Granules of composition containing polygala tenuifolia as well as preparation method and application of granules

Abstract

The invention discloses granules of a composition containing polygala tenuifolia. The granules further comprise an excipient and an adhesive, wherein the weight ratio of the dry paste powder of the composition to the excipient to the adhesive is (0.5-1.5): (0.5-2.5): (0.01-1), the composition comprises polygala tenuifolia, rhizoma acori graminei and poria with hostwood, the excipient is microcrystalline cellulose, and the adhesive is povidone and / or maltodextrin. The granules improve the compliance of clinical medication of patients, especially elderly patients, and meanwhile, a solution is provided for taste masking of other preparations containing polygala tenuifolia medicine taste related components.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a granule containing a composition of Polygala tenuifolia, its preparation method, and its application. Background Technology

[0002] As a common dosage form in the field of traditional Chinese medicine preparations, granules overcome the shortcomings of traditional Chinese medicine decoctions, such as cumbersome and time-consuming preparation, and difficulty in preservation and portability. They offer advantages such as precise dosage, safety and hygiene, convenient portability, and instant administration, making them more suitable for today's fast-paced lifestyle. Formulating prescriptions into granules not only largely replicates the decoction method described in ancient texts but also aligns with the medication characteristics of modern society. However, prescriptions containing Polygala tenuifolia (Yuanzhi) contain its characteristic flavor, which has a peculiar "pungent" taste. The components causing this taste transfer to the granules during the extraction process, and neither flavor-correcting nor flavor-masking methods can effectively reduce this taste. Furthermore, to ensure the replication of the ancient methods of administration, Chinese medicinal herbs are typically decocted together, making methods such as cyclodextrin inclusion complexation and ion exchange resin methods difficult to implement. Additionally, due to the complexity of Chinese medicine compound ingredients, it is difficult to achieve flavor masking through a single method, and there are currently few mature flavor-masking methods or dosage forms suitable for unpleasant tastes on the market.

[0003] No granules containing Polygala tenuifolia, a method for their preparation, or their application have been found in the prior art as claimed in this invention. Summary of the Invention

[0004] Based on this, the present invention provides a granule containing a composition of Polygala tenuifolia, characterized in that the granule further comprises an excipient and a binder;

[0005] The weight ratio of the dry powder, the excipient, and the adhesive in the composition is (0.5-1.5):(0.5-2.5):(0.01-1).

[0006] The composition contains Polygala tenuifolia, Acorus tatarinowii, and Poria cocos.

[0007] The excipient is microcrystalline cellulose;

[0008] The adhesive is povidone and / or maltodextrin.

[0009] Furthermore, the weight ratio of the dry paste powder, the excipient, and the adhesive in the composition is approximately 1:(0.9-2):(0.1-0.5).

[0010] Furthermore, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.1–5):(0.1–5):(0.1–5).

[0011] Furthermore, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.5–1.5):(0.5–1.5):(0.5–1.5).

[0012] Furthermore, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is approximately 1:1:1.

[0013] Furthermore, this *Polygala tenuifolia* is a processed form.

[0014] Furthermore, the weight of the dry extract powder of the composition = weight of the clear extract sample after constant weight / weight of the clear extract sample before drying × weight of the clear extract.

[0015] Furthermore, the composition further comprises one or more other pharmaceutically acceptable excipients.

[0016] Furthermore, the other pharmaceutically acceptable excipient is selected from one or more of the following: diluents, disintegrants, coating agents, flavoring agents, sustained-release agents, lubricants, dispersants, plasticizers, light-blocking agents, and antioxidants.

[0017] Furthermore, the coating agent is selected from one or more of the following: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer, ethyl acrylate and methyl methacrylate copolymer, and methacrylic acid and ethyl acrylate copolymer.

[0018] Furthermore, the composition further comprises one or more drugs for the prevention and / or treatment of Alzheimer's disease.

[0019] Furthermore, the drug is an acetylcholinesterase inhibitor, an N-methyl-D-aspartate receptor antagonist, and / or a brain metabolism activator.

[0020] Furthermore, the acetylcholinesterase inhibitor is donepezil, rivastigmine, and / or huperzine A.

[0021] Furthermore, the N-methyl-D-aspartate receptor antagonist is memantine.

[0022] Furthermore, the brain metabolism activator is piracetam.

[0023] According to another aspect of the present invention, a method for preparing granules of a composition comprising Polygala tenuifolia is provided, the method comprising the following steps:

[0024] (1) Weigh an appropriate amount of the composition and place it in a container. Add water for the first time, heat to extract, filter, and obtain the first filtrate and the residue.

[0025] (2) Add water to the residue, heat to extract, filter to obtain the second filtrate;

[0026] (3) Combine the first filtrate and the second filtrate to obtain a combined filtrate;

[0027] (4) The combined filtrate was concentrated to obtain a clear extract; and

[0028] (5) Add excipients and binders to the clear paste or the dry paste powder obtained by further drying the clear paste, granulate, dry, and obtain granules;

[0029] The composition contains Polygala tenuifolia, Acorus tatarinowii, and Poria cocos.

[0030] Furthermore, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.1–5):(0.1–5):(0.1–5).

[0031] Furthermore, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.5–1.5):(0.5–1.5):(0.5–1.5).

[0032] Furthermore, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is approximately 1:1:1.

