A kind of berberine hydrochloride taste-masking micropill and preparation method thereof

Abstract

The present invention provides a berberine hydrochloride taste-masked micro-pill and a preparation method thereof. The taste-masked micro-pill has an isolation layer between a pill core and an outer taste-masking layer. The taste-masked micro-pill has a good taste-masking effect and does not cause delayed release or slow release of the raw material drug, thereby ensuring the efficacy of the drug.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to berberine hydrochloride taste-masked micropills and a preparation method thereof. Background Art

[0002] Berberine, also known as berberine, is a quaternary amine and isoquinoline alkaloid extracted from the rhizomes of the Ranunculaceae plant Coptis chinensis. Its hydrochloride, also known as berberine hydrochloride, is often used clinically. Berberine hydrochloride is not only a broad-spectrum antibacterial agent, but also can regulate protein kinase to protect the myocardium, inhibit platelet aggregation to prevent cardiovascular and cerebrovascular diseases, regulate nitric oxide and nitric oxide synthase to improve blood pressure, regulate calcium ions to protect the myocardium, relieve anxiety, and protect brain tissue by anti-oxidation and scavenging free radicals; berberine has a significant hypoglycemic effect and can resist diabetic renal fibrosis; berberine can also play an anti-cancer role by inducing apoptosis of cancer cells; it can also significantly reduce blood total cholesterol and triglyceride levels, with definite efficacy and few adverse reactions.

[0003] Berberine hydrochloride has a long history of clinical application in my country, and it is safe to use and has reliable efficacy. Berberine, an intestinal anti-infective drug currently used, occupies nearly one-third of the market share. In 2016, Northeast Pharmaceutical Group applied for clinical trials of berberine hydrochloride sustained-release capsules and berberine hydrochloride tablets for type 2 diabetes and hyperlipidemia, indicating that berberine hydrochloride will bring good news to patients with type 2 diabetes or hyperlipidemia. However, berberine hydrochloride tablets or capsules prepared by traditional technology have poor medication compliance in special medication groups such as children, and berberine hydrochloride tastes extremely bitter. Therefore, it is very necessary to develop new dosage forms (such as dry mixed suspensions, granules, etc.) with high patient compliance and taste masking function.

[0004] According to the reference Research progress on berberine with a special focus on its oral bioavailability, the absolute oral bioavailability of berberine hydrochloride is less than 1%, and its poor absorption may be related to its own aggregation, poor permeability, P-glycoprotein (P-gp)-mediated efflux and hepatobiliary re-excretion.

[0005] Among the currently disclosed invention patents, the patents involving berberine hydrochloride and its taste-masking technology are as follows:

[0006] The patent document with publication number CN1273133C (applicant: Beijing Zhaoyan Bona New Drug Research Co., Ltd.) uses berberine hydrochloride raw material for direct coating, and the coating material is selected from Eudragit E100, EPO, L100 or hydroxypropyl methylcellulose. Berberine API has poor fluidity and is very easy to stick. Therefore, in the process of coating berberine hydrochloride powder, high requirements are placed on the fluidization state and drying efficiency of the powder, and the process feasibility is poor. Eudragit L100 dissolves under conditions of pH ≥ 6.0, and the drug coated with Eudragit L100 is partially released in the jejunum. The overall bioavailability of berberine hydrochloride is poor. If Eudragit L100 is used, the efficacy cannot be guaranteed, and when taken as a dry suspension, the coating film may rupture when it is soaked in water, and the taste-masking effect cannot be achieved. During the coating process of berberine hydrochloride API, hydrochloric acid may be released and combine with the dimethylamineethyl functional group of Eudragit E100 or Eudragit EPO to form a salt, resulting in poor uniformity of the coating film and poor taste-masking effect. Hydroxypropyl methylcellulose dissolves in cold water, and the dry suspension cannot achieve a taste-masking effect. In addition, the patent does not involve isolation layer coating.

[0007] Patent document with publication number CN1931137A (applicant: Han Zhiqiang) adopts centrifugal stratification method to prepare berberine hydrochloride micropellets, and the taste-masking material uses Eudragit E100, Eudragit EPO or Eudragit L100; the shortcomings of the three as berberine hydrochloride taste-masking materials are analyzed in detail in patent publication number CN1273313C, which will not be repeated here.

[0008] Patent document with publication number CN107536807A (applicant: Pan Zhengmao) adopts melt granulation process to prepare berberine hydrochloride drug-containing micro-pellets, and then coats them with gastric soluble coating material and water-insoluble coating material to obtain gastric soluble taste-masked pellets. The water-insoluble coating material of the invention is selected from Eudragit RL100, RS100, RL or RS. Eudragit RL and RS series are insensitive to pH and insoluble, and can swell in biological media for sustained-release coating. Berberine hydrochloride has low solubility, and the use of this series of Eudragit may limit the dissolution of berberine hydrochloride, thereby affecting the efficacy.

[0009] Patent document with publication number CN112587499A (applicant: Chengdu Jinhua Pharmaceutical Co., Ltd.) uses wet granulation and extrusion spheronization to prepare berberine hydrochloride pellets and encapsulate them. The capsules involved in this invention can meet the medication needs of people with special medication needs.

