Taste masking microspheres and their manufacturing process and uses

Abstract

The present invention provides taste-masking microspheres, their preparation method, and their use, which relate to the technical field of pharmaceutical formulations. The taste-masking microspheres contain, by weight, 1.5-21.2 parts of a drug component, 35-110 parts of a drug carrier, 0-30 parts of an alkalizing agent, and 0-8 parts of a plasticizer. The taste-masking microspheres of the present invention have the advantages of good taste-masking effect and wide applicability.

Description

[Technical Field]

[0001] The present invention relates to the technical field of pharmaceutical formulations, and in particular to taste-masking microspheres and their manufacturing process and uses. [Background technology]

[0002] Vonoprazan fumarate is a novel reversible proton pump inhibitor (RPPI) and potassium ion-competitive acid blocker (P-CAB), and its clinical mechanism of action is the H generated by its hydrolysis. + However, H in the gastric parietal cell secretory tubule membrane + / K + Newly synthesized H is actively transported into the gastric tubule lumen by H-ATPase. + / K + -ATPase is continuously blocked, producing a sustained acid-suppressing effect. Vonoprazan fumarate is primarily used to treat gastric ulcers, duodenal ulcers, and erosive esophagitis, as well as to eradicate Helicobacter pylori.

[0003] At the same time, vonoprazan fumarate has a strong bitter taste, which leads to poor patient compliance and limits its clinical application, and also limits the clinical use of other drugs that have a similarly strong bitter taste.

[0004] Current taste-masking technologies for oral drugs include pellet coating, macroporous resin adsorption, flavor masking, and microsphere technologies. For example, (1) Chinese Patent Application No. CN112353802A discloses the preparation of a taste-masking composition for vonoprazan fumarate using a static exchange method with the pharmaceutical API vonoprazan fumarate and an acidic cation exchange resin. (2) Chinese Patent Applications CN102512389A and CN1592622A disclose the preparation of pellets by coating drug-containing particles with EUDRAGIT resin in a fluidized bed. (3) Chinese Patent Application No. CN101822646A discloses the masking of the bitter taste of drugs by adding flavor masking agents. (4) Chinese Patent Application No. CN102958515A discloses the preparation of microspheres by a phase separation method, dissolving ethyl cellulose in an organic solvent, cyclohexane, and adding polyethylene or other phase inducers. (5) Chinese patent application CN101836965A discloses the preparation of drug-encapsulated microspheres by forming a solid dispersion using EUDRAGIT as a carrier material through a solvent evaporation method. (6) Chinese patent application CN101065116A discloses the preparation of polypeptide microspheres by a phase separation method using PLGA polymer as a carrier.

[0005] Disadvantages of pellet coating include complicated operations, pellet particle size of 300-1200 μm, and poor palatability (very gritty) when prepared as a dry suspension. Furthermore, pellet encapsulation is surface encapsulation (i.e., the coating solution is sprayed onto the surface of the API pellets and dried to form coated pellets), and when the suspension is prepared in vitro (pH 6.8), the API release rate is between 0.5-2% or more. Therefore, the taste-masking effect is poor when preparing an oral suspension for a drug with a very bitter API. Therefore, the taste-masking effect on vonoprazan fumarate is poor.

[0006] Regarding macroporous resin adsorption technology, macroporous resin has an adsorption effect, but the adsorption rate of resin is generally low at 5-20%, and the resin proportion is over 80%, so the proportion of resin ingested when taking drugs is high, which makes it easy to cause side effects. At the same time, the appearance of the product is not perfectly spherical, and the product fluidity is poor.

[0007] Flavor masking technology involves adding secondary ingredients such as flavoring agents to mask the taste. Adding secondary ingredients disrupts the sense of taste and reduces the bitterness, making it the simplest and least expensive method, but its effectiveness is limited and it is not effective for very bitter drugs or drugs with excellent water solubility. Therefore, it is not effective in masking the taste of vonoprazan fumarate.