[0033] Furthermore, this *Polygala tenuifolia* is a processed form.

[0034] Furthermore, the ratio of the volume of the first water to the mass of the composition is 6 to 20.

[0035] Furthermore, the ratio of the volume of the first water to the mass of the composition is 8 to 12, for example, about 10.

[0036] Furthermore, the heating extraction is a boiling extraction.

[0037] Furthermore, the extraction time is 0.3 to 3 hours per extraction.

[0038] Furthermore, the extraction time is 0.5 to 2 hours per extraction, for example, about 1 hour per extraction.

[0039] Furthermore, the filtration is performed using a 100-mesh sieve.

[0040] Furthermore, the ratio of the volume of the second water to the mass of the composition is 6 to 20.

[0041] Furthermore, the ratio of the volume of the second water to the mass of the composition is 8 to 12, for example, about 10.

[0042] Furthermore, the excipient is microcrystalline cellulose.

[0043] Furthermore, the excipient is not dextrin or maltodextrin.

[0044] Furthermore, the mass ratio of the excipient to the composition is 0.1 to 0.6.

[0045] Furthermore, the mass ratio of the excipient to the composition is 0.18 to 0.4.

[0046] Furthermore, this concentration is a vacuum concentration.

[0047] Furthermore, the endpoint of this vacuum concentration is that the relative density of the extract at a certain temperature is 1.05 to 1.15, for example, about 1.10.

[0048] Furthermore, this temperature is 45–60°C, for example, about 50°C.

[0049] Furthermore, the drying process is vacuum drying.

[0050] Furthermore, the temperature for this vacuum drying is 65–80°C.

[0051] Furthermore, the adhesive is selected from povidone or maltodextrin.

[0052] Furthermore, the mass ratio of the adhesive to the composition is 0.01 to 0.2.

[0053] Furthermore, the mass ratio of the adhesive to the composition is 0.02 to 0.1.

[0054] Furthermore, the granulation method is either rapid stirring granulation or fluidized bed granulation.

[0055] Furthermore, the wetting agent used in this rapid stirring granulation method is an alcohol, such as ethanol.

[0056] Furthermore, this ethanol is pharmaceutical grade ethanol.

[0057] Furthermore, the concentration of the ethanol used in this medicine is 80% to 100%, for example, about 90%.

[0058] Furthermore, the method further includes the step of coating the granules with a coating solution.

[0059] Furthermore, the coating instrument is a fluidized bed granulation and coating machine.

[0060] Furthermore, the preparation method of the coating solution includes the following steps: adding other excipients to the coating agent, adding water to obtain a suspension, stirring, and obtaining the coating solution.

[0061] Furthermore, the coating agent is selected from one or more of the following: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer, ethyl acrylate and methyl methacrylate copolymer, methacrylic acid and ethyl acrylate copolymer.

[0062] Furthermore, the other excipients are selected from one or more of the following: sodium dodecyl sulfate, stearic acid, talc, magnesium stearate, hydroxypropyl cellulose, polyethylene glycol, and hydroxypropyl methylcellulose.

[0063] Furthermore, the ratio of the total mass of the coating agent and the other excipients to the mass of the granules is 0.2 to 0.6.

[0064] Furthermore, the concentration of the suspension is 10% to 20%.

[0065] Furthermore, the concentration of the suspension is 15% to 16%.

[0066] According to another aspect of the invention, the use of the above-described granules in the preparation of a medicament for the prevention and / or treatment of Alzheimer's disease is provided.

[0067] The beneficial effects of this invention are:

[0068] Compared with common taste correction and taste masking techniques in the prior art, the present invention has the following advantages: (1) Common taste correction techniques for granules use sweeteners such as sucralose and neotame. The principle is to increase the sweetness sensation to confuse the brain's taste perception and reduce the taste perception of bitterness or astringency from the drug components. However, the unpleasant taste produced in the granules containing Polygala tenuifolia is not a taste sensation, but an irritating sensation from the throat. The present invention has found that adding taste correction agents cannot reduce this sensation, so the taste correction technique has failed to effectively solve the taste problem. The granule coating technology of the present invention can block the drug components from contacting the oral cavity and throat, and can fundamentally solve the taste problem; (2) Common taste masking techniques, such as cyclodextrin encapsulation, are based on embedding the drug into the hollow structure inside the cyclodextrin molecule to mask the odor. However, this method is often used in tablets and capsules. If this method is used in granules, the drug components may still dissolve into the liquid during the brewing process, making it difficult to improve the taste problem. Furthermore, due to the complex composition of traditional Chinese medicine after decoction, it is impossible to encapsulate specific components. The particle coating technology of this invention can achieve the purpose of masking taste in granule dosage forms, so that the drug components can be released quickly after the granules reach the stomach, preserving the dosage form characteristics of granules. While solving compliance, it can restore the medication method recorded in ancient books to the greatest extent. (3) By using a combination of different polymer coating materials, the release of drug particles in the intestinal tract can be controlled on the basis of achieving the purpose of masking taste in granules, providing a basis for the improvement and development of controlled-release formulations of granules containing Polygala tenuifolia. Detailed Implementation

[0069] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0070] Unless otherwise stated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by one of ordinary skill in the field of this invention or the field of application of such terms. While any methods, conditions, substances, or materials similar to or equivalent to those disclosed herein may be used in the practice of this invention, preferred methods, conditions, substances, or materials are described herein.

