Pediatric security powder and preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a pediatric Ba'an powder and a preparation method thereof. The application is directed to the pediatric Ba'an powder with multiple medicinal ingredients. The particle design technology is adopted to recombine particles on the basis of microcosmic level without adding excipients, so as to construct composite particles with stable properties and uniform distribution, thereby improving the oral compliance of the drug, and providing a basis for improving the safety and stability of the pediatric Ba'an powder and developing new clinical use. The dissolution experiment of the index substance of berberine hydrochloride of Coptis chinensis, the powder property of the powder before and after modification and the content uniformity are investigated. The results show that the oral compliance of the modified powder is improved, the dissolution degree is significantly improved, and the modified powder has the advantages of content uniformity, good flowability and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a children's health powder and its preparation method. Background Technology

[0002] Xiao'er Baoan Wan is a pediatric medicine with the effects of dispelling wind, calming convulsions, and eliminating phlegm. It is used for vomiting and diarrhea, indigestion, early stages of colds, infantile convulsions, and cough with excessive phlegm. It is made into large honey pills, each weighing 1.5g, by grinding 28 ingredients, including Pinellia ternata, Aucklandia lappa, Mentha haplocalyx, pearl, amber, cinnabar, and borneol, into a fine powder or water-milled into an extremely fine powder and then adding refined honey. Due to its large size, the honey pills are difficult to swallow and are not suitable for children.

[0003] Compared to pills, powders are easier for children to take. However, the traditional preparation process for powders is simple, generally involving direct mixing, pulverizing, and sieving to produce Chinese medicine powders. This can easily lead to randomness in the properties of the powder, making it impossible to guarantee uniform dispersion and making it uncontrollable. Furthermore, because the formula for Xiao'er Baoan San contains Coptis chinensis (Huanglian) with a strong bitter taste, Bombyx batryticatus (Jiangcan) with a fishy smell, and also contains Pinellia ternata (Banxia), Asarum heterotropoides (Xixin), and the heavy and toxic mineral cinnabar, poor taste and uniformity can easily lead to problems such as poor patient compliance, easy segregation, and medication safety.

[0004] In view of the above, this application is hereby submitted. Summary of the Invention

[0005] Based on this, this application provides a children's safety powder and its preparation method.

[0006] In a first aspect of this application, a children's safety powder is provided, the powder having a frame-like composite particle structure, the frame-like composite particle structure satisfying the following conditions:

[0007] The core particles are powdered borneol, ginger-processed Pinellia ternata, Asarum heterotropoides, silkworm pupa, Coptis chinensis and cinnabar, with a particle size of 80μm-800μm.

[0008] The shell particles are made from the powders of bitter almond cream, peppermint, gastrodia elata, poria cocos, patchouli, pearl, amber, malt, tangerine peel, platycodon grandiflorus, notopterygium incisum and medicated leaven, and the particle size of the shell particles is 2μm-80μm.

[0009] as well as,

[0010] The framework particles are composed of powders of Bupleurum chinense, Aucklandia lappa, Cinnamomum cassia, Atractylodes lancea, Magnolia officinalis, Peucedanum praeruptorum, Uncaria rhynchophylla, Areca catechu, Saposhnikovia divaricata, and Glycyrrhiza uralensis, with a particle size of 10μm-800μm.

[0011] In some specific embodiments of this application, the particle size of the nuclear particle does not exceed 500 μm, and the particle size ratio of the nuclear particle to the shell particle is (5-10):1.

[0012] In some specific embodiments of this application, the particle size of the nuclear particles is 100μm-200μm.

[0013] In some specific embodiments of this application, the particle size of the shell particles is 10μm-30μm.

[0014] In some specific embodiments of this application, the particle size of the framework particles is 10μm-40μm.

[0015] In some specific embodiments of this application, the pediatric safety powder comprises, by weight parts:

[0016]

[0017] In a second aspect of this application, a method for preparing the aforementioned pediatric safety powder is provided, the method comprising the following steps:

[0018] The nuclear particles, shell particles, and framework particles were prepared separately, mixed, and then used to prepare a children's safety powder.

[0019] In some specific embodiments of this application, the mixing step includes:

[0020] The nuclear particle and the shell particle come into full contact to form a core-shell particle; and,

[0021] The core-shell particles and framework particles are brought into full contact to prepare a children's safety powder.

[0022] In some specific embodiments of this application, the means of achieving full contact between the core particles and shell particles or / and between the core-shell particles and frame particles include ultrafine grinding.

[0023] In some specific embodiments of this application, the preparation steps of the nuclear particles include:

[0024] The mixture of ginger-processed Pinellia ternata, Asarum heterotropoides, Bombyx mori, cinnabar, and Coptis chinensis is subjected to a first-stage pulverization to prepare a first pulverized product; and,

[0025] The mixture of the first pulverized material and borneol is subjected to a second stage of pulverization to prepare nuclear particles.

[0026] In some specific embodiments of this application, the first stage of pulverization and / or the second stage of pulverization include ultrafine pulverization and / or air jet milling, the first stage of pulverization takes 10 min to 20 min, and the second stage of pulverization takes 1 min to 2 min.