[0010] The patent document with publication number CN112972398A (applicant: Jiangsu Ruishi Biotechnology Co., Ltd.) provides a berberine hydrochloride granule, which is composed of granules A and granules B; granules A include berberine hydrochloride and a blocker, and granules B include a filler, a sweetener, a binder, a flavor, a pigment and a flow aid; the differences in material types and properties of different granules during the preparation process will directly lead to differences in the particle size distribution of the two granules, which will directly affect the mixing uniformity of the product, thereby affecting the safety of the product.

[0011] The patent document with publication number CN112641718A (applicant: Shandong University) has a preparation method comprising: 1. preparing a bitter drug solution of appropriate concentration; 2. adding the drug solution to the porous carrier powder while stirring to obtain a bitter drug-porous carrier complex; 3. drying; 4. melt-granulating the bitter drug-porous carrier complex and the release regulator; 5. coating the prepared particles with a taste-masking layer in a fluidized bed. According to relevant literature records, the solubility of berberine hydrochloride in water is about 1:500, and the amount of water required to prepare the berberine hydrochloride drug solution is huge, so it is not easy to dry; if an organic solvent is used to dissolve berberine hydrochloride, the EHS risk cannot be ignored. In summary, the method for preparing berberine hydrochloride taste-masking particles provided by the invention is not suitable for large-scale production.

[0012] The dry suspension or granules have a small particle size and a larger specific surface area than tablets, so they are easier to disperse in the body, and can effectively avoid the self-aggregation of berberine hydrochloride after the berberine hydrochloride tablets disintegrate in the body, thereby ensuring the efficacy of the drug. In order to improve the compliance of patients with medication, it is very necessary to develop a berberine hydrochloride dry suspension or granules with a taste-masking effect. Summary of the invention

[0013] In view of the problems existing in the above-mentioned prior art, the present invention provides a berberine hydrochloride taste-masking micropill, which can not only effectively mask the unpleasant smell of berberine hydrochloride, but also avoid the self-aggregation of berberine hydrochloride in the body, and will not cause the delayed release or slow release of berberine hydrochloride, thereby ensuring the therapeutic effect and meeting the needs of special groups of people. It is particularly suitable for children and patients with dysphagia.

[0014] The technical solution adopted by the present invention is:

[0015] The invention discloses berberine hydrochloride taste-masked micropellets, which have an isolation layer between a pill core containing a drug and an outer taste-masking layer.

[0016] That is, the berberine hydrochloride taste-masked micro-pellets of the present invention include, from the inside to the outside, a pill core, an isolation layer, and a taste-masking layer. The pill core contains the main drug berberine hydrochloride.

[0017] The isolation layer comprises an adhesive and an anti-adhesive agent;

[0018] The binder is selected from polyvinyl pyrrolidone, hydroxypropyl cellulose and hypromellose; preferably hypromellose;

[0019] The anti-adherent agent is selected from talc and magnesium stearate;

[0020] The coating weight gain of the isolation layer is 5% to 10% of the pill core, preferably 5% to 8%.

[0021] The weight percentage of the binder is 2.5% to 5% based on the weight of the pill core;

[0022] The weight percentage of the anti-adhesive agent is 2.5% to 5% based on the weight of the pill core.

[0023] Preferably, the binder is hypromellose (eg, hypromellose E5LV); based on the weight of the pill core, the weight percentage content of hypromellose is 2.5% to 5%, preferably 4%.

[0024] Preferably, the anti-adhesive agent is talcum powder; based on the weight of the pill core, the weight percentage of talcum powder is 2.5-5%, preferably 4%.

[0025] Preferably, in the isolation layer, the weight ratio of the adhesive to the anti-adhesive agent is 1:1.

[0026] In the isolation layer, when polyvinyl pyrrolidone is used as an adhesive to coat the isolation layer to prepare taste-masked micropellets, the taste-masking effect is poor. It is speculated that polyvinyl pyrrolidone is hygroscopic, and the environmental moisture needs to be strictly controlled when the isolation micropellets are stored, otherwise the acid group of the raw material drug will diffuse into the taste-masking layer, resulting in the failure to achieve the taste-masking effect; when hydroxypropyl cellulose is used as an adhesive to coat the isolation layer to prepare the taste-masked micropellets, the liquid preparation time is relatively long, and if the liquid preparation process is not fully stirred, it is easy to form lumps that are difficult to disperse. Therefore, the adhesive is preferably hydroxypropyl methylcellulose.

[0027] In the isolation layer, when magnesium stearate is used as an anti-adhesive agent, it is difficult to disperse during the liquid preparation process. Therefore, the anti-adhesive agent is preferably talcum powder.

[0028] The pill core contains berberine hydrochloride, a filler, a binder and a disintegrant;

[0029] The filler is selected from microcrystalline cellulose; preferably microcrystalline cellulose PH101;

[0030] The binder is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, corn starch and pregelatinized starch; preferably pregelatinized starch;

[0031] The disintegrant is selected from sodium carboxymethyl starch.

[0032] In the drug-containing pill core, when corn starch is used as a binder, the process of preparing corn starch slurry using a slurrying method or a slurry boiling method is cumbersome and is not recommended; when hydroxypropyl methylcellulose or hydroxypropyl cellulose is used as a binder, the drug-containing pill core obtained by spheronization is in the shape of a short rod, which is not conducive to the fluidized bed coating process.