[0071] This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances.

[0072] The singular forms “a,” “an,” and “the” used in the specification and appended claims include plural indicators unless the context clearly specifies otherwise.

[0073] In this invention, the term "comprising" and "including" are synonymous. The terms "comprising," "including," "having," "containing," or any other variations thereof as used herein are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0074] As described in the background section, it is difficult to achieve the purpose of masking taste using a single method, and there are currently few mature masking methods or suitable dosage forms for preparations with unpleasant tastes on the market. To solve the above problems, the present invention provides a granule containing a composition of Polygala tenuifolia, characterized in that the granule further comprises an excipient and a binder;

[0075] The weight ratio of the dry powder, the excipient, and the adhesive in the composition is (0.5-1.5):(0.5-2.5):(0.01-1).

[0076] The composition contains Polygala tenuifolia, Acorus tatarinowii, and Poria cocos.

[0077] The excipient is microcrystalline cellulose;

[0078] The adhesive is povidone and / or maltodextrin.

[0079] In this invention, when a ratio, time, temperature, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range "0.5 to 1.5" is disclosed, the described range should be interpreted as including ranges such as "0.5 to 1.5", "0.5 to 1.3", "0.5 to 1.1", "0.5 to 0.9", "0.5 to 0.7", "0.7 to 1.5", "0.7 to 1.3", "0.7 to 1.1", "0.7 to 0.9", "0.9 to 1.5", "0.9 to 1.3", "0.9 to 1.1", "1.1 to 1.5", "1.1 to 1.3", "1.3 to 1.5", etc. When a range of values ​​is described in this document, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0080] In a preferred embodiment, the weight ratio of the dry paste powder, the excipient, and the adhesive in the composition is about 1:(0.9-2):(0.1-0.5).

[0081] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1" includes ±5% of 1, or from 0.95 to 1.05.

[0082] In a preferred embodiment, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.1-5):(0.1-5):(0.1-5).

[0083] In a preferred embodiment, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.5-1.5):(0.5-1.5):(0.5-1.5).

[0084] In a preferred embodiment, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is about 1:about 1:about 1.

[0085] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1" includes ±5% of 1, or from 0.95 to 1.05.

[0086] In a preferred embodiment, the Polygala tenuifolia is processed Polygala tenuifolia.

[0087] In a preferred embodiment, the weight of the dry extract powder of the composition = the weight of the extract sample after constant weight / the weight of the extract sample before drying × the weight of the extract.

[0088] In a preferred embodiment, the composition further comprises one or more other pharmaceutically acceptable excipients.

[0089] In a preferred embodiment, the other pharmaceutically acceptable excipient is selected from one or more of the following: diluents, disintegrants, coating agents, flavoring agents, sustained-release agents, lubricants, dispersants, plasticizers, light-blocking agents, and antioxidants.

[0090] In a preferred embodiment, the coating agent is selected from one or more of the following: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer, ethyl acrylate and methyl methacrylate copolymer, and methacrylic acid and ethyl acrylate copolymer.

[0091] In a preferred embodiment, the composition further comprises one or more drugs for the prevention and / or treatment of Alzheimer's disease.

[0092] In a preferred embodiment, the drug is an acetylcholinesterase inhibitor, an N-methyl-D-aspartate receptor antagonist, and / or a brain metabolism activator.

[0093] In a preferred embodiment, the acetylcholinesterase inhibitor is donepezil, rivastigmine, and / or huperzine A.

[0094] In a preferred embodiment, the N-methyl-D-aspartate receptor antagonist is memantine.

[0095] In a preferred embodiment, the brain metabolism activator is piracetam.

[0096] According to another aspect of the present invention, a method for preparing granules of a composition comprising Polygala tenuifolia is provided, the method comprising the following steps:

[0097] (1) Weigh an appropriate amount of the composition and place it in a container. Add water for the first time, heat to extract, filter, and obtain the first filtrate and the residue.

[0098] (2) Add water to the residue, heat to extract, filter to obtain the second filtrate;

[0099] (3) Combine the first filtrate and the second filtrate to obtain a combined filtrate;

[0100] (4) The combined filtrate was concentrated to obtain a clear extract; and

[0101] (5) Add excipients and binders to the clear paste or the dry paste powder obtained by further drying the clear paste, granulate, dry, and obtain granules;

[0102] The composition contains Polygala tenuifolia, Acorus tatarinowii, and Poria cocos.

[0103] In a preferred embodiment, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.1-5):(0.1-5):(0.1-5).

[0104] In a preferred embodiment, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.5-1.5):(0.5-1.5):(0.5-1.5).

[0105] In a preferred embodiment, the mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is about 1: about 1: about 1.

[0106] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1" includes ±5% of 1, or from 0.95 to 1.05.

[0107] In a preferred embodiment, the Polygala tenuifolia is processed Polygala tenuifolia.

[0108] In a preferred embodiment, the ratio of the volume of the first water to the mass of the composition is 6 to 20.

[0109] In a preferred embodiment, the ratio of the volume of the first water to the mass of the composition is 8 to 12, for example, about 10.

[0110] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 10" includes ±5% of 10, or from 9.5 to 10.5.

[0111] In a preferred embodiment, the heating extraction is a boiling extraction.