[0027] Compared to traditional technologies, the beneficial effects of the embodiments of this application include:

[0028] This application's embodiments target a children's health powder with many medicinal components. Utilizing particle design technology, without adding excipients, it recombines particles at the microscopic level to construct stable and uniformly distributed composite particles, thereby improving oral compliance and providing a basis for enhancing the safety and stability of the children's health powder and developing new clinical applications. This application's embodiments also examined the dissolution of berberine hydrochloride, an indicator substance of Coptis chinensis, as well as the powder properties and content uniformity of the powder before and after modification. The results showed that the modified powder exhibited improved oral compliance, significantly improved dissolution, and also possessed advantages such as content uniformity and good flowability. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of this application and to more completely understand this application and its beneficial effects, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0030] Figure 1 The relationship between ultrafine grinding time and particle size;

[0031] Figure 2 This is a diagram of the angle of repose.

[0032] Figure 3 To observe the morphological characteristics of the particles under a scanning electron microscope, Figure A shows physically mixed powder, and Figure B shows composite particle powder.

[0033] Figure 4 Images of physical mixed powder (A) and composite particle powder (B) for children's safety;

[0034] Figure 5 Dissolution curve of pediatric safety powder;

[0035] Figure 6 This is a dissolution experiment for berberine hydrochloride. Detailed Implementation

[0036] The present invention will be further described in detail below with reference to the accompanying drawings, embodiments, and examples. It should be understood that these embodiments and examples are for illustrative purposes only and are not intended to limit the scope of the invention. The purpose of providing these embodiments and examples is to enable a more thorough and complete understanding of the disclosure of the present invention. It should also be understood that the present invention can be implemented in many different forms and is not limited to the embodiments and examples described herein. Those skilled in the art can make various modifications or alterations without departing from the spirit of the present invention, and the equivalent forms obtained also fall within the protection scope of this application. Furthermore, numerous specific details are set forth in the following description to provide a fuller understanding of the present invention. It should be understood that the present invention can be implemented without one or more of these details.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for descriptive purposes only and is not intended to be limiting of the invention.

[0038] the term

[0039] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0040] The terms "and / or," "or / and," and "and / or" as used herein include any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that in this application, the technical solution undoubtedly includes technical solutions connected by "logical AND," and also undoubtedly includes technical solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0041] In this invention, terms such as "multiple", "various", "multiple times", and "multi-source" are used, and unless otherwise specified, they refer to a quantity greater than or equal to 2. For example, "one or more" means one or more types.

[0042] The terms “combinations of,” “any combination of,” and “any combination of” used in this article include all suitable combinations of any two or more of the listed items.

[0043] In this document, the term "suitable" as used in phrases such as "suitable combination," "suitable method," and "any suitable method" refers to the ability to implement the technical solution of this invention, solve the technical problem of this invention, and achieve the expected technical effect of this invention.

[0044] In this article, terms such as "preferred," "better," "more suitable," and "ideal" are merely used to describe implementation methods or examples that achieve better results, and should be understood not to limit the scope of protection of this invention.

[0045] In this invention, terms such as "further," "even more," and "particularly" are used for descriptive purposes and to indicate differences in content, but should not be construed as limiting the scope of protection of this invention.

[0046] In this invention, "optionally," "optionally," and "optional" mean that they are optional, that is, they are selected from either "with" or "without." If multiple "options" appear in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, each "option" is independent.

[0047] In this invention, the terms "first aspect," "second aspect," "third aspect," "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," "fourth," etc., serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on the quantity.

[0048] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0049] In this invention, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, the selected numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. In this document, this is equivalent to directly listing every integer. For example, if t is an integer selected from 1 to 10, it means that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0050] Unless otherwise specified, the temperature parameters in this invention can be either constant temperature treatment or variations within a certain temperature range. It should be understood that the constant temperature treatment allows temperature fluctuations within the precision range controlled by the instrument. Fluctuations are permitted within ranges such as ±5℃, ±4℃, ±3℃, ±2℃, and ±1℃.

[0051] In this invention, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass-volume percentage.

[0052] All references to this invention are incorporated herein by reference as if each document were individually incorporated by reference. Unless they conflict with the inventive purpose and / or technical solution of this application, the referenced documents involved in this invention are incorporated in their entirety and for all purposes. When references are made in this invention, the definitions of relevant technical features, terms, nouns, phrases, etc., are also incorporated herein by reference. When references are made in this invention, examples and preferred embodiments of the relevant technical features cited may also be incorporated herein by reference, but only to the extent that they enable the implementation of this invention. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or modifications shall be made adaptively based on the description in this application.

[0053] The particle size in this application refers to the D90 particle size, specifically the particle size corresponding to the cumulative particle size distribution number of a sample reaching 90%.

[0054] Based on the concept of "drug-excipient integration", particle design technology is used to prepare drugs with stable properties as "excipients" and unstable or drugs that need improvement as "main drugs". Different drugs are pulverized to different degrees, and the stable drugs are wrapped around the surface of the drugs that need improvement by intermolecular forces to construct composite particles with core-shell structure, thereby improving the oral compliance and quality of Xiaobao Ansan.