[0033] The taste-masking layer comprises a taste-masking material, a plasticizer or a stabilizer, and an anti-sticking agent;

[0034] The taste masking material is Eudragit E100 or Eudragit EPO;

[0035] The plasticizer or stabilizer is sodium lauryl sulfate or triethyl citrate;

[0036] The anti-sticking agent is stearic acid or talc.

[0037] The coating weight gain of the taste masking layer is 5% to 15% of the isolated pellets coated with the isolation layer.

[0038] The use of gastric-soluble Eudragit material as the taste-masking material can avoid the delayed release of the preparation caused by enteric-coated Eudragit material, ensuring that the preparation is fully absorbed and the efficacy is guaranteed.

[0039] In the drug-containing pill core, based on the weight of the drug-containing pill core,

[0040] The weight percentage content of berberine hydrochloride is 30% to 60%, more preferably 45% to 55%, and most preferably 50%;

[0041] The weight percentage content of the filler (e.g., microcrystalline cellulose; for example, microcrystalline cellulose PH101) is 30% to 50%, more preferably 35% to 45%, and most preferably 40%;

[0042] The weight percentage content of the binder (e.g., pregelatinized starch) is 5% to 15%, more preferably 5% to 10%, and most preferably 5%;

[0043] The weight percentage content of the disintegrant (eg sodium starch glycolate) is 5% to 15%, more preferably 5% to 10%, and most preferably 5%.

[0044] In the taste-masking layer, based on the weight of the taste-masking material Eudragit E100 or Eudragit EPO,

[0045] The weight percentage content of sodium lauryl sulfate or triethyl citrate is 5% to 10%, wherein sodium lauryl sulfate is preferably 10% and triethyl citrate is preferably 5%;

[0046] The weight percentage content of stearic acid or talc is 15% to 20%, wherein stearic acid is preferably 15% and talc is preferably 20%.

[0047] Preferably, when the solvent used for coating the taste-masking layer is an organic solvent, the taste-masking material is Eudragit E100, the plasticizer is triethyl citrate, and the anti-sticking agent is talcum powder; the organic solvent is 50% to 85% ethanol (aqueous solution); the coating weight gain of the taste-masking layer is 5% to 15% of the isolated pellets coated with the isolation layer; or,

[0048] When the solvent used for coating the taste-masking layer is water, the taste-masking material is Eudragit EPO, the stabilizer is sodium lauryl sulfate, and the anti-sticking agent is stearic acid; the coating weight gain of the taste-masking layer is 10% to 15% of the isolated micropellets coated with the isolation layer.

[0049] Preferably, the drug-containing pellet core is prepared by an extrusion spheronization process; and the isolation layer and the taste-masking layer are coated by a fluidized bed coating process.

[0050] In a specific embodiment, the berberine hydrochloride taste-masking pellets comprise the following components and their contents:

[0051] Contains pill core:

[0052]

[0053] Isolation layer:

[0054] 8 parts by weight of Hydroxypropyl methylcellulose

[0055] 8 parts by weight of talc

[0056] Taste masking layer:

[0057] Eudragit E100 / EPO 17.28 parts by weight / 17.28 parts by weight

[0058] Triethyl citrate / sodium lauryl sulfate 0.86 parts by weight / 1.72 parts by weight

[0059] Talc / stearic acid 3.46 parts by weight / 2.60 parts by weight

[0060] Preferably, in a specific embodiment, the berberine hydrochloride taste-masking pellets comprise the following components and their contents:

[0061] Contains pill core:

[0062]

[0063] Isolation layer:

[0064] 8 parts by weight of Hydroxypropyl methylcellulose

[0065] 8 parts by weight of talc

[0066] Taste masking layer:

[0067] Eudragit E100 17.28 parts by weight

[0068] Triethyl citrate 0.86 parts by weight

[0069] 3.46 parts by weight of talc

[0070] Another object of the present invention is to provide a method for preparing the berberine hydrochloride taste-masked pellets, comprising the following steps:

[0071] (1) berberine hydrochloride, microcrystalline cellulose PH101, pregelatinized starch, sodium carboxymethyl starch and an appropriate amount of water (e.g., purified water) are placed in a wet granulator to make soft material, and the stirring paddle speed is set to 120 rpm to 180 rpm, the cutting knife speed is set to 1500 rpm to 1800 rpm, the atomization pressure is set to 0.10 MPa to 0.20 MPa, and the total granulation time is 3 min to 4 min; the soft material is placed in an extruder for extrusion, the orifice diameter of the extruder is 0.4 mm, and the extrusion speed is set to 40 rpm to 60 rpm; the extrudate is placed in a spheronizer for spheronization, and the spheronization speed is set to 1000 rpm to 1500 rpm, and the spheronization time is 1 min to 2 min; the pellets are placed in an oven for drying, and the drying temperature is set to 50° C. to 60° C., until the moisture content of the particles is ≤3%; the dried drug-containing pellet cores are sieved with a 30-mesh sieve to remove large particles, and sieved with a 50-mesh sieve to remove fine powder, to obtain useful drug-containing pellet cores with a particle size between 30 mesh and 50 mesh;