[0112] In a preferred embodiment, the extraction time is 0.3 to 3 hours per extraction.

[0113] In a preferred embodiment, the extraction time is 0.5 to 2 hours per extraction, for example, about 1 hour per extraction.

[0114] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1" includes ±5% of 1, or from 0.95 to 1.05.

[0115] In a preferred embodiment, the filtration is a 100-mesh sieve filtration.

[0116] In a preferred embodiment, the volume ratio of the second water to the mass of the composition is 6 to 20.

[0117] In a preferred embodiment, the ratio of the volume of the second water to the mass of the composition is 8 to 12, for example, about 10.

[0118] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 10" includes ±5% of 10, or from 9.5 to 10.5.

[0119] In a preferred embodiment, the excipient is microcrystalline cellulose.

[0120] In a preferred embodiment, the excipient is not dextrin or maltodextrin.

[0121] In a preferred embodiment, the mass ratio of the excipient to the composition is 0.1 to 0.6.

[0122] In a preferred embodiment, the mass ratio of the excipient to the composition is 0.18 to 0.4.

[0123] In a preferred embodiment, the concentration is a vacuum concentration.

[0124] In a preferred embodiment, the endpoint of the reduced pressure concentration is that the relative density of the extract at a certain temperature is 1.05 to 1.15, for example, about 1.10.

[0125] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.10" includes ±5% of 1.10, or from 1.045 to 1.155.

[0126] In a preferred embodiment, the temperature is 45–60°C, for example, about 50°C.

[0127] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 50" includes 50 ± 5%, or from 47.5 to 52.5.

[0128] In a preferred embodiment, the drying is vacuum drying.

[0129] In a preferred embodiment, the temperature for vacuum drying is 65–80°C.

[0130] In a preferred embodiment, the adhesive is selected from povidone or maltodextrin.

[0131] In a preferred embodiment, the mass ratio of the adhesive to the composition is 0.01 to 0.2.

[0132] In a preferred embodiment, the mass ratio of the adhesive to the composition is 0.02 to 0.1.

[0133] In a preferred embodiment, the granulation method is rapid stirring granulation or fluidized bed granulation.

[0134] In a preferred embodiment, the wetting agent used in this rapid stirring granulation method is an alcohol, such as ethanol.

[0135] In a preferred embodiment, the ethanol is pharmaceutical grade ethanol.

[0136] In a preferred embodiment, the concentration of the pharmaceutical ethanol is 80% to 100%, for example, about 90%.

[0137] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 90%" includes 90% ± 5%, or from 85.5% to 94.5%.

[0138] In a preferred embodiment, the method further includes the step of spraying the granules with a coating liquid for coating.

[0139] In a preferred embodiment, the coating apparatus is a fluidized bed granulation and coating machine.

[0140] In a preferred embodiment, the preparation method of the coating solution includes the following steps: adding other excipients to the coating agent, adding water to obtain a suspension, stirring, and obtaining the coating solution.

[0141] In a preferred embodiment, the coating agent is selected from one or more of the following: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer, ethyl acrylate and methyl methacrylate copolymer, methacrylic acid and ethyl acrylate copolymer.

[0142] In a preferred embodiment, the other excipients are selected from one or more of the following: sodium dodecyl sulfate, stearic acid, talc, magnesium stearate, hydroxypropyl cellulose, polyethylene glycol, and hydroxypropyl methylcellulose.

[0143] In a preferred embodiment, the ratio of the sum of the mass of the coating agent and the other excipients to the mass of the granules is 0.2 to 0.6.

[0144] In a preferred embodiment, the concentration of the suspension is 10% to 20%.

[0145] In a preferred embodiment, the concentration of the suspension is 15% to 16%.

[0146] According to another aspect of the invention, the use of the above-described granules in the preparation of a medicament for the prevention and / or treatment of Alzheimer's disease is provided.

[0147] The purpose of this invention is to provide a flavor-masking granule containing Polygala tenuifolia, its preparation method and application, to improve patient compliance, especially elderly patients, in clinical medication, and also to provide a solution for masking the flavor of other traditional Chinese medicine preparations containing Polygala tenuifolia-related ingredients.

[0148] The objective of this invention is achieved as follows: The herbal decoction pieces in a composition containing Polygala tenuifolia are extracted and granulated. The granules are then coated with a pH-dependent polymer coating material. Since this type of coating material dissolves only in solutions with a pH less than 5, and the pH of the drinking water used for granule administration is generally 6.5–8.5, this method prevents the granules containing Polygala tenuifolia from contacting the aqueous solution, thus preventing the drug components from dissolving in water. Therefore, the irritating components to the throat remain in the coated granules. When the granules are ingested and pass through the digestive tract to the stomach, the outer coating of the granules dissolves in the gastric juice (pH 0.9–1.8), simultaneously dissolving the granules and releasing the drug components, thereby masking the taste. Furthermore, by combining different types of pH-dependent polymer materials, the granules containing Polygala tenuifolia can be released into the intestinal tract while simultaneously masking the taste, achieving a controlled-release effect.

[0149] The method described in this invention includes the following process steps:

[0150] Step 1: Take appropriate amounts of the prepared Polygala tenuifolia, Acorus tatarinowii, and Poria cocos from the prescription containing Polygala tenuifolia, place them in an extraction container, add 10 times the amount of water, heat to boiling and extract for 1 hour, filter to obtain the aqueous extract, add 10 times the amount of water to the residue and heat to boiling and extract for 1 hour, combine the two aqueous extracts.

