Water-free swallowing granules and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to water-free swallowing granules and a preparation method thereof. The water-free swallowing granules provided by the invention comprise drug-containing taste-masking granules and a taste-modifying material, and the drug-containing taste-masking granules are prepared from drug-containing pellets and the taste-masking material; the raw material of the drug-containing pellet comprises an adhesive, and the adhesive is selected from one or more of povidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose or starch slurry; the weight ratio of the drug-containing pellet to the taste masking material is (2-10): 1; the taste masking material comprises a coating component and an anti-sticking agent, wherein the coating component is selected from one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate and carboxymethyl ethyl cellulose; the anti-sticking agent is selected from one or two of lauryl sodium sulfate and talcum powder, and the obtained water-free swallowing granules are easy to swallow and good in stability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to anhydrous swallowable granules and a preparation method thereof. Background Art

[0002] Many Chinese medicines are bitter. Most Chinese medicine granules and oral liquid preparations prepared using modern preparation technology still have a more obvious bitter taste, and the taste has not improved significantly. Although there has always been a saying that "good medicine tastes bitter", as people's living standards improve, patients have higher requirements for the taste and smell of medicines. The poor taste and smell of Chinese medicine preparations may reduce patients' compliance with medication, which may affect clinical efficacy.

[0003] In recent years, various taste-masking technologies have been successfully applied to the taste-masking of chemical drugs and have achieved good results. Common taste-masking methods have different disadvantages when applied to traditional Chinese medicine preparations: 1. The use of ion exchange resins and the addition of bitterness eliminators are more suitable for chemical drugs with clear ingredients, but the ingredients of traditional Chinese medicine are complex and the dosage is large, so it is difficult to determine the specific material components that produce bitterness and develop targeted taste-masking methods; 2. The use of cyclodextrin inclusion technology has problems such as low drug loading, complex process, and high cost; 3. The large-scale use of sweeteners can mask part of the bitterness of the drug. Some patients need to take traditional Chinese medicine preparations for a long time. Long-term and large-scale use of sweeteners may have an impact on health, such as liver and kidney damage, nervous system damage, metabolic disorders, etc. At this stage, most traditional Chinese medicine preparations use universal methods such as adding sweeteners and flavors to mask the taste, but the effect is limited.

[0004] In response to the above problems, Ningbo Cixi Institute of Biomedical Engineering disclosed the patent "A drug taste-masking method, drug and its application" (CN114699384A). The patent states that "Chinese medicine micropowder or Chinese medicine component powder is granulated by fluidized bed or high-speed shear wet method to obtain Chinese medicine or Chinese medicine component particles." The Chinese medicine particles prepared by this method provided by the patent are irregular in shape and uneven in size. First, when further masking coating is applied, the coating film is uneven due to the presence of edges and corners of the particles, resulting in poor taste-masking effect. Second, the particles are not round enough, resulting in poor fluidity. Patients find it difficult to swallow the medicine when it is administered and need to take it with water. In the process of taking it with water, the taste-masking coating layer is easily destroyed, resulting in the escape of bitterness. Therefore, there is room for improvement in taste-masking effect and difficulty of swallowing. Summary of the invention

[0005] The invention provides an anhydrous swallowable granule and a preparation method thereof, which are used to solve the defect of the prior art that an anhydrous swallowable granule with good taste-masking effect is lacking in the field of traditional Chinese medicine preparations.

[0006] The present invention provides a water-free swallowable granule, comprising a drug-containing taste-masking granule and a taste-correcting material, wherein the drug-containing taste-masking granule is made of a drug-containing micro-pellet and the taste-masking material; The raw materials of the drug-containing pellets include a binder, and the binder is selected from one or more (two or more, such as two, three or four, etc., the same below) of povidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose or starch slurry; The weight ratio of the drug-containing pellets to the taste-masking material is 2-10:1; The raw materials of the taste masking material include a coating component and an anti-adherent agent, wherein the coating component is selected from one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, and carboxymethyl ethyl cellulose; The anti-sticking agent is selected from one or both of sodium lauryl sulfate and talc.

[0007] The present invention utilizes the above-mentioned drug-containing taste-masking particles and taste-correcting materials to prepare drug-containing micro-pellets that are more rounded. When the drug-containing micro-pellets are coated with the taste-masking materials, the coating film is more complete and more uniform, and the taste-masking effect is better. The obtained water-free swallowable particles have a moderate particle size, are not easy to adhere to the oral cavity, and have a better taste, so that the water-free swallowable particles are easy to swallow and can be taken without being washed down with water.

[0008] Most Chinese medicine ingredients are alkaline or acidic (for example, berberine is a quaternary ammonium alkaloid with a pH of 11.50 and is alkaline, while berberine hydrochloride is a strong acid and weak base salt and is acidic), which are prone to compatibility problems with some excipients, resulting in poor stability. The active ingredients in the present invention have good compatibility with the excipients, and the anhydrous swallowable granules have good stability.

[0009] Ethyl cellulose is the ethyl ether of cellulose, a long-chain polymer with β-anhydroglucose as the unit connected by acetal, and is one of the most widely used water-insoluble cellulose derivatives. Ethyl cellulose is a non-toxic and biodegradable polymer with unique properties such as the formation of oil gels, the delivery of active ingredients, and the ability to form films in the food and pharmaceutical fields. Ethyl cellulose can be used as an excipient, such as a coating agent, a flavoring agent, a tablet filler, etc. The present invention uses it as one of the raw materials of the taste masking material to mask the bitter taste of the drug.