[0055] First aspect of the invention

[0056] In a first aspect of this application, a children's safety powder is provided, the powder having a frame-like composite particle structure, the frame-like composite particle structure satisfying the following conditions:

[0057] The core particles are powdered borneol, ginger-processed Pinellia ternata, Asarum heterotropoides, silkworm pupa, Coptis chinensis and cinnabar, with a particle size of 80μm-800μm.

[0058] The shell particles are made from the powders of bitter almond cream, peppermint, gastrodia elata, poria cocos, patchouli, pearl, amber, malt, tangerine peel, platycodon grandiflorus, notopterygium incisum and medicated leaven, and the particle size of the shell particles is 2μm-80μm.

[0059] as well as,

[0060] The framework particles are composed of powders of Bupleurum chinense, Aucklandia lappa, Cinnamomum cassia, Atractylodes lancea, Magnolia officinalis, Peucedanum praeruptorum, Uncaria rhynchophylla, Areca catechu, Saposhnikovia divaricata, and Glycyrrhiza uralensis, with a particle size of 10μm-800μm.

[0061] In some specific embodiments of this application, the particle size of the nuclear particle does not exceed 500 μm, and the particle size ratio of the nuclear particle to the shell particle is (5-10):1.

[0062] In some specific embodiments of this application, the particle size of the nuclear particles is 100μm-200μm.

[0063] In some specific embodiments of this application, the particle size of the shell particles is 10μm-30μm.

[0064] In some specific embodiments of this application, the particle size of the framework particles is 10μm-40μm.

[0065] In some specific embodiments of this application, the pediatric safety powder comprises, by weight parts:

[0066]

[0067]

[0068] Second aspect of the embodiments of this application

[0069] In a second aspect of this application, a method for preparing the aforementioned pediatric safety powder is provided, the method comprising the following steps:

[0070] The nuclear particles, shell particles, and framework particles were prepared separately, mixed, and then used to prepare a children's safety powder.

[0071] In some specific embodiments of this application, the mixing step includes:

[0072] The nuclear particle and the shell particle come into full contact to form a core-shell particle; and,

[0073] The core-shell particles and framework particles are brought into full contact to prepare a children's safety powder.

[0074] In some specific embodiments of this application, the means of achieving full contact between the core particles and shell particles or / and between the core-shell particles and frame particles include ultrafine grinding.

[0075] In some specific embodiments of this application, the preparation steps of the nuclear particles include:

[0076] The mixture of ginger-processed Pinellia ternata, Asarum heterotropoides, Bombyx mori, cinnabar, and Coptis chinensis is subjected to a first-stage pulverization to prepare a first pulverized product; and,

[0077] The mixture of the first pulverized material and borneol is subjected to a second stage of pulverization to prepare nuclear particles.

[0078] In some specific embodiments of this application, the first stage of pulverization and / or the second stage of pulverization include ultrafine pulverization and / or air jet milling, the first stage of pulverization takes 10 min to 20 min, and the second stage of pulverization takes 1 min to 2 min.

[0079] The embodiments of the present invention will be described in detail below with reference to examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. For experimental methods in the following embodiments where specific conditions are not specified, please refer to the guidelines given in this invention, or follow experimental manuals or conventional conditions in the art, or follow the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0080] In the specific embodiments described below, the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.

[0081] Example 1: Preparation of the Pediatric Safety Powder of the Present Invention

[0082] Based on previous research results and the collation of prescription medicinal materials, and focusing on the ease of pulverization, Bupleurum, Aucklandia, Cinnamon Twig, Atractylodes, Magnolia Bark, Peucedanum, Uncaria, Areca Peel, Saposhnikovia, and Licorice were classified as difficult-to-pulverize medicinal materials, while Prunus armeniaca Powder, Peppermint, Gastrodia, Poria, Patchouli, Pearl, Amber, Malt, Tangerine Peel, Platycodon, Notopterygium, and Shenqu were classified as easily pulverized medicinal materials. Borneol, Cinnabar, Coptis (with a bitter taste), Asarum (with a pungent taste), Bombyx Batryticatus, and Slightly Toxic Pinellia (with ginger) were used as core particles, easily pulverized medicinal materials as shell particles, and difficult-to-pulverize medicinal materials as framework particles to prepare a core-shell framework composite structure.

[0083] Table 1

[0084]

[0085]

[0086] 1. Preparation of ultrafine powder for samples

[0087] Twenty-eight medicinal materials, including ginger-processed Pinellia ternata, Asarum heterotropoides, Poria cocos, Platycodon grandiflorus, Pogostemon cablin, Bupleurum chinense, Coptis chinensis, Areca catechu peel, Glycyrrhiza uralensis, Aucklandia lappa, ginger-processed Gastrodia elata, Cinnamomum cassia, ginger-processed Magnolia officinalis, Uncaria rhynchophylla, Notopterygium incisum, Amber, Citrus reticulata peel, Saposhnikovia divaricata, Mentha haplocalyx, bitter almond powder, Atractylodes lancea, Peucedanum praeruptorum, Bombyx mori, Pearl, roasted malt, Shenqu (medicated leaven), Cinnabar, and Borneol, are dried by forced-air drying (or vacuum drying) until the moisture content is 3wt%-5wt%.