[0072] (2) Seal layer coating: dissolve hydroxypropyl methylcellulose in an appropriate amount of water (e.g., purified water), add talcum powder, and stir to obtain a seal layer coating solution; place the pill cores obtained in step (1) in a fluidized bed, set the air inlet temperature to 60°C to 70°C, control the material temperature to 40°C to 45°C, set the atomization pressure to 0.10Mpa to 0.2Mpa, set the spray speed to 1Hz to 5Hz, and set the fan air volume to 3Hz to 8Hz; after the seal layer coating is completed, dry for 20min to 30min, remove large particles with a 30-mesh sieve, and remove fine powder with a 50-mesh sieve to obtain seal micro-pellets with a particle size between 30 and 50 mesh;

[0073] (3) Taste-masking coating:

[0074] a) Aqueous dispersion: dissolve sodium dodecyl sulfate in water (e.g., purified water), add stearic acid and Eudragit® EPO, and homogenize using a high shear homogenizer until a clear colloidal solution is formed; place the isolated pellets obtained in step (2) in a fluidized bed, set the air inlet temperature to 35°C to 40°C, control the material temperature to 25°C to 30°C, set the atomization pressure to 0.10Mpa to 0.2Mpa, set the spray speed to 1Hz to 5Hz, and set the fan air volume to 4Hz to 12Hz; after the taste masking layer is coated, dry for 20min to 30min, remove large particles with a 30-mesh sieve, and remove fine powder with a 50-mesh sieve to obtain berberine hydrochloride taste masked pellets with a particle size between 30 and 50 meshes; or,

[0075] b) Organic solvent dispersion: Pour triethyl citrate into 50% to 85% ethanol aqueous solution and disperse it evenly, dissolve Eudragit E100 under stirring to form a clear solution, then add talcum powder and stir evenly; place the isolated pellets obtained in step (2) in a fluidized bed, set the inlet air temperature to 30°C to 35°C, control the material temperature to 20°C to 25°C, set the atomization pressure to 0.10Mpa to 0.2Mpa, set the spray speed to 2Hz to 3Hz, and set the fan air volume to 4Hz to 8Hz; after the taste masking layer coating is completed, dry it for 20min to 30min, remove large particles with 30 mesh, and remove fine powder with 50 mesh, to obtain berberine hydrochloride taste masking pellets with a particle size between 30 mesh and 50 mesh.

[0076] Another object of the present invention is to provide a dry suspension or granules containing berberine hydrochloride, which contains the berberine hydrochloride taste-masked pellets described in the present invention or the berberine hydrochloride taste-masked pellets prepared by the preparation method of the present invention, and pharmaceutically acceptable excipients.

[0077] The taste-masking micro-pellets of the present invention have good taste-masking effect, and will not cause delayed release or slow release of the raw material medicine, thereby ensuring the efficacy of the medicine. The dry suspension or granules prepared subsequently can meet the needs of special groups of people while ensuring the efficacy, and are particularly suitable for children and patients with dysphagia, and have good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 Comparison of the dissolution curves of the isolated micropellets with different isolation layer weight gains in Example 2 and the reference preparation in aqueous medium (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37° C.).

[0079] Figure 2 The dissolution curves of the isolated micropellets with different isolation layer weight gains in Example 2 and the reference preparation in 0.1N hydrochloric acid medium are compared (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37°C).

[0080] Figure 3 The dissolution curves of the berberine hydrochloride taste-masked pellets prepared in Example 3 Prescription 2 and Example 5 Prescription 7 were compared with those of the reference preparation in aqueous medium (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37° C.).

[0081] Figure 4 The dissolution curves of the berberine hydrochloride taste-masked micropellets prepared in Example 3 Prescription 2 and Example 5 Prescription 7 were compared with those of the reference preparation in 0.1N hydrochloric acid medium (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37°C). DETAILED DESCRIPTION

[0082] In order to further illustrate the present invention, the berberine hydrochloride taste-masked pellets provided by the present invention are described in detail below through examples, but they should not be construed as limiting the scope of protection of the present invention.

[0083] Example 1: Preparation of berberine hydrochloride-containing pellet core

[0084] According to the prescription in Table 1, weigh berberine hydrochloride, microcrystalline cellulose PH101, pregelatinized starch and sodium carboxymethyl starch, and weigh an appropriate amount of purified water for use; place the above materials in a wet granulator to make soft materials, set the stirring paddle speed to 120rpm~180rpm, the cutting knife speed to 1500rpm~1800rpm, the atomization pressure to 0.10Mpa~0.20Mpa, and the total granulation time to 3min~4min. Place the soft material in an extruder for extrusion, the orifice diameter of the extruder is 0.4mm, and the extrusion speed is set to 40~60rpm; place the extrudate in a spheronizer for spheronization, set the spheronization speed to 1000rpm~1500rpm, and the spheronization time to 1min~2min. The pellets are placed in an oven for drying at a temperature of 50°C to 60°C until the moisture content of the particles is ≤3%. The dried drug-containing pellets are sieved with a 30-mesh sieve to remove large particles and a 50-mesh sieve to remove fine powder to obtain useful drug-containing pellet cores with a particle size between 30 and 50 meshes.