[0010] Binder is one of the main pharmaceutical excipients, which is a viscous substance that can connect two separated materials together by virtue of its viscosity. The binder in the present invention includes starch slurry, cellulose derivatives, povidone, etc. Among them, cellulose derivatives specifically include hypromellose, methylcellulose, hydroxypropyl cellulose, etc.

[0011] In some preferred embodiments of the present invention, the weight ratio of the drug-containing pellets to the taste-masking material is 1-7:1, and more preferably 2-6:1.

[0012] According to the anhydrous swallowable granules provided by the present invention, the weight ratio of the coating component to the anti-adherent agent is 2-14: 1. Within this ratio range, the drug-containing pellets have a better coating effect when the taste-masking material is used for taste-masking coating.

[0013] In some preferred embodiments of the present invention, the weight ratio of the coating component to the anti-adherent agent is 2-10:1, more preferably 6-9:1.

[0014] In some embodiments of the present invention, in the anhydrous Chinese medicine swallowable granules, the taste-masking material is a polymer material.

[0015] According to the anhydrous swallowable granules provided by the present invention, the flavoring material includes one or more of a sour agent, a sweetener and an essence.

[0016] The sweetener is selected from at least one, two or more of aspartame, xylitol, maltitol, mannitol, erythritol, sucralose, acesulfame potassium and cyclamate, and more preferably anhydrous swallowable granules of aspartame and mannitol.

[0017] The acidulant is selected from one, two or more of citric acid, citric acid, lactic acid, tartaric acid, malic acid, adipic acid, fumaric acid, metatartaric acid, gluconic acid, acetic acid, ascorbic acid, succinic acid and fumaric acid, and more preferably citric acid.

[0018] Preferably, the ratio of the sweetener to the sour agent is 0.1-10:2-20. With this ratio, the prepared anhydrous swallowable granules have moderate sweetness and sourness and better taste.

[0019] In some preferred embodiments of the present invention, the ratio of the sweetener to the sour agent is 0.5-5:1, preferably 0.8-2.5:1.

[0020] According to the anhydrous swallowable granules provided by the present invention, the active ingredients in the drug-containing micro-pellets are Chinese medicine ingredients or Western medicine ingredients, preferably Chinese medicine ingredients or Western medicine ingredients with bitter taste.

[0021] In some embodiments of the present invention, the active ingredient in the drug-containing pellets is one or more of Sophora flavescens, Rheum officinale, Coptis chinensis, Astragalus membranaceus, and Andrographis paniculata and their extracts; Preferably, the mass proportion of the active ingredient in the drug-containing taste-masking particles is 10-50%, preferably 15-45%, and more preferably 20-30%.

[0022] And / or, the mass ratio of the active ingredient to the taste-masking material is 0.8-3: 1, preferably 0.8-2.5: 1, and more preferably 0.8-2: 1. Controlling the amount of the taste-masking material within the above range can control the coating thickness of the taste-masking material, thereby effectively masking the taste and controlling its dissolution time, and the taste is not affected by the pH value of the digestive tract, and the bioavailability is high and the stability is good.

[0023] And / or, the mass ratio of the active ingredient to the binder is 1-20:1, preferably 15:1, and more preferably 1-10:1.

[0024] According to the anhydrous swallowable granules provided by the present invention, the drug-containing micro-pellets further include a filler, and the filler is selected from one or more of microcrystalline cellulose, lactose, starch and mannitol.

[0025] Preferably, the weight ratio of the filler to the active ingredient is 0.5-5:1.

[0026] Preferably, the weight ratio of the filler to the binder is 10-30:1.

[0027] Fillers are also one of the main pharmaceutical excipients. The main function of fillers is to shape and improve the fluidity of the mixed material. Mannitol in the present invention can be used as a filler or a sweetener. By selecting such fillers and limiting the ratio of fillers to active ingredients or binders within the above range, the prepared drug-containing micro-pellets have better particle shape, better subsequent coating effect, better fluidity, and are more conducive to swallowing.

[0028] In some embodiments of the present invention, the weight ratio of the filler to the active ingredient is 0.5-3.5:1, preferably 1-3:1.

[0029] In some embodiments of the present invention, the weight ratio of the filler to the binder is 15-25:1, preferably 18-22:1.

[0030] In some embodiments of the present invention, the drug-containing taste-masking particles further include other optional pharmaceutical excipients.

[0031] Pharmaceutical excipients refer to the general term for all other materials added to make the drug into a suitable dosage form. They are substances added during the molding of pharmaceutical preparations to maintain their stability, safety or homogeneity, or to adapt to the characteristics of the preparation to promote dissolution, sustained release, etc. Pharmaceutical excipients should be inactive, their properties should be stable and not react with the drug, and should not affect the determination of the drug content.

[0032] Other optional pharmaceutical excipients include disintegrants, lubricants, release regulators, colorants, flavoring agents, etc. In specific embodiments, they can be added as needed.

[0033] In some embodiments of the present invention, the drug-containing taste-masking particles consist only of traditional Chinese medicine ingredients, taste-masking materials, binders and fillers.

[0034] According to the water-free swallowable granules provided by the present invention, the flavoring material is provided in the form of pellets (granules).