[0088] Since pearl, amber, cinnabar, and borneol in commercially available medicinal materials are already in fine powder form, except for pearl, amber, cinnabar, and borneol, the remaining 24 medicinal materials are taken and pulverized using a conventional pulverizer to produce powder that passes through a 100-mesh (150μm) sieve, thus obtaining fine powder of each medicinal material.

[0089] Using each fine powder as an initial sample, 200g of each powder was placed in an ultrafine pulverizer and pulverized. Samples were taken at 0, 5, 10, 15, 20, 25, and 30 minutes, and stored in a desiccator in a sealed container for later use.

[0090] Weigh out the following ingredients according to the prescription proportions: 11.5g ginger-processed Pinellia ternata, 7g costus root, 11.5g peppermint, 7g asarum, 11.5g gastrodia elata, 14g bitter almond powder, 11.5g poria cocos, 7g cinnamon twig, 11.5g atractylodes lancea, 14g platycodon grandiflorus, 11.5g magnolia officinalis, 21g angelica dahurica, 11.5g patchouli, 14g uncaria rhynchophylla, 11.5g silkworm pupa, 28g bupleurum chinense, 11.5g notopterygium incisum, 7.5g pearl, 11. 5g Coptis chinensis, 15g amber, 11.5g roasted malt, 30g cinnabar, 11.5g dried tangerine peel, 19g borneol, 11.5g areca peel, 11.5g Saposhnikovia divaricata, 11.5g Shenqu (medicated leaven), and 7g licorice are placed in a universal grinder and ground into the finest powder. The powder is then passed through a 120-mesh (125μm) sieve to obtain the physical mixed powder of Xiao'er Baoan San (the physical mixed powder is the same as the prescription with a core-shell framework composite structure).

[0091] 2. Investigation of particle size-time relationship

[0092] The Mastersizer 2000 laser particle size analyzer was used to determine the particle size corresponding to the cumulative particle size distribution of each medicinal material sample reaching 10%, 50%, and 90% under the dry method test, namely d10, d50, and d90.

[0093] The particle size testing parameters were: injection air pressure 322.5 kPa, injection speed 80%, shading range 0.5%–6%, sample measurement time 10 s, and background correction time 10 s. Each group was measured in triplicate. A regression equation was established between the 90% particle size value (Y) and the grinding time (X) to investigate the relationship between ultrafine grinding time and particle size. (See...) Figure 1 .

[0094] Figure 1 This is a graph showing the relationship between particle size and grinding time for pediatric protective powder. Through the determination of the particle size of the medicinal materials, d90 showed a good correlation with grinding time. Figure 1 It can be seen that during the pulverization process, the particle size of each medicinal material mainly changes in three stages: "fast pulverization - slow pulverization - pulverization equilibrium". The smallest pulverized particle size of the nucleus particles is mainly concentrated in the pulverization time of 15 minutes, while that of the shell particles and framework particles is concentrated in the pulverization time of 30 minutes.

[0095] 3 Mixing and Grinding Test

[0096] Weigh out the fine powder of the medicinal slices according to the prescription ratio, place them in an ultra-micro pulverizer, pulverize for 50 minutes, take intermittent samples, measure the particle size, establish a regression equation of particle size (Y) on pulverization time (X), and the results are shown in Table 2 below, so as to determine the pulverization time for the formation of shell and core particles.

[0097] The results showed that the longer the pulverization time, the smaller the particle size, and there was a good correlation between pulverization time and the material d90. According to the mechanical method for preparing "shell-core" model composite particles, the core particle size should ideally be below 500 μm, otherwise it is easily broken; the core-shell particle size ratio should be above 10:1, and should not be lower than 5:1.

[0098] The d90 regression equation shows that: after 15 minutes of crushing, the particle size of nuclear particles can reach 165 μm; after 35 minutes of crushing, the particle size of shell particles can reach approximately 20 μm; and after 40 minutes of crushing, the particle size of framework particles can be as small as 21 μm. Therefore, it is set that the shell particles are crushed for about 35 minutes before adding the nuclear particles directly.

[0099] Table 2. Regression equations of d90(Y)-time(X) for nuclei, shells, and frames of particles in children's health products.

[0100]

[0101] 4. Core-shell particle size determination

[0102] The dried medicinal material coarse powder constituting the shell and core particles was weighed separately. The shell particle coarse powder was put into an ultrafine pulverizer and pulverized for 35 minutes. Then, the core particles were added, mixed, and pulverized. Samples were taken at 0, 2, 4, 6, 8, 10, and 12 minutes to determine the particle size. The results are shown in Table 3. The results show that when the core-shell composite time is 10 minutes, the particle size tends to reach equilibrium. Excessive composite time will destroy the particle structure.

[0103] Table 3. Particle size of Pediatric Safety Powder Core-Shell Particles

[0104] Grinding time / min d10 / μm d50 / μm d90 / μm 0 9.807 77.058 240.245 2 4.704 66.318 200.880 4 4.251 58.103 115.945 6 3.832 47.051 98.930 8 3.764 34.008 93.593 10 3.293 26.934 85.155 12 3.284 27.562 84.678

[0105] 5. Pediatric Security Powder Phosphate Evaluation

[0106] To further clarify the recombination time of core-shell particles, powder science was conducted on shell particles, core particles, framework particles, and particles recombinating for 2 min, 4 min, 6 min, 8 min, and 10 min.