[0085] Table 1 Composition of berberine hydrochloride pill core formula

[0086] Element mg / single dose Berberine Hydrochloride 100mg Microcrystalline Cellulose PH101 80mg Pregelatinized starch 10mg Sodium starch glycolate 10mg

[0087] Example 2: Preparation of berberine hydrochloride isolated pellets

[0088] According to the prescription in Table 2, berberine hydrochloride isolated pellets with different coating weight gain were prepared. Weigh the prescribed amount of hydroxypropyl methylcellulose (specifically, hydroxypropyl methylcellulose E5LV) and talcum powder, dissolve the hydroxypropyl methylcellulose in an appropriate amount of purified water, add talcum powder, and stir evenly to obtain an isolation layer coating solution. The berberine hydrochloride pill core prepared in Example 1 was placed in a fluidized bed, and the inlet temperature was set to 60°C to 70°C, the material temperature was controlled at 40°C to 45°C, the atomization pressure was set to 0.10Mpa to 0.2Mpa, the spray speed was set to 1Hz to 5Hz, and the fan air volume was set to 3Hz to 8Hz; after the isolation layer coating was completed, dry for 20min to 30min, remove large particles with 30 mesh, remove fine powder with 50 mesh, and obtain berberine hydrochloride isolated pellets with a particle size between 30 mesh and 50 mesh.

[0089] Table 2 Berberine hydrochloride isolated pellets formulation composition

[0090]

[0091] Example 3: Preparation of berberine hydrochloride taste-masked pellets

[0092] According to the prescription in Table 3, triethyl citrate is poured into an appropriate amount of 50% to 85% ethanol aqueous solution and dispersed evenly, and the prescribed amount of Eudragit E100 is dissolved under stirring to form a clear solution, and then the prescribed amount of talcum powder is added and stirred evenly. The three isolated pellets prepared in Example 2 are placed in a fluidized bed respectively, and the inlet air temperature is set to 30°C to 35°C, the material temperature is controlled at 20°C to 25°C, the atomization pressure is set to 0.10Mpa to 0.2Mpa, the spray speed is set to 2Hz to 3Hz, and the fan air volume is set to 4Hz to 8Hz; after the taste masking layer coating is completed, dry for 20min to 30min, remove large particles with a 30-mesh sieve, and remove fine powder with a 50-mesh sieve to obtain berberine hydrochloride taste masking pellets with a particle size between 30 mesh and 50 mesh.

[0093] Table 3 Composition of berberine hydrochloride taste-masked pellets

[0094]

[0095] Example 4: Preparation of berberine hydrochloride taste-masked pellets with different taste-masking layers

[0096] According to the prescription in Table 4, triethyl citrate is poured into an appropriate amount of 50% to 85% ethanol aqueous solution and dispersed evenly, and the prescription amount of Eudragit E100 is dissolved under stirring to form a clear solution, and then the prescription amount of talcum powder is added and stirred evenly. The isolated pellets prepared by the prescription 0-2 of Example 2 are placed in the fluidized bed respectively, and the inlet air temperature is set to 30°C to 35°C, the material temperature is controlled at 20°C to 25°C, the atomization pressure is set to 0.10Mpa to 0.2Mpa, the spray speed is set to 2Hz to 3Hz, and the fan air volume is set to 4Hz to 8Hz; after the taste masking layer coating is completed, dry for 20min to 30min, remove large particles with a 30-mesh sieve, and remove fine powder with a 50-mesh sieve to obtain berberine hydrochloride taste masking pellets with a particle size between 30 mesh and 50 mesh.

[0097] Table 4 Composition of berberine hydrochloride taste-masked pellets

[0098]

[0099] Example 5: Preparation of berberine hydrochloride taste-masked pellets with different taste-masking layers

[0100] According to the prescription in Table 5, the prescribed amount of sodium dodecyl sulfate is dissolved in an appropriate amount of purified water, stearic acid and Eudragit EPO are added, and a high shear homogenizer is used for homogenization for 30 minutes until a clear colloidal solution is formed. The berberine hydrochloride isolation coat drug-containing micropellets prepared in Example 2 Prescription 0-2 are placed in a fluidized bed, and the inlet air temperature is set to 35°C to 40°C, the material temperature is controlled at 25°C to 30°C, the atomization pressure is set to 0.10Mpa to 0.2Mpa, the spray speed is set to 1Hz to 5Hz, and the fan air volume is set to 4Hz to 12Hz; after the taste masking layer coating is completed, dry for 20min to 30min, remove large particles with a 30-mesh sieve, remove fine powder with a 50-mesh sieve, and obtain berberine hydrochloride taste masking micropellets with a particle size between 30 mesh and 50 mesh.