[0035] Since the anhydrous swallowable granules are a mixture of drug-containing taste-masking micropellets and flavor-correcting materials, if the flavor-correcting materials are provided in the form of micropellets, both of the micropellets are in a round state, both are in a round pellet state, have good fluidity, and are more convenient to swallow directly without the need for water.

[0036] According to the anhydrous swallowable granules provided by the present invention, the weight ratio of the drug-containing taste-masking granules to the taste-correcting material is 10-100: 1. The present invention can achieve the taste-masking effect with a small amount of taste-correcting material, which is more beneficial to health.

[0037] It is preferably 10-30:1, and more preferably 15-25:1.

[0038] According to the anhydrous swallowable granules provided by the present invention, the D90 of the drug-containing taste-masking granules is 200 μm-350 μm.

[0039] According to the anhydrous swallowable granules provided by the present invention, the raw materials of the drug-containing pellets include 45-55 parts of povidone or hypromellose, 450-550 parts of active ingredients and 800-1200 parts of microcrystalline cellulose in parts by weight; The taste masking material comprises 200-600 parts of ethyl cellulose or cellulose acetate, 5-25 parts of sodium lauryl sulfate and 20-60 parts of talc; The flavoring material comprises 45-55 parts of citric acid, 40-110 parts of mannitol and 2-8 parts of aspartame.

[0040] In some embodiments of the present invention, the raw materials of the drug-containing pellets include 450-550 parts of active ingredients, 800-1200 parts of microcrystalline cellulose and 45-55 parts of hypromellose, the raw materials of the taste masking material include 200-300 parts of ethyl cellulose, 8-12 parts of sodium lauryl sulfate and 20-30 parts of talc, and the flavoring material includes 45-55 parts of citric acid, 90-110 parts of mannitol and 3-7 parts of aspartame; In some embodiments of the present invention, the raw materials of the drug-containing micropellets include 450-550 parts of drug ingredients, 800-1200 parts of microcrystalline cellulose and 45-55 parts of povidone, the raw materials of the taste-masking material include 450-550 parts of cellulose acetate, 15-25 parts of sodium lauryl sulfate and 40-60 parts of talc, and the flavoring material includes 45-55 parts of citric acid, 40-110 parts of mannitol and 3-7 parts of aspartame.

[0041] The present invention also provides a method for preparing the anhydrous swallowable granules, comprising the following steps: (1) mixing the raw materials in the drug-containing pellets uniformly, and obtaining drug-containing pellets (granules) by extrusion and spheronization; (2) coating the drug-containing pellets (granules) with the taste-masking material to obtain the drug-containing taste-masked granules (pellets); (3) The drug-containing taste-masking granules (pellets) obtained in step (2) are mixed with a flavor-correcting material to obtain anhydrous swallowable granules.

[0042] In some embodiments of the present invention, the method comprises the steps of preparing the drug-containing taste-masking particles and the flavor-correcting particles separately and then mixing the two.

[0043] Compared with the existing process, the particles prepared by the preparation method of the present invention are round pellets and the particle size is controlled within a certain range, avoiding the problems of poor taste-masking coating effect, poor fluidity, and difficulty in swallowing caused by irregular particle shape or excessively large particles.

[0044] In some embodiments of the present invention, the drug-containing micropellets and flavor-correcting micropellets are prepared by an extrusion spheronization process.

[0045] In some embodiments of the present invention, the following steps are included: 1) The raw materials for preparing the drug-containing micro-pellets are placed in an extrusion spheronization granulator, stirring and shearing are started to mix the materials evenly, purified water is added under stirring to prepare a soft material, and extruded to prepare drug-containing micro-pellets.

[0046] Preferably, in step 1), a 0.5-0.7 mm aperture screen is used for extrusion at a speed of 45-55 rpm, and spheronization is performed at a speed of 1400-1600 rpm for 4-6 min.

[0047] 2) dispersing the cellulose derivative and the anti-sticking agent in the taste masking material in water to prepare a coating solution.

[0048] 3) The micro-pellets in step 1) are placed in a fluidized bed and air is turned on to mix the materials evenly. The coating liquid in step 2) is evenly coated on the surface of the drug-containing particles by bottom spraying to prepare water-free swallowable particles.

[0049] The preparation method of the water-free swallowable granules of the present invention has the following advantages: first, the drug-containing micro-pills are prepared by the extrusion spheronization process as round micro-pills. When the micro-pills are coated with taste-masking coating, the coating film is more complete and more uniform, and the taste-masking effect is better; second, the taste-correcting granules (micro-pills) are prepared by the extrusion spheronization process, which can make the drug have a good taste and flavor; third, both particles are in the form of round pellets with good fluidity and can be swallowed directly without water; fourth, the Chinese medicine ingredients are used in combination with suitable excipients or coating ingredients, and the process avoids high temperature during the preparation process to avoid stability problems caused by the compatibility of raw and excipients or excessively severe process conditions. The above method solves the problems of compliance and stability of Chinese medicine, and is particularly suitable for people with swallowing difficulties such as children and the elderly.

[0050] The water-free swallowable granules provided by the present invention are prepared by preparing drug-containing micropills and taste-masking materials, coating the drug-containing micropills with the taste-masking materials to obtain drug-containing taste-masked granules, and then mixing with the taste-correcting materials, which can effectively mask the taste and can be directly swallowed without water, greatly improving drug administration compliance, and are particularly suitable for children, the elderly and other people with swallowing difficulties.