[0151] Step 2: Concentrate the aqueous extract to a clear paste with a relative density of 1.05-1.15 using a vacuum concentration method (60℃), add excipients and binders, granulate, and dry to obtain granules containing Polygala tenuifolia, for later use.

[0152] Step 3: Using a polymer coating material, the composition particles containing Polygala tenuifolia are coated through a fluidized bed apparatus to obtain flavor-masked granules containing Polygala tenuifolia.

[0153] The excipient is microcrystalline cellulose; the amount of the excipient is 90% to 200% of the weight of the dry extract powder containing Polygala tenuifolia.

[0154] The adhesive is one or more of povidone and maltodextrin; the amount of the adhesive is 10% to 50% of the weight of the dry extract of the composition containing Polygala tenuifolia.

[0155] The aforementioned percentage increase in weight of the coating material is 10% to 80% of the weight of the polymer coating the particle surface, which is equivalent to the weight of the composition particles containing Polygala tenuifolia before coating.

[0156] The coating materials used in this invention are soluble in aqueous environments with a pH value less than 5 or greater than 6. Specifically, they include one of the following: butyl methacrylate, a copolymer of dimethylaminoethyl methacrylate and methyl methacrylate, a copolymer of ethyl acrylate and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate. By combining different types of coating materials, it is possible to achieve the goal of being insoluble in drinking water and acidic solutions, but soluble in slightly alkaline or alkaline environments.

[0157] Through repeated research, this invention has found that the coated granules containing Polygala tenuifolia do not release the drug in drinking water for up to one hour, and the aqueous solution has no throat irritation after tasting. Then, the following operations are performed: (1) Filter the granules in the drinking water medium, take the granules, and add them to a hydrochloric acid solution with a pH of 1.0 to 2.2. The coating of the granules breaks down and dissolves completely within 2 to 5 minutes, and the drug is basically released into the solution; (2) Or filter the granules in the drinking water medium, take the granules, add them to a hydrochloric acid solution with a pH of 1.0 to 2.2, stir for about 5 minutes, then filter the granules in the hydrochloric acid solution, take the granules, and add them to a phosphate buffer solution with a pH of 6.8. The coating of the granules breaks down and dissolves completely within 2 to 5 minutes, and the drug is basically released.

[0158] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0159] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0160] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this patent specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0161] Example

[0162] The method for determining the weight of the dry extract powder contained in the ointment of the present invention is as follows: A certain volume of the ointment sample is accurately measured into a suitable glass weighing bottle that has been dried to constant weight, and then placed in a drying oven at 105°C until constant weight is achieved. The weight is then calculated using the following formula:

[0163] G = W1 / W2 × W

[0164] In the formula, G represents the weight of the dry ointment powder contained in the ointment.

[0165] W1 is the weight of the test sample after constant weight.

[0166] W2 represents the weight of the extract sample before drying.

[0167] W represents the weight of the ointment.

[0168] In all subsequent embodiments, the calculation method for dry powder is the same as the above formula.

[0169] Example 1

[0170] Take 300g of prepared Polygala tenuifolia slices, 300g of Acorus tatarinowii slices, and 300g of Poria cocos slices, place them in an extraction container, add 9000g of water, heat to boiling, and extract for 1 hour. Filter the liquid through a 100-mesh sieve to obtain the extract, and set it aside. Add another 7200g of water to the residue, heat to boiling, and extract for 1 hour. Filter the liquid through a 100-mesh sieve to obtain the extract. Combine the two extracts.

[0171] The extract was concentrated to a clear paste with a relative density of 1.10 (50℃) by vacuum concentration.

[0172] Using a fluidized bed granulation and coating machine, 162g of microcrystalline cellulose was used as an excipient and 18g of povidone as a binder to prepare granules containing Polygala tenuifolia. The granules were sized, mixed evenly, and set aside for later use. These granules correspond to sample number 1 in Table 1.

[0173] A copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2:1) was used as the coating material, with appropriate amounts of sodium dodecyl sulfate and stearic acid added. The total amount of these three materials was 20% of the weight of the granules containing Polygala tenuifolia. Water was added to prepare a 15% suspension, which was stirred evenly to obtain the coating solution. The granules containing Polygala tenuifolia were coated with the coating solution using a fluidized bed granulator, then dried, mixed evenly, and packaged to obtain the flavor-masking granules containing Polygala tenuifolia.

[0174] Example 2

[0175] Take 300g of prepared Polygala tenuifolia slices, 300g of Acorus tatarinowii slices, and 300g of Poria cocos slices, place them in an extraction container, add 9000g of water, heat to boiling, and extract for 2 hours. Filter the liquid through a 100-mesh sieve to obtain the extract, and set it aside. Add another 9000g of water to the residue, heat to boiling, and extract for 1 hour. Filter the liquid through a 100-mesh sieve to obtain the extract, and combine the two extracts.

[0176] The extract was concentrated to a clear paste with a relative density of 1.10 (50℃) by vacuum concentration.

[0177] Using a fluidized bed granulation and coating machine, 360g of microcrystalline cellulose was used as an excipient and 60g of povidone as a binder to prepare granules containing Polygala tenuifolia. The granules were sized, mixed evenly, and set aside for later use. These granules correspond to sample number 2 in Table 1.