[0107] 5.1 Kawakita Equation

[0108] The Kawakita equation explores the relationship between pressure and the change in volume of the compressed material, as shown in equation (1).

[0109] This paper uses the tapping method for determination: shell particles, core particles, framework particles, core-shell composite particles at different times, and physically mixed powders are respectively poured into a 100mL graduated cylinder at a uniform and slow rate using a funnel until the loose volume is 75mL. The graduated cylinder containing the powder is then dropped freely onto a horizontal table from a height of 1cm, and the number of drops (n) and the corresponding volume (V) are recorded.n Fit the linear regression equation between n / c and n, and calculate a and b. a is the fractional reduction in relative volume (final volume reduction) when the number of taps is infinite. The smaller a is, the better the powder flowability. The smaller 1 / b is, the fewer taps are required for the powder to fill to the minimum volume, and the better the powder filling performance.

[0110] n / c=n / a+1 / ab(1)

[0111] The fitting results of the Kawakita equation are shown in Table 4. Compared with physically mixed powder, the core-shell framework particle powder obtained by mixing the core-shell particles with the framework particles after 10 min of core-shell particle composite has the smallest a value and the largest b value, and has good flowability and filling properties.

[0112] Table 4. Kawakita equation and related parameters for Xiao'er Baoan San (a traditional Chinese medicine formula).

[0113]

[0114]

[0115] 5.2 Hausner ratio

[0116] The bulk density (ρ) of each formulation was determined using a tap density meter. b ) and tap density (ρ t The values ​​were measured in parallel three times, and the results are shown in Table 5. The Hausner ratio was calculated according to formula (2).

[0117] Hausner ratio = ρ t / ρ b (2)

[0118] As shown in Table 5, the Hausner ratio of the composite particles of Xiaobei Ansan is smaller than that of the physically mixed powder, indicating that particle design technology can improve the flowability of Xiaobei Ansan.

[0119] Table 5. Hausner ratio and related parameters of Xiao'er Anbao San (a traditional Chinese medicine formula)

[0120] prescription <![CDATA[Bulk density (ρ b )]]> <![CDATA[Tap density (ρ t )]]> Hausner ratio shell particles 0.3282 0.5655 1.7232 nuclear particles 0.7076 1.1480 1.6225 Frame particles 0.3598 0.5877 1.6333 Core-shell particle pulverization for 2 minutes 0.3757 0.6658 1.7722 Core-shell particle pulverization 4 min 0.4008 0.6823 1.7021 Core-shell particle pulverization for 6 minutes 0.3511 0.5372 1.5301 Core-shell particle pulverization 8 min 0.3898 0.5495 1.4096 Core-shell particle pulverization for 10 minutes 0.3610 0.4892 1.3550 Children's Safety Powder (Physical Mixture) 0.3984 0.6507 1.6333

[0121] 5.3 Angle of repose

[0122] The angle of repose is a simple method to test the flowability of powder. By using an angle of repose measuring instrument, the sample is slowly poured into the funnel wall until the tip of the powder cone formed on the fixed platform touches the opening of the funnel. The value of the measured angle is the angle of repose.

[0123] The angle of repose of a powder directly reflects its flowability; the smaller the angle of repose, the better the flowability. Figure 2It can be seen that the repose angle of the core-shell framework particle powder obtained by mixing with the core-shell particles after 10 minutes of core-shell particle composite is 53.5°, which is less than that of the physically mixed powder (62°). This indicates that particle design technology can improve the flowability of the pediatric safety powder. Figure 2 This is a diagram of the angle of rest.

[0124] 5.4 Micromorphological Evaluation

[0125] Small amounts of core-shell framework particle powder and physically mixed powder were respectively placed on the sample holder, sputtered with gold for 20 seconds, and then the morphology of the particles was observed under a scanning electron microscope. Figure 3 As can be seen from the scanning electron microscope images of the samples, the particle-designed powder is more uniformly mixed and has a looser texture compared to physically mixed powder. The overall microstructure is blocky, and fine particles are attached to the particle surface, indicating that the core-shell framework composite particles are well formed.

[0126] 5.5 Preparation of composite particles

[0127] Particle design process: Bupleurum, Aucklandia, Cinnamon Twig, Atractylodes, Magnolia Bark, Peucedanum, Uncaria, Areca Peel, Saposhnikovia, and Licorice are designed as framework particles; Bitter Almond Powder, Peppermint, Gastrodia, Poria, Patchouli, Pearl, Amber, Malt, Tangerine Peel, Platycodon, Notopterygium, and Shenqu are designed as shell particles; Borneol, Cinnamon, Coptis, Asarum, Bombyx Batryticatus, and Pinellia are designed as core particles. All medicinal materials are pulverized and passed through a 100-mesh sieve for later use.