[0051] The water-free swallowable granules provided by the present invention have a high drug loading capacity and can simultaneously solve the compliance and stability problems of Chinese medicine administration, and are particularly suitable for people with swallowing difficulties such as children and the elderly.

[0052] The preparation method of the anhydrous swallowable granules of the present invention is simple, has low requirements on equipment, is low in cost, and is suitable for large-scale production.

[0053] The preparation method of the anhydrous swallowable granules provided by the present invention has a preparation temperature between 30 and 45° C. during the preparation process. The preparation method of the present invention can avoid high temperature. Compared with the hot melt coating preparation method in which the preparation temperature needs to reach 60 to 80° C., the stability problems caused by the compatibility of raw materials and auxiliary materials or excessively severe process conditions can be avoided, and the drug effectiveness of the active ingredients is not affected. DETAILED DESCRIPTION

[0054] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0055] Unless otherwise specified, the raw materials involved in the embodiments of the present invention can be obtained from commercial sources.

[0056] The dimethylaminoethyl methacrylate butyl / methacrylate / methyl methacrylate copolymer in Comparative Example 2 of the present invention is Eudragit E, a product of Rohm Company of Germany.

[0057] Berberine hydrochloride is a major alkaloid contained in the rhizome of Coptis chinensis, a plant of the Ranunculaceae family. It can be extracted from Coptis chinensis, Phellodendron amurense, or Tripterygium wilfordii. Berberine hydrochloride is relatively stable under strong acid, oxidation, and light conditions, but unstable under high temperature and strong alkaline conditions.

[0058] Sophora flavescens extract is an alkaloid extracted from the plant Sophora flavescens of the Leguminosae family, containing matrine, oxymatrine, hydroxymatrine, N-methylcytisine, anagerine, indigoferine, dehydromatrine, d-isomatrine, matrinedine, normatrinenone, matrinedineol, matrinenol, neomatrinenol, normatrinenol, isomatrinenone, and formononetin.

[0059] Coptis chinensis extract is a natural product with multiple pharmacological activities, mainly derived from the dried rhizomes of Coptis chinensis, Coptis chinensis triangularis or Coptis chinensis of the Ranunculaceae family. Its main components are alkaloids, especially berberine, which can reach 10%. It also contains palmatine, coptis chinensis, methyl coptis chinensis, jatrorrhizine and magnolamine, all of which are benzylisoquinoline derivatives.

[0060] Example 1

[0061] This embodiment provides a berberine anhydrous swallowable granule, wherein the berberine anhydrous swallowable granule is a mixture of drug-containing taste-masking granules and taste-correcting granules; The raw materials for the drug-containing taste-masking granules include materials for preparing drug-containing granules and taste-masking materials, the materials for preparing drug-containing granules include berberine 500g, microcrystalline cellulose 1000g and hypromellose 50g; the taste-masking material includes ethyl cellulose 260g, sodium lauryl sulfate 10g and talc 25g; The raw materials of the flavor-correcting granules include 50 g of citric acid, 100 g of mannitol and 5 g of aspartame.

[0062] This embodiment also provides a method for preparing the berberine anhydrous swallowable granules, which comprises the following steps: (1) Preparation of drug-containing granules

[0063] Take the formulated amount of berberine, microcrystalline cellulose and hypromellose, place them in an extrusion spheronization granulator, start stirring and shearing to mix the materials evenly, add purified water under stirring to prepare a soft material, extrude it at a speed of 50 rpm through a 0.6 mm aperture screen, spheronize it at a speed of 1500 rpm for 5 minutes, further use an oven or fluidized bed to dry it at 40°C~60°C until the moisture content does not exceed 5%, and prepare drug-containing particles (micropellets) with a D90 of 200μm-350μm through screening.

[0064] (2) Preparation of taste-masking particles

[0065] The taste-masking coating solution was prepared by dispersing ethyl cellulose, sodium lauryl sulfate and talc in water.

[0066] The drug-containing particles are placed in a fluidized bed and air is turned on to mix the materials evenly. The material temperature is controlled within the range of 35°C to 45°C by bottom spraying, and the taste-masking material is evenly coated on the surface of the drug-containing particles to prepare drug-containing taste-masked particles.

[0067] (3) Preparation of flavor-correcting granules

[0068] The citric acid, mannitol and aspartame are mixed evenly in a mixer to obtain flavoring agent granules.

[0069] (4) Total mixing

[0070] The drug-containing taste-masking granules and the flavor-correcting granules in the formula amounts are respectively taken and mixed evenly in a mixer to obtain the water-free Chinese medicine swallowable granules.

[0071] The anhydrous swallowable granules prepared in this example are round, non-bitter, easy to swallow, moderately sweet and acidic, non-bitter, and easy to swallow.

[0072] Example 2

[0073] This embodiment provides a berberine anhydrous swallowable granule, wherein the berberine anhydrous swallowable granule is a mixture of drug-containing taste-masking granules and taste-correcting granules; The raw materials of the drug-containing taste-masking granules include materials for preparing drug-containing granules and taste-masking materials, the materials for preparing drug-containing granules include berberine 500g, microcrystalline cellulose 1000g and povidone 50g; the taste-masking material includes cellulose acetate 500g, sodium lauryl sulfate 20g and talc 50g; The raw materials of the flavor-correcting granules include 50 g of citric acid, 100 g of mannitol and 5 g of aspartame.