[0101] Table 5 Composition of berberine hydrochloride taste-masked pellets

[0102]

[0103] Comparative Example 1: Preparation of berberine hydrochloride taste-masked pellets

[0104] According to the prescription in Table 6, the prescribed amount of sodium dodecyl sulfate is dissolved in an appropriate amount of purified water, stearic acid and Eudragit EPO are added, and a high shear homogenizer is used for homogenization for 30 minutes until a clear colloidal solution is formed. The berberine hydrochloride pill core prepared in Example 1 is placed in a fluidized bed, the inlet air temperature is set to 35°C to 40°C, the material temperature is controlled at 25°C to 30°C, the atomization pressure is set to 0.10Mpa to 0.2Mpa, the spray speed is set to 1Hz to 5Hz, and the fan air volume is set to 4Hz to 12Hz; after the taste masking layer coating is completed, dry for 20min to 30min, remove large particles with a 30-mesh sieve, remove fine powder with a 50-mesh sieve, and obtain berberine hydrochloride taste masking micropills with a particle size between 30 mesh and 50 mesh.

[0105] Table 6 Composition of berberine hydrochloride taste-masked pellets

[0106] Element mg / single dose Eudragit EPO 17.28mg Sodium Lauryl Sulfate 1.72mg Stearic acid 2.60mg Purified water Moderate

[0107] Experimental Example 1: Test on weight gain effect of isolation layer coating

[0108] The present invention investigates the effect of different isolation layer weight gain on product dissolution in Example 2. The dissolution results are as follows: Figure 1-2 shown. Figure 1 The dissolution curves of the isolated micropellets with different isolation layer weight gains in Example 2 and the reference preparation Kyoberin (100 mg berberine hydrochloride tablets) produced by Nippon Kayaku Co., Ltd. in aqueous media are compared (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37°C). Figure 2 The dissolution curves of the isolated micropellets with different isolation layer weight gains in Example 2 and the reference preparation Kyoberin (100 mg berberine hydrochloride tablets) produced by Nippon Kayaku Co., Ltd. in 0.1N hydrochloric acid medium are compared (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37°C).

[0109] Figure 1 and Figure 2 The dissolution results show that when the weight gain of the isolation layer is 5% to 10% of the core, the dissolution effect of the isolation pellets is similar to that of the reference preparation. Within this weight gain range, the more the isolation layer is weighted, the slower the dissolution in 0.1N hydrochloric acid medium, but the dissolution in purified water medium is not affected.

[0110] Experimental Example 2: Taste-masking effect test

[0111] Berberine hydrochloride is a yellow crystalline powder, and the taste masking material Eudragit E100 or Eudragit EPO can swell and penetrate in water, but does not dissolve. The dissolved berberine hydrochloride is dispersed in water under the action of osmotic pressure, showing a clear yellow color.

[0112] The taste masking effect of the berberine hydrochloride taste-masked micropellets prepared in Examples 3, 4 and 5 and Comparative Example 1 was tested. The method is as follows: 0.5 g of berberine hydrochloride taste-masked micropellets were added to 50 ml of warm water bath (water bath temperature 45°C, simulating the normal medication of dry suspension), and the color change of the solution was observed every 5 minutes and the taste was tasted orally.

[0113] The results are shown in Table 6, where:

[0114] √: The suspension system of berberine hydrochloride taste-masked pellets has neither color change nor bitter taste;

[0115] ○: The suspension system of berberine hydrochloride taste-masked pellets begins to turn yellow, with no bitterness or acceptable bitterness;

[0116] ×: The bitter taste of the suspension system of berberine hydrochloride taste-masked micropellets is unacceptable.

[0117] Table 6 Summary of taste-masking effects of berberine hydrochloride taste-masking micropellets

[0118]

[0119]

[0120] From the results in Table 6 above, it can be seen that when the coating weight gain of the isolation layer is 5% to 10%, the taste-masking effect of the taste-masking pellets with different coating weight gain of the isolation layer is not much different (prescription 1, prescription 2 and prescription 3); when the coating weight gain of the taste-masking layer is consistent, the taste-masking effect of the organic solvent-coated taste-masking layer (prescription 2, prescription 4 and prescription 5) is better than the taste-masking effect of the water solvent-coated taste-masking layer (prescription 6, prescription 7 and prescription 8); the reason is that the film-forming mechanism of the organic solvent-coated taste-masking layer and the water dispersion-coated taste-masking layer is different, and the film continuity of the taste-masking pellets with low weight gain of the water dispersion-coated taste-masking layer is poor, so it is preferred that the coating weight gain of the taste-masking layer of the water dispersion-coated taste-masking layer is 10% to 15% of the isolation pellets. The more the coating weight gain of the taste-masking layer is, the better the taste-masking effect is; the taste-masking effect of the taste-masking pellets of Comparative Example 1, i.e., the taste-masking effect of the taste-masking pellets without an isolation layer, is poor.

[0121] In general, the taste-masking effect of the higher weight-added taste-masking layer formulations of Examples 4 and 5 is better, and the effect of Example 4 is better than that of Example 5. The taste-masking layer formulations of Example 5 and Comparative Example 1 have the same composition and the same coating process parameters, but the taste-masking effects are quite different, which shows that the isolation layer has a greater influence on the taste-masking effect.

[0122] Experimental Example 3: Dissolution Effect Test

[0123] In addition to sensory testing, the taste-masking effect can also be demonstrated through in vitro dissolution experiments.

[0124] The increase in coating weight gain of the taste masking layer and the isolation layer will inevitably lead to a longer coating time, while too low coating weight gain will have an adverse effect on the taste masking effect or dissolution of the product. After comprehensive consideration, Example 3 Prescription 2 and Example 5 Prescription 7 were selected for dissolution effect testing.