[0128] The following herbs were separately prepared: coarse powder of framework herbs (Bupleurum chinense, Aucklandia lappa, Cinnamomum cassia, Atractylodes lancea, Magnolia officinalis, Peucedanum praeruptorum, Uncaria rhynchophylla, Areca catechu, Saposhnikovia divaricata, Glycyrrhiza uralensis), coarse powder of kernel herbs (Pinellia ternata, Asarum sieboldii, Bombyx mori, Coptis chinensis, Cinnabar), and coarse powder of shell herbs (Almond syrup, Mentha haplocalyx, Gastrodia elata, Poria cocos, Pogostemon cablin, Pearl, Amber, Malt, Tangerine peel, Platycodon grandiflorus, Notopterygium incisum, and Shenqu). These were then stirred, mixed, dried, and pulverized. The framework herbs were pulverized to a particle size of 21 μm (framework particles); the kernel herbs to a particle size of 165 μm (kernel particles); and the shell herbs to a particle size of 20 μm (shell particles). The shell herbs, kernel herbs, and borneol powder were then mixed and vibrated for 10 minutes to obtain the kernel and shell. The core-shell powder and the framework-type medicinal material powder are vibrated and mixed for 1 minute to prepare core-shell-framework particles, which are the pediatric safety powder with a framework-type composite particle structure. The framework particles, core particles and shell particles are directly mixed to prepare a physically mixed powder.

[0129] 6. Examination of the uniformity of active ingredient content

[0130] Weigh an appropriate amount of berberine hydrochloride reference standard accurately, add methanol to prepare a reference standard solution containing 90.5 μg per mL, and then dilute with methanol to prepare solutions of 0.177, 0.354, 1.770, 3.540, and 10.620 μg / mL, respectively.-1 Berberine hydrochloride reference solution.

[0131] Plotting peak area on the ordinate and concentration of the reference solution on the abscissa, the linear regression equation is y = 21.394x + 1.2881, R0. 2 =0.9999, and the methodological results show that the precision, repeatability, stability, accuracy and recovery rate of this detection method are all good.

[0132] Accurately weigh 1g of the pediatric safety powder composite particles and physical mixed powder prepared in step 5.5, place them in a stoppered conical flask, accurately add 50mL of a mixed solution of hydrochloric acid solution (1→18) and methanol (1:1), weigh the solution, sonicate (300W power, 40kHz frequency) for 30min, cool, weigh the solution again, replenish the lost weight with the mixed solution of hydrochloric acid solution (1→18) and methanol (1:1), shake well, filter, and take the filtrate for HPLC analysis.

[0133] The results showed that the uniformity of berberine hydrochloride content in the Xiaobaoan San composite particle powder (RSD 2.66%) was significantly better than that in the physically mixed powder (RSD 15.10%).

[0134] 7. Pediatric Safety Powder Cinnabar Uniformity Test

[0135] Accurately weigh 1g each of the pediatric safety powder composite particles and the physically mixed powder from step 5.5, place them in an Erlenmeyer flask, add 20mL of sulfuric acid and 2g of potassium nitrate, heat to dissolve, cool, add 50mL of water, and add 1% potassium permanganate solution until a pink color appears. Then add 2% ferrous sulfate solution until the red color disappears, add 2mL of ferric ammonium sulfate indicator solution, and titrate with ammonium thiocyanate solution (0.05mol·L⁻¹). -1 Titration. Each 1 mL of ammonium thiocyanate titrant (0.05 mol·L⁻¹) -1 This is equivalent to 5.815 mg of mercuric sulfide (HgS).

[0136] Table 6. Cinnabar content in Xiao'er Baoan San (a traditional Chinese medicine formula)

[0137]

[0138] Figure 4 For children's safety, physical mixed powder (A) and composite particle powder (B) are used.

[0139] Combined with Table 6 Figure 4 It can be seen that the physically mixed powder is lighter in color and unevenly mixed, while the composite particle mixed powder using particle design technology is darker in color, and the cinnabar color is evenly mixed. Furthermore, under the same treatment conditions, compared to the physically mixed powder, the mercury sulfide content in the particle-designed formulation is reduced by 17%, effectively reducing the toxicity risk of cinnabar in the children's protective powder.

[0140] 8. Dissolution test of children's safety powder

[0141] Take the prepared pediatric safety powder composite particles and physically mixed powder from step 5.5, and use the apparatus of the second method (paddle method) for dissolution and release determination according to the Chinese Pharmacopoeia (2020 edition, Part IV), with 500 mL of deionized water after degassing as the release medium, and a rotation speed of 50 r·min. -1 The temperature was 37±0.5℃. 3mL samples were taken at 15, 30, 45, 60, 90, 120, 180, 240, 300, 600, 900, and 1200s, filtered, and 3mL of release medium at the same temperature was added in time.

[0142] Accurately pipette 2 mL of the dissolution solution, filter it through a 0.45 μm filter membrane, and inject it into HPLC chromatography to calculate the cumulative dissolution rate of berberine hydrochloride at each time point.

[0143] Figure 5 The dissolution curve of Xiao'er Baoan San is shown. The dissolution test results show that berberine hydrochloride dissolves less than 35% in the composite particle powder using particle design technology within 60 seconds, and reaches 98% within 4 minutes. In contrast, the physical mixed powder dissolves 50% within 60 seconds and 88% within 15 minutes. This indicates that particle design technology can mask the taste of Xiao'er Baoan San and also has rapid-release characteristics.