[0074] This embodiment also provides a method for preparing the berberine anhydrous swallowable granules, which comprises the following steps: (1) Preparation of drug-containing granules

[0075] Take the formulated amount of berberine, microcrystalline cellulose and povidone, put them in an extrusion spheronization granulator, start stirring and shearing to mix the materials evenly, add purified water under stirring to prepare a soft material, use a 0.6 mm aperture screen at a speed of 50 rpm to extrude, spheronize at a speed of 1500 rpm for 5 minutes, further use an oven or a fluidized bed to dry it at 40°C~60°C to a moisture content of no more than 5%, and prepare drug-containing particles (micropills) with a D90 of 200μm-350μm by sieving.

[0076] (2) Preparation of taste-masking particles

[0077] The taste-masking coating solution is prepared by dispersing cellulose acetate, sodium lauryl sulfate and talc in water.

[0078] The drug-containing particles are placed in a fluidized bed and air is turned on to mix the materials evenly. The material temperature is controlled within the range of 35°C to 45°C by bottom spraying, and the taste-masking material is evenly coated on the surface of the drug-containing particles to prepare drug-containing taste-masked particles.

[0079] (3) Preparation of flavor-correcting granules

[0080] The citric acid, mannitol and aspartame are mixed evenly in a mixer to obtain flavoring agent granules.

[0081] (4) Total mixing

[0082] The drug-containing taste-masking granules and the flavor-correcting granules in the formula amounts are respectively taken and mixed evenly in a mixer to obtain the water-free Chinese medicine swallowable granules.

[0083] The anhydrous swallowable granules prepared in this example are round, non-bitter, easy to swallow, moderately sweet and acidic, non-bitter, and easy to swallow.

[0084] Example 3

[0085] This embodiment provides a sophora flavescens extract anhydrous swallowable granules, wherein the sophora flavescens extract anhydrous swallowable granules are a mixture of drug-containing taste-masking granules and taste-correcting granules; The raw materials for the drug-containing taste-masking granules include materials for preparing drug-containing granules and taste-masking materials, the materials for preparing drug-containing granules include 500g of Sophora flavescens extract, 1000g of microcrystalline cellulose and 50g of hypromellose; the taste-masking materials include 260g of ethyl cellulose, 10g of sodium lauryl sulfate and 25g of talc; The raw materials of the flavor-correcting granules include 50 g of citric acid, 100 g of mannitol and 5 g of aspartame.

[0086] This embodiment also provides a method for preparing the anhydrous swallowable granules of Sophora flavescens extract, which comprises the following steps: (1) Preparation of drug-containing granules

[0087] Take the formulated amount of Sophora flavescens extract, microcrystalline cellulose and hypromellose, place them in an extrusion spheronization granulator, start stirring and shearing to mix the materials evenly, add purified water under stirring to prepare a soft material, use a 0.6 mm aperture screen at a speed of 50 rpm to extrude, spheronize at a speed of 1500 rpm for 5 minutes, further use an oven or a fluidized bed to dry it at 40°C~60°C until the moisture content does not exceed 5%, and prepare drug-containing particles (micropills) with a D90 of 200μm-350μm by sieving.

[0088] (2) Preparation of taste-masking particles

[0089] The taste-masking coating solution was prepared by dispersing ethyl cellulose, sodium lauryl sulfate and talc in water.

[0090] The drug-containing particles are placed in a fluidized bed and air is turned on to mix the materials evenly. The material temperature is controlled within the range of 35°C to 45°C by bottom spraying, and the taste-masking material is evenly coated on the surface of the drug-containing particles to prepare drug-containing taste-masked particles.

[0091] (3) Preparation of flavor-correcting granules

[0092] The citric acid, mannitol and aspartame are mixed evenly in a mixer to obtain flavoring agent granules.

[0093] (4) Total mixing

[0094] The drug-containing taste-masking granules and the flavor-correcting granules in the formula amounts are respectively taken and mixed evenly in a mixer to obtain the water-free Chinese medicine swallowable granules.

[0095] The anhydrous swallowable granules prepared in this example are round, non-bitter, easy to swallow, moderately sweet and acidic, non-bitter, and easy to swallow.

[0096] Example 4

[0097] This embodiment provides an anhydrous swallowable granule of Coptis chinensis extract, wherein the anhydrous swallowable granule of Coptis chinensis extract is a mixture of drug-containing taste-masking granules and taste-correcting granules; The raw materials for the drug-containing taste-masking granules include materials for preparing drug-containing granules and taste-masking materials, the materials for preparing drug-containing granules include 500g of Coptis chinensis extract, 1000g of microcrystalline cellulose and 50g of povidone; the taste-masking material includes 500g of cellulose acetate, 20g of sodium lauryl sulfate and 50g of talc; The raw materials of the flavor-correcting granules include 50 g of citric acid, 50 g of mannitol and 5 g of aspartame.

[0098] This embodiment also provides a method for preparing the anhydrous swallowable granules of the Coptis chinensis extract, which comprises the following steps: (1) Preparation of drug-containing granules

[0099] Take the formulated amount of Coptis chinensis extract, microcrystalline cellulose and povidone, place them in an extrusion spheronization granulator, start stirring and shearing to mix the materials evenly, add purified water under stirring to prepare a soft material, use a 0.6 mm aperture screen at a speed of 50 rpm to extrude, spheronize at a speed of 1500 rpm for 5 minutes, further use an oven or a fluidized bed to dry it at 40°C~60°C to a moisture content of no more than 5%, and prepare drug-containing particles (micropills) with a D90 of 200μm-350μm by sieving.