[0178] Using ethyl acrylate and methyl methacrylate (1:1) copolymer as coating material and adding an appropriate amount of hydroxypropyl methylcellulose, the total amount of the two is 30% of the weight of the composition particles containing Polygala tenuifolia. Water is added to make a suspension with a concentration of 15%, and the mixture is stirred evenly to form coating solution 1 for later use.

[0179] A 15% suspension was prepared by adding a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2:1) as the coating material, along with appropriate amounts of sodium dodecyl sulfate and stearic acid. The total amount of these three materials was 30% of the weight of the granules containing Polygala tenuifolia. The suspension was stirred until homogeneous and prepared as coating solution 2. Using a fluidized bed granulator, the granules containing Polygala tenuifolia were sprayed with coating solution 1 for coating, dried, and then sprayed with coating solution 2 again for coating, followed by drying. After homogeneous mixing and packaging, the flavor-masking granules containing Polygala tenuifolia were obtained.

[0180] Example 3

[0181] Take 300g of prepared Polygala tenuifolia slices, 300g of Acorus tatarinowii slices, and 300g of Poria cocos slices, place them in an extraction container, add 9000g of water, heat to boiling, and extract for 1 hour. Filter the liquid through a 100-mesh sieve to obtain the extract, and set it aside. Add another 9000g of water to the residue, heat to boiling, and extract for 0.5 hours. Filter the liquid through a 100-mesh sieve to obtain the extract. Combine the two extracts.

[0182] The extract was concentrated to a clear paste with a relative density of 1.10 (50℃) by vacuum concentration, and then dried to obtain a smart dry paste powder by vacuum drying (drying temperature 65℃~80℃).

[0183] Using a high-speed mixing granulator, the dry extract powder containing Polygala tenuifolia was used as raw material. 180g of microcrystalline cellulose was added as an excipient, 90g of maltodextrin was added as a binder, and 90% pharmaceutical ethanol was used as a wetting agent to make granules containing Polygala tenuifolia (corresponding to serial number 3 in Table 1). The granules were dried, sized, and mixed evenly for later use. These granules correspond to sample number 3 in Table 1.

[0184] A copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2:1) was used as the coating material, with appropriate amounts of sodium dodecyl sulfate and stearic acid added. The total amount of these three materials was 60% of the weight of the granules containing Polygala tenuifolia. Water was added to prepare a 16% suspension, which was stirred evenly to obtain the coating solution. The granules containing Polygala tenuifolia were coated with the coating solution using a fluidized bed granulator, then dried, mixed evenly, and packaged to obtain the flavor-masking granules containing Polygala tenuifolia.

[0185] Comparative Example 1

[0186] Take 300g of prepared Polygala tenuifolia slices, 300g of Acorus tatarinowii slices, and 300g of Poria cocos slices, place them in an extraction container, add 9000g of water, heat to boiling, and extract for 2 hours. Filter the liquid through a 100-mesh sieve to obtain the extract, and set it aside. Add another 9000g of water to the residue, heat to boiling, and extract for 1 hour. Filter the liquid through a 100-mesh sieve to obtain the extract, and combine the two extracts.

[0187] The extract was concentrated to a clear paste with a relative density of 1.10 (50℃) by vacuum concentration.

[0188] Using a fluidized bed granulation and coating machine, 162g of dextrin was used as an excipient and 18g of povidone as a binder to prepare granules containing Polygala tenuifolia. The granules were sized, mixed evenly, and set aside for later use. These granules correspond to sample number 4 in Table 1.

[0189] A copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2:1) was used as the coating material, with appropriate amounts of sodium dodecyl sulfate and stearic acid added. The total amount of these three materials was 20% of the weight of the granules containing Polygala tenuifolia. Water was added to prepare a 15% suspension, which was stirred evenly to obtain the coating solution. The granules containing Polygala tenuifolia were coated with the coating solution using a fluidized bed granulator, then dried, mixed evenly, and packaged to obtain the flavor-masking granules containing Polygala tenuifolia.

[0190] Comparative Example 2

[0191] Take 300g of prepared Polygala tenuifolia slices, 300g of Acorus tatarinowii slices, and 300g of Poria cocos slices, place them in an extraction container, add 9000g of water, heat to boiling, and extract for 2 hours. Filter the liquid through a 100-mesh sieve to obtain the extract, and set it aside. Add another 9000g of water to the residue, heat to boiling, and extract for 1 hour. Filter the liquid through a 100-mesh sieve to obtain the extract, and combine the two extracts.

[0192] The extract was concentrated to a clear paste with a relative density of 1.10 (50℃) by vacuum concentration.

[0193] Using a fluidized bed granulation and coating machine, 162g of maltodextrin as an excipient and 18g of povidone as a binder, granules containing Polygala tenuifolia were prepared, granulated, mixed evenly, and set aside for later use. These granules correspond to sample number 5 in Table 1.

[0194] A copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2:1) was used as the coating material, with appropriate amounts of sodium dodecyl sulfate and stearic acid added. The total amount of these three materials was 20% of the weight of the granules containing Polygala tenuifolia. Water was added to prepare a 15% suspension, which was stirred evenly to obtain the coating solution. The granules containing Polygala tenuifolia were coated with the coating solution using a fluidized bed granulator, then dried, mixed evenly, and packaged to obtain the flavor-masking granules containing Polygala tenuifolia.