[0144] Example 2

[0145] This embodiment is a variation of Embodiment 1, and the changes compared to the scheme described in section 5.5 of Embodiment 1 include:

[0146] (1) The particle size of the nuclear particles is 253 μm;

[0147] (2) The shell particles have a particle size of 55 μm;

[0148] (3) The particle size of the framework particles is 58 μm.

[0149] Example 3

[0150] This embodiment is a variation of Embodiment 1, and the changes compared to the scheme described in section 5.5 of Embodiment 1 include:

[0151] (1) The particle size of the nuclear particles is 82 μm;

[0152] (2) The shell particles have a particle size of 15 μm;

[0153] (3) The particle size of the framework particles is 96 μm.

[0154] Comparative Example 1

[0155] This comparative example is a comparative example of Example 1, and the differences from the scheme described in section 5.5 of Example 1 include:

[0156] (1) The particle size of the nuclear particles is 56 μm;

[0157] (2) The particle size of the shell particles is 20 μm;

[0158] (3) The particle size of the framework particles is 21 μm.

[0159] Comparative Example 2 is a comparative example of Example 1, and the differences between it and the scheme described in section 5.5 of Example 1 include:

[0160] (1) The particle size of the nuclear particles is 165 μm;

[0161] (2) The particle size of the shell particles is 179 μm;

[0162] (3) The particle size of the framework particles is 21 μm.

[0163] Comparative Example 3 is a comparative example of Example 1, and its differences from the scheme described in section 5.5 of Example 1 include:

[0164] (1) The particle size of the shell particles is 165 μm;

[0165] (2) The particle size of the shell particles is 20 μm;

[0166] (3) The particle size of the framework particles is 823 μm.

[0167] Table 7

[0168]

[0169] Performance tests of Examples 1 to 3

[0170] The contact angles of core particles, shell particles, framework particles, and physically mixed powders of different particle sizes were measured using a powder contact angle meter. The results are as follows:

[0171] Table 8

[0172]

[0173]

[0174] Compared to physically mixed powders, composite particles have a particle size in the micrometer range. Because the particle size of composite particles is smaller, the contact angle is smaller, the surface energy of the composite particle powder is greater, which is beneficial to the stability of the composite particles.

[0175] The density difference of composite particle powders and physically mixed powders with different classifications of core particles, shell particles, and framework particles was investigated. Small amounts of composite particle powders from Examples 1, 2, and 3 and physically mixed powders from Example 1 were taken respectively. The powders were allowed to slide freely into 1.5 mL EP tubes using a fixed funnel method. Excess samples were scraped off, and the samples were accurately weighed. The density was calculated using the formula ρ = M / V. This process was repeated 10 times.

[0176] The results showed that the RSDs of the composite particle densities in Examples 1, 2, and 3 were 0.34%, 0.52%, and 0.49%, respectively, all lower than the RSD of 2.30% for the density of the physically mixed powder. The comparison indicates that the composite particles with particle design have a more uniform density, while the density distribution of ordinary physically mixed powders is more dispersed.

[0177] Performance tests of Comparative Examples 1 to 3

[0178] Dissolution experiments of berberine hydrochloride were conducted on the powders of Comparative Examples 1 to 3, and the results are as follows: Figure 6 .

[0179] The results showed that the dissolution behavior varied significantly depending on the particle size ratio of the core and shell particles. Compared to Example 1, the particle size ratios of the core and shell particles in Comparative Examples 1 and 2 were 2.8:1 and 0.9:1, respectively, making it difficult to form a core-shell structure. This resulted in incomplete dissolution of berberine hydrochloride from the core particle component of Coptis chinensis. Furthermore, the dissolution rate of berberine hydrochloride reached 48.96% within 45 seconds, indicating excessively rapid dissolution and poor taste masking effect of the powder. Although Comparative Example 3 could form a core-shell structure, the frame particles were too large, resulting in a faster dissolution rate and poorer taste masking effect compared to Example 1.

[0180] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0181] The above-described embodiments are merely illustrative of several implementation methods of the present invention, facilitating a detailed and specific understanding of the technical solutions of the present invention. However, they should not be construed as limiting the scope of protection of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Furthermore, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and the equivalent forms obtained also fall within the scope of protection of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided by the present invention through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this invention patent should be determined by the content of the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A pediatric safety powder, characterized in that, The pediatric security powder has a framework type composite particle structure, and the framework type composite particle structure satisfies the following conditions: The powder particles of bupleurum, costus, cassia twig, cangzhu, pinellia, peony root, and licorice are used as the framework particles, and the particle size of the framework particles is 21 μm; The raw medicinal materials of the pediatric security powder are as follows in terms of mass parts: Borneol 3.7-3.9 parts, Pinellia 2.2-2.4 parts, Asarum 1.3-1.5 parts, Cicada 2.2-2.4 parts, Coptis 2.2-2.4 parts, Cinnabar 5.9-6.1 parts, Bitter apricot kernel cream 2.7-2.9 parts, Mint 2.2-2.4 parts, Gastrodia 2.2-2.4 parts, Poria 2.2-2.4 parts, Ravensare 2.2-2.4 parts, Pearl 1.4-1.6 parts, Amber 2.9-3.1 parts, Malt 2.2-2.4 parts, Dried tangerine or orange peel 2.2-2.4 parts, Platycodon 2.7-2.9 parts, Notopterygium 2.2-2.4 parts, Sixianqu 2.2-2.4 parts, Bupleurum 5.5-5.7 parts, Costus 1.3-1.5 parts, Cassia twig 1.3-1.5 parts, Cangzhu 2.2-2.4 parts, Pinellia 2.2-2.4 parts, Peony root 4.1-4.3 parts, Uncaria 2.7-2.9 parts, Large abdominal skin 2.2-2.4 parts, Notopterygium 2.2-2.4 parts, and Licorice 1.3-1.6 parts; The preparation method of the pediatric security powder comprises the following steps: The obtained shell medicinal material micro powder, core medicinal material pinellia, asarum, cicada, coptis, and cinnabar micro powder, and borneol micro powder are mixed, vibrated and ground for 10 minutes to obtain a core-shell powder; The obtained core-shell powder and the framework medicinal material micro powder are vibrated and ground for 1 minute to prepare a core-shell-framework particle, that is, the pediatric security powder with a framework type composite particle structure is obtained.