[0125] In vitro dissolution test method: Chinese Pharmacopoeia 2020 edition, using 1000ml of water as the dissolution medium, the speed is 120 revolutions per minute, the dissolution results are as follows Figure 3 shown. Figure 3 The dissolution curves of the berberine hydrochloride taste-masked pellets prepared in Example 3 Prescription 2 and Example 5 Prescription 7 were compared with those of the reference preparation in aqueous medium (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37° C.).

[0126] The presence of the isolation layer and the taste-masking layer should not limit the dissolution of the product and affect the efficacy of the product. The berberine hydrochloride taste-masked pellets prepared in Example 3 Prescription 2 and Example 5 Prescription 7 were compared with the reference preparation Kyoberin (berberine hydrochloride tablets 100 mg) of Nippon Kayaku Co., Ltd. for quality comparison.

[0127] Eudragit E100 / Eudragit EPO can dissolve rapidly when the pH is less than 5. When the pH is greater than 5, Eudragit E100 / Eudragit EPO will limit the dissolution of the raw material berberine hydrochloride.

[0128] The present invention adopts a lower dissolution medium: 0.1N hydrochloric acid, and the dissolution curves of the berberine hydrochloride masked pellets prepared by Example 3 Prescription 2 and Example 5 Prescription 7 and the reference preparation are tested under the condition of 120 revolutions of the paddle method. The results are as follows Figure 4 shown. Figure 4 The dissolution curves of the berberine hydrochloride taste-masked micropellets prepared in Example 3 Prescription 2 and Example 5 Prescription 7 were compared with those of the reference preparation in 0.1N hydrochloric acid medium (dissolution conditions: paddle method, 1000 ml dissolution medium, 120 rpm, 37°C).

[0129] The results showed that the dissolution effects of the berberine hydrochloride taste-masked microcapsules of Example 3 Prescription 2 and Example 5 Prescription 7 of the present invention were similar to those of the reference preparations, indicating that the berberine hydrochloride taste-masked microcapsules of the present invention had similar therapeutic effects to those of the reference preparations, and thus the therapeutic effects could be guaranteed.

[0130] The berberine hydrochloride taste-masked micropellets of the present invention are prepared into dry suspensions or granules, which can meet the needs of special groups of people while ensuring the therapeutic effect, and are particularly suitable for children and patients with dysphagia, and have good application prospects.

[0131] The above contents are specific implementation methods with better effects of the present invention. The protection scope of the present invention should also cover the technical solutions and inventive concepts of the present invention.

Claims

1. A berberine hydrochloride taste-masking micro-pellet, comprising from the inside to the outside: Contains pill core, isolation layer, and taste-masking layer; The pill core contains berberine hydrochloride, a filler, a binder and a disintegrant; In the pill core, based on the weight of the pill core, the weight percentage of berberine hydrochloride is 45% to 55%, the weight percentage of the filler is 35% to 45%, the weight percentage of the binder is 5% to 10%, and the weight percentage of the disintegrant is 5% to 10%; the filler is selected from microcrystalline cellulose, the binder is selected from pregelatinized starch, and the disintegrant is selected from sodium carboxymethyl starch; The isolation layer comprises a binder and an anti-adhesive agent; based on the weight of the pill core, the weight percentage of the binder is 2.5% to 5%, and the weight percentage of the anti-adhesive agent is 2.5% to 5%; the binder is selected from hypromellose, and the anti-adhesive agent is selected from talc; the coating weight gain of the isolation layer is 5% to 10% of the pill core; The taste-masking layer comprises a taste-masking material, a plasticizer or a stabilizer and an anti-adherent; the taste-masking material is Eudragit E100 or Eudragit EPO, the plasticizer or stabilizer is sodium lauryl sulfate or triethyl citrate, and the anti-adherent is stearic acid or talcum powder; based on the weight of the taste-masking material Eudragit E100 or Eudragit EPO, the weight percentage content of sodium lauryl sulfate or triethyl citrate is 5% to 10%, and the weight percentage content of stearic acid or talcum powder is 15% to 20%; wherein: When the solvent used for coating the taste-masking layer is an organic solvent, the taste-masking material is Eudragit E100, the plasticizer is triethyl citrate, and the anti-sticking agent is talcum powder; the organic solvent is 50% to 85% ethanol; the coating weight gain of the taste-masking layer is 5% to 15% of the isolated micropellets coated with the isolation layer; or, When the solvent used for coating the taste-masking layer is water, the taste-masking material is Eudragit EPO, the stabilizer is sodium lauryl sulfate, and the anti-sticking agent is stearic acid; the coating weight gain of the taste-masking layer is 10% to 15% of the isolated micropellets coated with the isolation layer.

2. The berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: In the isolation layer: The weight percentage content of the hypromellose is 4% based on the weight of the pill core; Calculated by the weight of the pill core, the weight percentage content of the talc is 4%.

3. The berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: In the pill-containing core, the filler is selected from microcrystalline cellulose PH101; In the isolation layer, the adhesive is selected from hypromellose E5LV.