[0100] (2) Preparation of taste-masking particles

[0101] The taste-masking coating solution is prepared by dispersing cellulose acetate, sodium lauryl sulfate and talc in water.

[0102] The drug-containing particles are placed in a fluidized bed and air is turned on to mix the materials evenly. The material temperature is controlled within the range of 35°C to 45°C by bottom spraying, and the taste-masking material is evenly coated on the surface of the drug-containing particles to prepare drug-containing taste-masked particles.

[0103] (3) Preparation of flavor-correcting granules

[0104] The citric acid, mannitol and aspartame are mixed evenly in a mixer to obtain flavoring agent granules.

[0105] (4) Total mixing

[0106] The drug-containing taste-masking granules and the flavor-correcting granules in the formula amounts are respectively taken and mixed evenly in a mixer to obtain the water-free Chinese medicine swallowable granules.

[0107] The anhydrous swallowable granules prepared in this example are round, non-bitter, easy to swallow, moderately sweet and acidic, non-bitter, and easy to swallow.

[0108] Comparative Example 1

[0109] This comparative example provides a berberine anhydrous swallowable granule, which is a mixture of drug-containing taste-masking granules and flavor-correcting granules; The raw materials for the drug-containing taste-masking granules include materials for preparing drug-containing granules and taste-masking materials, the materials for preparing drug-containing granules include berberine 500g, microcrystalline cellulose 1000g and gelatin 50g; the taste-masking material includes ethyl cellulose 260g, sodium lauryl sulfate 10g and talc 25g; The raw materials of the flavor-correcting granules include 50 g of citric acid, 100 g of mannitol and 5 g of aspartame.

[0110] This comparative example also provides a preparation method of the berberine anhydrous swallowable granules, which comprises the following steps: (1) Preparation of drug-containing granules

[0111] Take the formulated amount of berberine, microcrystalline cellulose and gelatin, put them in an extrusion spheronization granulator, start stirring and shearing to mix the materials evenly, add purified water under stirring to prepare a soft material, use a 0.6 mm aperture screen at a speed of 50 rpm to extrude, spheronize at a speed of 1500 rpm for 5 minutes, further use an oven or fluidized bed to dry it at 40°C~60°C until the moisture content does not exceed 5%, and prepare drug-containing particles (micropellets) by screening, with D90 of about 100-150μm.

[0112] (2) Preparation of taste-masking particles

[0113] The taste-masking coating solution was prepared by dispersing ethyl cellulose, sodium lauryl sulfate and talc in water.

[0114] The drug-containing particles are placed in a fluidized bed and air is turned on to mix the materials evenly. The taste-masking material is evenly coated on the surface of the drug-containing particles by bottom spraying to prepare the drug-containing taste-masked particles.

[0115] (3) Preparation of flavor-correcting granules

[0116] The citric acid, mannitol and aspartame are mixed evenly in a mixer to obtain flavoring agent granules.

[0117] (4) Total mixing

[0118] The drug-containing taste-masking granules and the flavor-correcting granules in the formula amounts are respectively taken and mixed evenly in a mixer to obtain the water-free Chinese medicine swallowable granules.

[0119] In comparative example 1, gelatin was used as a binder when preparing drug-containing granules, but the granulation effect was poor, and the obtained granules were fine, with a D90 of about 100-150 μm.

[0120] The anhydrous swallowable granules prepared in Comparative Example 1 have no bitter taste, moderate sweetness and acidity, but the granules are too fine, easily adhere to the oral cavity, and are difficult to swallow.

[0121] Comparative Example 2

[0122] This comparative example provides a berberine anhydrous swallowable granule, which is a mixture of drug-containing taste-masking granules and flavor-correcting granules; The raw materials for the drug-containing taste-masking granules include materials for preparing drug-containing granules and taste-masking materials, the materials for preparing drug-containing granules include 500g of berberine, 1000g of microcrystalline cellulose and 50g of hypromellose; the taste-masking material includes 500g of dimethylaminoethyl methacrylate butyl / methacrylate / methyl methacrylate copolymer, 10g of sodium lauryl sulfate and 25g of talc; The raw materials of the flavor-correcting granules include 50 g of citric acid, 100 g of mannitol and 5 g of aspartame.

[0123] This comparative example also provides a preparation method of the berberine anhydrous swallowable granules, which comprises the following steps: (1) Preparation of drug-containing granules

[0124] Take the formulated amount of berberine, microcrystalline cellulose and povidone, put them in an extrusion spheronization granulator, start stirring and shearing to mix the materials evenly, add purified water under stirring to prepare a soft material, use a 0.6 mm aperture screen at a speed of 50 rpm to extrude, spheronize at a speed of 1500 rpm for 5 minutes, further use an oven or a fluidized bed to dry it at 40°C~60°C to a moisture content of no more than 5%, and prepare drug-containing particles (micropills) with a D90 of 200μm-350μm by sieving.

[0125] (2) Preparation of drug-containing taste-masking granules

[0126] The taste-masking coating liquid was prepared by dispersing dimethylaminoethyl methacrylate butyl / methacrylate / methyl methacrylate copolymer, sodium lauryl sulfate and talc in water.

[0127] The drug-containing particles are placed in a fluidized bed and air is turned on to mix the materials evenly. The taste-masking material is evenly coated on the surface of the drug-containing particles by bottom spraying to prepare the drug-containing taste-masked particles.