[0195] Comparative Example 3

[0196] Take 300g of prepared Polygala tenuifolia slices, 300g of Acorus tatarinowii slices, and 300g of Poria cocos slices, place them in an extraction container, add 9000g of water, heat to boiling, and extract for 2 hours. Filter the liquid through a 100-mesh sieve to obtain the extract, and set it aside. Add another 9000g of water to the residue, heat to boiling, and extract for 1 hour. Filter the liquid through a 100-mesh sieve to obtain the extract, and combine the two extracts.

[0197] The extract was concentrated to a clear paste with a relative density of 1.10 (50℃) by vacuum concentration.

[0198] Using a fluidized bed granulation and coating machine, 540g of microcrystalline cellulose was used as an excipient and 36g of povidone as a binder to prepare granules containing Polygala tenuifolia. The granules were sized, mixed evenly, and set aside for later use. These granules correspond to sample number 6 in Table 1.

[0199] A copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2:1) was used as the coating material, with appropriate amounts of sodium dodecyl sulfate and stearic acid added. The total amount of these three materials was 20% of the weight of the granules containing Polygala tenuifolia. Water was added to prepare a 15% suspension, which was stirred evenly to obtain the coating solution. The granules containing Polygala tenuifolia were coated with the coating solution using a fluidized bed granulator, then dried, mixed evenly, and packaged to obtain the flavor-masking granules containing Polygala tenuifolia.

[0200] This invention has found that granules containing Polygala tenuifolia, prepared using microcrystalline cellulose as an excipient, exhibit superior pharmaceutical properties compared to granules prepared using common excipients (such as dextrin and maltodextrin) during pharmaceutical testing. Specifically, they dissolve more rapidly in aqueous solutions at 37–38°C, produce larger particle sizes, have a lower percentage of defective particles, and exhibit better flowability, as shown in Table 1.

[0201] Table 1. Pharmaceutical testing of granules containing Polygala tenuifolia prepared with different excipients.

[0202]

[0203]

[0204] The above experimental results show that the granules containing Polygala tenuifolia prepared by using microcrystalline cellulose as an excipient have a shorter dissolution time in aqueous solution at 37-38°C than granules prepared by using common excipients (such as dextrin and maltodextrin). This ensures that after the coating of the coated granules dissolves, the granules can dissolve in a shorter time, allowing the drug components to be fully released into the gastric juice. Therefore, the present invention uses microcrystalline cellulose as an excipient.

[0205] Furthermore, through comparative studies on different ratios of microcrystalline cellulose and binder in the formulation, it can be seen that when the amount of microcrystalline cellulose is 90% to 200% of the weight of the dry extract powder containing Polygala tenuifolia and the amount of binder is 10% to 50% of the weight of the dry extract powder containing Polygala tenuifolia, the granulation effect is optimal, which is reflected in the large particle size, small proportion of unqualified particles, and good flowability, which is beneficial to the implementation of coating and inner packaging processes in production.

[0206] The taste-masked granules containing Polygala tenuifolia studied in this invention are prepared by extracting and concentrating the medicinal slices in the formula containing Polygala tenuifolia with water, adding excipients to form granules, and then coating the granules. The particle size of the granules can be controlled within a small range through the granulation process. Therefore, in clinical use, the taste-masked granules containing Polygala tenuifolia can be dispersed in drinking water, resulting in small particle sizes that are easy to swallow. The granules are then transported to the stomach via the digestive tract using water as a medium. In the gastric and intestinal juices, the granule coating dissolves, and the drug particles dissolve in the gastrointestinal fluids, releasing the drug components. This method of use largely avoids medication compliance problems caused by the taste of the drug.

[0207] The embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, any changes or modifications made by those skilled in the art based on the ideas of the present invention, its specific implementation methods, and its application scope, are all within the scope of protection of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A granule formulation comprising a composition containing Polygala tenuifolia, characterized in that, The granules further comprise excipients and binders; The weight ratio of the dry powder, the excipient, and the adhesive in the composition is (0.5–1.5):(0.5–2.5):(0.01–1). The composition comprises Polygala tenuifolia, Acorus tatarinowii, and Poria cocos; The excipient is microcrystalline cellulose; The adhesive is povidone and / or maltodextrin.

2. The granule according to claim 1, characterized in that, The weight ratio of the dry powder of the composition, the excipient, and the binder is about 1:(0.9-2):(0.1-0.5); Preferably, the mass ratio of the Polygala tenuifolia, the Acorus tatarinowii, and the Poria cocos is (0.1-5):(0.1-5):(0.1-5); Preferably, the mass ratio of the Polygala tenuifolia, the Acorus tatarinowii, and the Poria cocos is (0.5-1.5):(0.5-1.5):(0.5-1.5). Preferably, the mass ratio of the Polygala tenuifolia, the Acorus tatarinowii, and the Poria cocos is about 1:about 1:about 1; Preferably, the Polygala tenuifolia is processed Polygala tenuifolia; Preferably, the weight of the dry extract powder of the composition = the weight of the clear extract sample after constant weight / the weight of the clear extract sample before drying × the weight of the clear extract.