4. The berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: In the pill core, based on the weight of the pill core, the weight percentage content of berberine hydrochloride is 50%, the weight percentage content of the filler is 40%, the weight percentage content of the binder is 5%, and the weight percentage content of the disintegrant is 5%; In the taste-masking layer, based on the weight of the taste-masking material Eudragit E100 or Eudragit EPO, the weight percentage content of sodium lauryl sulfate is 10%, the weight percentage content of triethyl citrate is 5%, the weight percentage content of stearic acid is 15%, and the weight percentage content of talc is 20%.

5. The berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: The coating weight gain of the isolation layer is 5% to 8% of the pill core.

6. The berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: The drug-containing pill core is prepared by an extrusion spheronization process; and the isolation layer and the taste-masking layer are coated by a fluidized bed coating process.

7. The berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: Contains the following components and their contents: Contains pill core: Isolation layer: 8 parts by weight of Hydroxypropyl methylcellulose 8 parts by weight of talc Taste masking layer: Eudragit E100 / Eudragit EPO 17.28 parts by weight / 17.28 parts by weight Triethyl citrate / sodium lauryl sulfate 0.86 parts by weight / 1.72 parts by weight Talc / stearic acid 3.46 parts by weight / 2.60 parts by weight.

8. The berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: Contains the following components and their contents: Contains pill core: Isolation layer: 8 parts by weight of Hydroxypropyl methylcellulose 8 parts by weight of talc Taste masking layer: Eudragit E100 17.28 parts by weight Triethyl citrate 0.86 parts by weight Talc 3.46 parts by weight.

9. A method for preparing the berberine hydrochloride taste-masked pellets according to claim 1, characterized in that: Includes the following: (1) Place berberine hydrochloride, microcrystalline cellulose PH101, pregelatinized starch, sodium carboxymethyl starch and an appropriate amount of water into a wet granulator to make soft material, set the stirring paddle speed to 120rpm-180rpm, the cutting knife speed to 1500rpm-1800rpm, the atomization pressure to 0.10Mpa-0.20Mpa, and the total granulation time to 3min-4min; place the soft material into an extruder for extrusion, the orifice diameter of the extruder is 0.4mm, and the extrusion speed is set to 40rpm-60rpm; place the extrudate into a spheronizer for spheronization, set the spheronization speed to 1000rpm-1500rpm, and the spheronization time to 1min-2min; place the pellets into an oven for drying, set the drying temperature to 50℃-60℃, until the moisture content of the pellets is ≤3%; use a 30-mesh sieve to remove large particles from the dried pill cores, and a 50-mesh sieve to remove fine powder to obtain useful pill cores with a particle size between 30 mesh and 50 mesh; (2) Seal coating: dissolve hydroxypropyl methylcellulose in an appropriate amount of water, add talcum powder, and stir to obtain a seal coating solution; place the pill cores obtained in step (1) in a fluidized bed, set the air inlet temperature to 60°C to 70°C, control the material temperature to 40°C to 45°C, set the atomization pressure to 0.10Mpa to 0.2Mpa, set the spray speed to 1Hz to 5Hz, and set the fan air volume to 3Hz to 8Hz; after the seal coating is completed, dry for 20min to 30min, remove large particles with a 30-mesh sieve, and remove fine powder with a 50-mesh sieve to obtain seal micro-pellets with a particle size between 30 and 50 mesh; (3) Taste-masking coating: a) aqueous dispersion: dissolve sodium dodecyl sulfate in water, add stearic acid and Eudragit EPO, and homogenize using a high shear homogenizer until a clear colloidal solution is formed; place the isolated pellets obtained in step (2) in a fluidized bed, set the air inlet temperature to 35°C-40°C, control the material temperature to 25°C-30°C, set the atomization pressure to 0.10Mpa-0.2Mpa, set the spray speed to 1Hz-5Hz, and set the fan air volume to 4Hz-12Hz; after the taste masking layer coating is completed, dry for 20min-30min, remove large particles with a 30-mesh sieve, and remove fine powder with a 50-mesh sieve to obtain berberine hydrochloride taste masked pellets with a particle size between 30 mesh and 50 mesh; or, b) Organic solvent dispersion: Pour triethyl citrate into 50% to 85% ethanol aqueous solution and disperse it evenly, dissolve Eudragit E100 under stirring to form a clear solution, then add talcum powder and stir evenly; place the isolated pellets obtained in step (2) in a fluidized bed, set the inlet air temperature to 30°C to 35°C, control the material temperature to 20°C to 25°C, set the atomization pressure to 0.10Mpa to 0.2Mpa, set the spray speed to 2Hz to 3Hz, and set the fan air volume to 4Hz to 8Hz; after the taste masking layer coating is completed, dry it for 20min to 30min, remove large particles with 30 mesh, and remove fine powder with 50 mesh, to obtain berberine hydrochloride taste masking pellets with a particle size between 30 mesh and 50 mesh.

10. A dry suspension or granules containing berberine hydrochloride, characterized in that: Containing the berberine hydrochloride taste-masked micropellets according to any one of claims 1 to 8 or the berberine hydrochloride taste-masked micropellets prepared by the preparation method according to claim 9, and pharmaceutically acceptable excipients.

Images