2. A preparation method of a pediatric security powder, characterized in that, The pediatric security powder has a framework type composite particle structure, and the framework type composite particle structure satisfies the following conditions: The powder particles of bupleurum, costus, cassia twig, cangzhu, pinellia, peony root, and licorice are used as the framework particles, and the particle size of the framework particles is 21 μm; The raw medicinal materials of the pediatric security powder are as follows in terms of mass parts: Borneol 3.7-3.9 parts, Pinellia 2.2-2.4 parts, Asarum 1.3-1.5 parts, Cicada 2.2-2.4 parts, Coptis 2.2-2.4 parts, Cinnabar 5.9-6.1 parts, Bitter apricot kernel cream 2.7-2.9 parts, Mint 2.2-2.4 parts, Gastrodia 2.2-2.4 parts, Poria 2.2-2.4 parts, Ravensare 2.2-2.4 parts, Pearl 1.4-1.6 parts, Amber 2.9-3.1 parts, Malt 2.2-2.4 parts, Dried tangerine or orange peel 2.2-2.4 parts, Platycodon 2.7-2.9 parts, Notopterygium 2.2-2.4 parts, Sixianqu 2.2-2.4 parts, Bupleurum 5.5-5.7 parts, Costus 1.3-1.5 parts, Cassia twig 1.3-1.5 parts, Cangzhu 2.2-2.4 parts, Pinellia 2.2-2.4 parts, Peony root 4.1-4.3 parts, Uncaria 2.7-2.9 parts, Large abdominal skin 2.2-2.4 parts, Notopterygium 2.2-2.4 parts, and Licorice 1.3-1.6 parts; The raw materials of the pediatric security powder are, in parts by mass: Borneolum syntheticum 3.7-3.9 parts, Rhizoma pinelliae praeparatum 2.2-2.4 parts, Asarum 1.3-1.5 parts, Semen cassiae praeparatum 2.2-2.4 parts, Coptidis rhizoma 2.2-2.4 parts, Cinnabaris 5.9-6.1 parts, Amygdalae amarae concretum 2.7-2.9 parts, Menthae herba 2.2-2.4 parts, Gastrodiae rhizoma 2.2-2.4 parts, Poria 2.2-2.4 parts, Agastache rugosa 2.2-2.4 parts, Margarita 1.4-1.6 parts, Amber 2.9-3.1 parts, Hordei fructus 2.2-2.4 parts, Citri reticulatae pericarpium 2.2-2.4 parts, Platycodi grandiflori caulis 2.7-2.9 parts, Notopterygii herba 2.2-2.4 parts, Massa medicata fermentata 2.2-2.4 parts, Bupleuri radix 5.5-5.7 parts, Aucklandiae radix 1.3-1.5 parts, Cinnamomi ramulus 1.3-1.5 parts, Atractylodis lanceae 2.2-2.4 parts, Magnoliae officinalis cortex 2.2-2.4 parts, Peucedani radix 4.1-4.3 parts, Uncariae ramulus 2.7-2.9 parts, Citri reticulatae pericarpium 2.2-2.4 parts, Saposhnikoviae radix 2.2-2.4 parts, and Glycyrrhizae radix 1.3-1.6 parts; The preparation method comprises the following steps: The frame medicinal material coarse powder, the core medicinal material Rhizoma pinelliae praeparatum, Asarum, Semen cassiae praeparatum, Coptidis rhizoma, and Cinnabaris coarse powder, and the shell medicinal material coarse powder are stirred, mixed, dried, and crushed respectively; The obtained shell medicinal material micro powder, the core medicinal material Rhizoma pinelliae praeparatum, Asarum, Semen cassiae praeparatum, Coptidis rhizoma, and Cinnabaris micro powder, and Borneolum syntheticum micro powder are mixed, and vibration grinding is performed for 10 min to obtain a core-shell powder; The obtained core-shell powder is mixed with the frame medicinal material micro powder by vibration grinding for 1 min to prepare a core-shell-frame particle, thereby obtaining the pediatric security powder with a frame type composite particle structure.

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