3. The granule according to claim 1, characterized in that, The composition further comprises one or more other pharmaceutically acceptable excipients; Preferably, the other pharmaceutically acceptable excipients are selected from one or more of the following: diluents, disintegrants, coating agents, flavoring agents, sustained-release agents, lubricants, dispersants, plasticizers, light-blocking agents, and antioxidants; More preferably, the coating agent is selected from one or more of the following: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer, ethyl acrylate and methyl methacrylate copolymer, and methacrylic acid and ethyl acrylate copolymer.

4. The granule according to claim 1, characterized in that, The composition further comprises one or more medicines for the prevention and / or treatment of Alzheimer's disease; Preferably, the drug is an acetylcholinesterase inhibitor, an N-methyl-D-aspartate receptor antagonist, and / or a brain metabolism activator; More preferably, the acetylcholinesterase inhibitor is donepezil, rivastigmine, and / or huperzine A; More preferably, the N-methyl-D-aspartate receptor antagonist is memantine; More preferably, the brain metabolism activator is piracetam.

5. A method for preparing granules of a composition containing Polygala tenuifolia, characterized in that, The method includes the following steps: (1) Weigh an appropriate amount of the composition and place it in a container. Add water for the first time, heat to extract, filter, and obtain the first filtrate and the residue. (2) Add water to the dregs, heat to extract, filter, and obtain the second filtrate; (3) Combine the first filtrate and the second filtrate to obtain a combined filtrate; (4) Concentrate the combined filtrate to obtain a clear extract; and (5) Add excipients and binders to the clear paste or the dry paste powder obtained by further drying the clear paste, granulate, dry, and obtain granules; The composition contains Polygala tenuifolia, Acorus tatarinowii, and Poria cocos.

6. The method according to claim 5, characterized in that, The mass ratio of the Polygala tenuifolia, Acorus tatarinowii, and Poria cocos is (0.1-5):(0.1-5):(0.1-5); Preferably, the mass ratio of the Polygala tenuifolia, the Acorus tatarinowii, and the Poria cocos is (0.5-1.5):(0.5-1.5):(0.5-1.5). Preferably, the mass ratio of the Polygala tenuifolia, the Acorus tatarinowii, and the Poria cocos is about 1: about 1: about 1; More preferably, the Polygala tenuifolia is processed Polygala tenuifolia.

7. The method according to claim 5, characterized in that, The ratio of the volume of the first water to the mass of the composition is 6 to 20; Preferably, the ratio of the volume of the first water to the mass of the composition is 8 to 12, for example, about 10; Preferably, the heating extraction is a boiling extraction; More preferably, the extraction time is 0.3 to 3 hours per extraction; More preferably, the extraction time is 0.5 to 2 hours per extraction, for example, about 1 hour per extraction; More preferably, the filtration is a 100-mesh sieve filtration; More preferably, the ratio of the volume of the second water to the mass of the composition is 6 to 20; Preferably, the ratio of the volume of the second water to the mass of the composition is 8 to 12, for example, about 10.

8. The method according to claim 5, characterized in that, The excipient is microcrystalline cellulose; Preferably, the excipient is not dextrin or maltodextrin; Preferably, the mass ratio of the excipient to the composition is 0.1 to 0.6; Preferably, the mass ratio of the excipient to the composition is 0.18 to 0.4; Preferably, the concentration is vacuum concentration; Preferably, the endpoint of the reduced pressure concentration is that the relative density of the extract at a certain temperature is 1.05 to 1.15, for example, about 1.10; Preferably, the temperature is 45–60°C, for example, about 50°C; Preferably, the drying is vacuum drying; Preferably, the temperature for vacuum drying is 65–80°C; Preferably, the adhesive is selected from povidone or maltodextrin; Preferably, the mass ratio of the adhesive to the composition is 0.01 to 0.2; Preferably, the mass ratio of the adhesive to the composition is 0.02 to 0.1; Preferably, the granulation method is rapid stirring granulation or fluidized bed granulation; Preferably, the wetting agent used in the rapid stirring granulation method is an alcohol, such as ethanol; Preferably, the ethanol is pharmaceutical grade ethanol; More preferably, the concentration of the pharmaceutical ethanol is 80% to 100%, for example, about 90%.

9. The method according to claim 5, characterized in that, The method further includes the step of spraying the granules into a coating liquid for coating; Preferably, the coating instrument is a fluidized bed granulation and coating machine; Preferably, the preparation method of the coating solution includes the following steps: adding other excipients to the coating agent, adding water to obtain a suspension, stirring, and obtaining the coating solution; Preferably, the coating agent is selected from one or more of the following: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer, ethyl acrylate and methyl methacrylate copolymer, methacrylic acid and ethyl acrylate copolymer; Preferably, the other excipients are selected from one or more of the following: sodium dodecyl sulfate, stearic acid, talc, magnesium stearate, hydroxypropyl cellulose, polyethylene glycol, and hydroxypropyl methylcellulose; Preferably, the ratio of the total mass of the coating agent and the other excipients to the mass of the granules is 0.2 to 0.

6. Preferably, the concentration of the suspension is 10% to 20%; More preferably, the concentration of the suspension is 15% to 16%.

10. Use of any of the granules according to claims 1 to 4 in the preparation of a medicament for the prevention and / or treatment of Alzheimer's disease.

Images