[0128] (3) Preparation of flavor-correcting granules

[0129] The citric acid, mannitol and aspartame are mixed evenly in a mixer to obtain flavoring agent granules.

[0130] (4) Total mixing

[0131] The drug-containing taste-masking granules and the flavor-correcting granules in the formula amounts are respectively taken and mixed evenly in a mixer to obtain the water-free Chinese medicine swallowable granules.

[0132] The anhydrous swallowable granules provided in Comparative Example 2 have almost no bitterness, moderate sweetness and acidity, and are easy to swallow. However, due to the compatibility problem between the taste masking material and the raw materials, the stability is poor.

[0133] Comparative Example 3

[0134] This comparative example provides a berberine anhydrous swallowable granule, which is a mixture of drug-containing taste-masking granules and flavor-correcting granules; The raw materials for the drug-containing taste-masking granules include materials for preparing drug-containing granules and taste-masking materials, the materials for preparing drug-containing granules include berberine 500g, microcrystalline cellulose 1000g and hypromellose 50g; the taste-masking material includes ethyl cellulose 260g, sodium lauryl sulfate 10g and talc 25g; The raw materials of the flavor-correcting granules include 10 g of phosphoric acid and 200 g of sucrose.

[0135] This comparative example also provides a preparation method of the berberine anhydrous swallowable granules, which comprises the following steps: (1) Preparation of drug-containing granules

[0136] Take the formulated amount of berberine, microcrystalline cellulose and hypromellose, place them in an extrusion spheronization granulator, start stirring and shearing to mix the materials evenly, add purified water under stirring to prepare a soft material, extrude it at a speed of 50 rpm through a 0.6 mm aperture screen, spheronize it at a speed of 1500 rpm for 5 minutes, further use an oven or fluidized bed to dry it at 40°C~60°C until the moisture content does not exceed 5%, and prepare drug-containing particles (micropellets) with a D90 of 200μm-350μm through screening.

[0137] (2) Preparation of taste-masking particles

[0138] The taste-masking coating solution was prepared by dispersing ethyl cellulose, sodium lauryl sulfate and talc in water.

[0139] The drug-containing particles are placed in a fluidized bed and air is turned on to mix the materials evenly. The taste-masking material is evenly coated on the surface of the drug-containing particles by bottom spraying to prepare the drug-containing taste-masked particles.

[0140] (3) Preparation of flavor-correcting granules

[0141] Phosphoric acid and sucrose are mixed uniformly in a mixer to obtain flavoring agent granules.

[0142] (4) Total mixing

[0143] The drug-containing taste-masking granules and the flavor-correcting granules are respectively taken in the formula amount and mixed evenly to obtain the water-free Chinese medicine swallowable granules.

[0144] The anhydrous swallowable granules prepared in Comparative Example 3 have no bitter taste, are too sweet, and are not acidic enough, and are easier to swallow.

[0145] Experimental example

[0146] 1. Palatability (mouthfeel) and ease of swallowing

[0147] Without informing the product, 20 volunteers were given oral test of the water-free swallowable granules prepared in Examples 1-3 and Comparative Examples 1-3. One bag of the preparation was administered to each volunteer. No water was allowed to be consumed within 3 minutes after administration. After 5 minutes, the palatability and ease of swallowing were scored using a 0-100 VAS scoring method. The results are shown in Table 1.

[0148] Table 1 Comparison of palatability (mouth feel) and ease of swallowing

[0149] Note: The palatability (taste) evaluation index takes 100 as the full score, and evaluates whether the taste is good and whether there is any peculiar smell, and the scores are calculated as the average value; the ease of swallowing evaluation index takes complete swallowing within 2 minutes, smooth swallowing without gritty feeling as the full score of 100, and the scores are calculated as the average value.

[0150] The results show that: (1) The particles (pellets) prepared by the extrusion spheronization process in Examples 1-4 are more rounded. Particles that are too fine or too coarse are not easy to swallow. The particle size of the drug-containing taste-masking particles is within a certain range (D90: 200-350 μm) and is easier to swallow. Among them, the drug-containing taste-masking particles obtained by using gelatin as a binder in Comparative Example 1 are too fine (D90: 100-150 μm), have poor fluidity, and adhere to the mouth, making it difficult to swallow.

[0151] (2) The taste masking effect of the particles (pellets) in Examples 1-4 was better after coating, with almost no bitterness, and the appropriate amount of sour agent and sweetener was added, resulting in a higher taste score. The particles in Comparative Example 2 used butyl dimethylaminoethyl methacrylate / methacrylate / methyl methacrylate copolymer as the taste masking material. Although it had a certain taste masking effect, the taste masking effect was worse than that of Examples 1-4. Although the particles in Comparative Example 3 were taste masked and had no bitterness, the taste was poor due to the low sweetness of sucrose and the high acidity of phosphoric acid.

[0152] 2. Stability

[0153] The anhydrous swallowable granule sample prepared in Example 1 and the anhydrous swallowable granule sample prepared in Comparative Example 2 were packaged in aluminum-plastic composite film bags and placed under accelerated conditions (40°C / 75%RH) for 3 months. Samples were taken in January, February and March, and the HPLC method was used to detect the change in the content of berberine (berberine hydrochloride). The results are shown in Table 2.

