aluminum plastic packaging machine.

[0040] Example 2 Different from Example 1, in step (1), the amount of hydroxypropyl-β-cyclodextrin was 8 times the weight of the menthol oil melt.

[0041] The rest is the same as Example 1.

[0042] Example 3 Different from Example 1, in step (1), the amount of hydroxypropyl-β-cyclodextrin was 12 times the weight of the menthol oil melt.

[0043] The rest is the same as Example 1.

[0044] Example 4 Different from Example 1, in step (1), the grinding time was 30 min. The rest is the same as Example 1.

[0045] Example 5 Different from Example 1, in step (1), the grinding time was 60 min. The rest is the same as Example 1.

[0046] Comparative Example 1 A preparation method of a compound grass coral lozenge, the steps are as follows: (1) inclusion: 0.5 g of menthol and 0.3 mL of peppermint oil were prepared into a menthol oil melt using water bath heating, and the water bath temperature was not more than 60°C; β-cyclodextrin 10 times the weight of the menthol oil melt was weighed, 140 g of water was added to prepare a β-cyclodextrin solution, and the menthol oil melt was ground in a colloid mill for 45 min to obtain an inclusion compound for standby; (2) granulation: 425 g of sorbitol and 30 g of ardisia japonica extract were added to a granulator, and the inclusion compound was sprayed into the granulator as a binder to granulate, dry and granulate to obtain granules; Steps (3)-(6) are the same as Example 1.

[0047] Comparative Example 2 Different from Example 1, the ardisia japonica extract was added during granulation in step (2).

[0048] A preparation method of a compound grass coral lozenge, the steps are as follows: (1) Inclusion: 0.5 g of menthol and 0.3 mL of peppermint oil were heated using a water bath, and the water bath temperature was not higher than 60℃, to prepare a menthol oil melt; Hydroxypropyl-β-cyclodextrin was weighed in an amount of 10 times the weight of the menthol oil melt, added to 30 g of purified water to prepare a hydroxypropyl-β-cyclodextrin solution, and ground with the menthol oil melt in a colloid mill for 45 min to obtain an inclusion compound for standby use. (2) Granulation: 425 g of sorbitol and 30 g of ardisia japonica extract were added to a granulator, and the inclusion compound was sprayed into the granulator as a binder to perform granulation, drying, and whole granulation to obtain granules. Steps (3)-(6) are the same as in Example 1.

[0049] Comparative Example 3 The compound grass leafflower tablet was prepared according to the preparation method of compound grass leafflower tablet in the Chinese Pharmacopoeia (2020 edition).

[0050] Comparative Example 4 The difference between Example 1 and Comparative Example 4 is that the amount of hydroxypropyl-β-cyclodextrin is 4 times the weight of the menthol oil melt.

[0051] The rest is the same as in Example 1.

[0052] I. Effect detection The preparation time of the preparation process, the inclusion effect, the stability of the tablet, and the menthol content (stability) of the compound grass leafflower tablet were detected for all the prepared compound grass leafflower tablets in the examples and comparative examples.

[0053] Menthol content detection method: Gas chromatography Chromatographic conditions and system usability test: capillary column with cross-linked bonded 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 should not be less than 10000 calculated by the menthol peak.

[0054] Determination method: about 1 g of the product was accurately weighed, dissolved and diluted to the mark in a 25 mL volumetric flask with anhydrous ethanol, shaken well to serve as the test solution, 1 μL was accurately injected into the gas chromatograph, and the chromatogram was recorded. The menthol reference substance was accurately weighed, dissolved in anhydrous ethanol to prepare a solution containing about 0.05 mg per 1 mL, and determined by the same method. The peak area was calculated by external standard method, and the result was obtained.

[0055] Inclusion rate calculation method: inclusion rate (%) = total menthol content of inclusion compound / total menthol content in menthol oil melt x 100%.

[0056] Uniformity detection method: 10 samples were taken from each group of examples and comparative examples, and the menthol content was detected according to the above gas chromatography method, and the relative standard deviation (RSD) of each group of data was calculated. The relative standard deviation result is the uniformity result.

[0057] 1. Preparation time The preparation time for 10,000 tablets is shown in Table 1.

[0058] Table 1

[0059] As can be seen from Table 1, the preparation method of the present application can significantly reduce the preparation time compared to Comparative Example 1, and the process is simple and convenient, saving time.

[0060] 2. Inclusion effect The inclusion rate, menthol content and uniformity results of each example and comparative example during the preparation of compound grass coral lozenge are shown in Table 2.

[0061] Table 2

[0062] As can be seen from Table 2, the preparation method of the present application can significantly improve the inclusion rate and the content of menthol; compared with the method of the comparative example, the uniformity is significantly improved.

[0063] 3. Stability of coated tablets During the preparation of compound grass coral lozenges of each example and comparative example, the menthol content (mg / g) of the coated tablets (not subjected to aluminum plastic packaging, stored at room temperature with the opening) was detected to represent the stability results of the coated tablets, and the detection results are shown in Table 3.

[0064] Table 3

[0065] As can be seen from Table 3, the preparation method of the present application can significantly improve the stability of the menthol content of the coated tablets; compared with the method of the comparative example, the stability of menthol is significantly improved.

[0066] 4. Stability investigation of compound grass coral lozenge finished products After the compound grass coral lozenges obtained from each example and comparative example were aluminum-plastic packaged and subpackaged, the finished products were placed in a constant temperature and humidity box with high temperature (40℃) and high humidity (relative humidity 75%) for accelerated testing for 3 months, and the menthol content was detected at 0 days, 1 month and 3 months, respectively.

[0067] The menthol content results are shown in Table 4.

[0068] Table 4

[0069] As can be seen from Table 4, the preparation method of the present application can significantly improve the stability of the compound grass leathery coral lozenge, and the content of menthol changes little after inclusion by a specific process.

[0070] In summary, compared with the traditional preparation method and the comparative examples, the preparation method of the present application can significantly shorten the preparation time, improve the inclusion rate, uniformity and stability of the compound grass leathery coral lozenge.

[0071] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A method for preparing compound herbal lozenges, characterized in that, Including the following steps: (1) Inclusion: Menthol and peppermint oil were melted to obtain menthol oil melt; the menthol oil melt was mixed with hydroxypropyl-β-cyclodextrin and euphorbia humifusa extract and ground to prepare inclusion complex; (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 8-12 times the weight of the menthol oil melt.

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

6. 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.

7. The preparation method according to claim 1, characterized in that, In step (1), the amount of the herb extract is 60 times the mass of menthol.

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

9. 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.

10. The compound herbal lozenges prepared by the preparation method according to any one of claims 1-9.

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