[0154] Table 2 Stability of berberine (berberine hydrochloride)

[0155] The results show that: The sample of Example 1 has good stability, and the content has almost no change under accelerated conditions, while the sample of Comparative Example 2 has poor stability, and the content shows a decreasing trend under accelerated conditions. The taste-masking material used in Comparative Example 2 is a copolymer of dimethylaminoethyl methacrylate butyl / methacrylate / methyl methacrylate, which is alkaline, so the film formed is soluble in acidic solutions below pH 5, and insoluble in solutions above pH 5, so it can be used as a taste-masking coating. However, berberine hydrochloride is a strong acid and weak base salt, which is sensitive to alkaline conditions, so the samples prepared by the two have compatibility problems with raw materials and auxiliary materials, resulting in a downward trend in content. The taste-masking coating material screened in Example 1 is a neutral component, and there is no compatibility problem with raw materials and auxiliary materials with berberine hydrochloride, so it has good stability.

[0156] In the description of this specification, the description with reference to the term "some embodiments" means that the specific features, materials or characteristics described in conjunction with the embodiment are included in at least one embodiment of the embodiments of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples without contradiction.

[0157] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A water-free swallowable granule, comprising a drug-containing taste-masking granule and a taste-correcting material, characterized in that: The drug-containing taste-masking particles are made of drug-containing micropellets and taste-masking materials; The raw materials of the drug-containing pellets include a binder, and the binder is selected from one or more of povidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose or starch slurry; The weight ratio of the drug-containing pellets to the taste-masking material is 2-10:1; The raw materials of the taste masking material include a coating component and an anti-adherent agent, wherein the coating component is selected from one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, and carboxymethyl ethyl cellulose; The anti-sticking agent is selected from one or both of sodium lauryl sulfate and talc.

2. The anhydrous swallowable granules according to claim 1, characterized in that: The weight ratio of the coating component to the anti-adherent agent is 2-14:1, preferably 2-10:1, and more preferably 6-9:

1.

3. The anhydrous swallowable granules according to claim 1 or 2, characterized in that: The flavoring material includes one or more of a sour agent, a sweetener and an essence; The sweetener is selected from at least one, two or more of aspartame, xylitol, maltitol, mannitol, erythritol, sucralose, acesulfame potassium and sodium cyclamate, and more preferably anhydrous swallowable granules of aspartame and mannitol; The acidulant is selected from one, two or more of citric acid, citric acid, lactic acid, tartaric acid, malic acid, adipic acid, fumaric acid, metatartaric acid, gluconic acid, acetic acid, ascorbic acid, succinic acid and fumaric acid, and is more preferably citric acid; Preferably, the ratio of the sweetener to the sour agent is 0.1-10:2-20, preferably 0.5-5:1, and more preferably 0.8-2.5:

1.

4. The anhydrous swallowable granules according to any one of claims 1 to 3, characterized in that: The active ingredients in the drug-containing micropills are one or more of Sophora flavescens, Rheum officinale, Coptis chinensis, Astragalus membranaceus, Andrographis paniculata, and their extracts; Preferably, the mass proportion of the active ingredient in the drug-containing taste-masking particles is 10-50%, preferably 15-45%, and more preferably 20-30%; and / or, the mass ratio of the active ingredient to the taste-masking material is 0.8-3:1, preferably 0.8-2.5:1, and more preferably 0.8-2:1; And / or, the mass ratio of the active ingredient to the binder is 1-20:1, preferably 15:1, and more preferably 1-10:

1.

5. The anhydrous swallowable granules according to any one of claims 1 to 4, characterized in that: The drug-containing pellets also include a filler, which is selected from one or more of microcrystalline cellulose, lactose, starch and mannitol; Preferably, the weight ratio of the filler to the active ingredient is 0.5-5:1, preferably 0.5-3.5:1, and more preferably 1-3:1; Preferably, the weight ratio of the filler to the binder is 10-30:1, preferably 15-25:1, and more preferably 18-22:

1.

6. The anhydrous swallowable granules according to any one of claims 1 to 5, characterized in that: The flavoring material is provided in the form of pellets.

7. The anhydrous swallowable granules according to any one of claims 1 to 6, characterized in that: The weight ratio of the drug-containing taste-masking particles to the flavor-correcting material is 10-100:1, preferably 10-30:1, and more preferably 15-25:

1.

8. The anhydrous swallowable granules according to any one of claims 1 to 7, characterized in that: The D90 of the drug-containing taste-masking particles is 200 μm-350 μm.

9. The anhydrous swallowable granules according to any one of claims 1 to 8, characterized in that: The raw materials of the drug-containing pellets include 45-55 parts of povidone or hypromellose, 450-550 parts of active ingredients and 800-1200 parts of microcrystalline cellulose by weight; The taste masking material comprises 200-600 parts of ethyl cellulose or cellulose acetate, 5-25 parts of sodium lauryl sulfate and 20-60 parts of talc; The flavoring material comprises 45-55 parts of citric acid, 40-110 parts of mannitol and 2-8 parts of aspartame.

10. The method for preparing the anhydrous swallowable granules according to any one of claims 1 to 9, characterized in that: The following steps are involved: (1) mixing the raw materials in the drug-containing pellets uniformly, and obtaining the drug-containing pellets by extrusion and spheronization; (2) coating the drug-containing pellets with the taste-masking material to obtain the drug-containing taste-masked granules; (3) The drug-containing taste-masking granules obtained in step (2) are mixed with a flavor-correcting material to obtain anhydrous swallowable granules.

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