[0008] Microspheres refer to spheres with a particle size on the order of microns. In the field of drug delivery, drug-loaded microspheres refer to microspheres or sphere-like bodies formed by dissolving or dispersing drugs in polymeric materials, with particle sizes generally ranging from 1 to 250 μm. The principle of drug loading in microspheres is to embed or adsorb drugs onto or inside the polymer surface by physical means. Depending on their structure, microspheres can be divided into pore-forming microspheres, bilayer microspheres, and magnetic microspheres. Microsphere technology is primarily used in the pharmaceutical field for injectable and oral formulations. Current microsphere manufacturing techniques include emulsification / volatilization, phase separation, spray drying, and hot-melt extrusion.

[0009] The basic principle of the emulsion-volatilization method is to add an organic solvent to dissolve the drug and polymer to a continuous (aqueous) phase containing a surfactant under high-speed stirring to form an emulsion. The organic solvent in the emulsion is then volatilized under physical conditions (vacuum, stirring, membrane evaporation, etc.). The more soluble or more volatile solvent in the continuous phase rapidly diffuses and removes, causing the polymer on the outside of the emulsion droplets to precipitate, harden, and deposit to form a thin film. As the organic solvent further diffuses and evaporates, the internal polymer hardens and shrinks from the inside out, forming a cavity in the center and hardening the microspheres. The emulsion-volatilization method is generally suitable for producing microspheres from drugs with poor water solubility. However, the organic solvent remains in the product, making it difficult to remove, resulting in a low encapsulation rate of 20-80%.

[0010] The manufacturing principle of microspheres using the phase separation method is essentially an extraction technique: a third component, typically an organic non-solvent, is added to a polymer-drug-solvent system while stirring. The addition of the third component reduces the solubility of the polymer, causing the two phases to coalesce at a certain point, resulting in phase separation between the solvent and the polymer, forming very soft drug-loaded droplets. The system is then transferred to another organic non-solvent, and the microspheres are hardened to obtain the final microspheres. While the phase separation method is suitable for highly water-soluble drugs, it requires complex operational steps and poor process reproducibility, making it unsuitable for industrial production. It requires a wide variety of organic solvents, requires large amounts of them, has high unit consumption, often results in high residual solvent content in microsphere products, and generally results in low encapsulation rates of around 20-80%.

[0011] The principle of spray-drying microsphere production is to spray liquid raw materials and auxiliary materials into a hot drying medium, and then convert the raw materials and auxiliary materials into dry powder in a spray-drying device. Although the spray-drying method is suitable for heat-sensitive drugs, it requires a fixed drying device, consumes high energy, and the appearance of the microspheres is imperfectly spherical, with irregular granular surfaces.

[0012] The principle of hot-melt extrusion microspheres is to mix the appropriate amounts of drug and auxiliary materials, heat and melt them, extrude them through a sieve plate, and then rapidly cool them to form a strip-shaped solid, which is then crushed to produce microspheres. Hot-melt extrusion is suitable for heat-resistant drugs, but the resulting microspheres tend to be unrounded, with some columnar particles, poor flowability, and large particle sizes of 200-1000 μm.

[0013] Therefore, how to develop a microsphere manufacturing process that has good taste masking effect, high encapsulation rate, wide applicability (regardless of water-soluble or fat-soluble drugs), small particle size, good roundness of the product, high fluidity, and low residual solvent content is an issue that needs to be resolved as soon as possible.

[0014] Helicobacter pylori (Hp) is a spiral-shaped, Gram-negative, microaerophilic bacterium. H. pylori infection is the primary etiology of chronic gastritis, peptic ulcers, and gastric mucosa-associated lymphoid tissue lymphoma, and is also an important cause of gastric cancer. Generally, people are susceptible to Hp infection. In recent years, resistance to drugs such as clarithromycin and metronidazole has increased year by year, and the clinical failure rate of traditional triple and quadruple PPI treatments has been increasing. Therefore, the issues of eradicating Hp infection and drug resistance must also be addressed. Currently, no combination anti-Hp infection products based on P-CAB inhibitors (e.g., vonoprazan fumarate) have emerged. Summary of the Invention

[0015] The object of the present invention is to provide taste-masking microspheres with good taste-masking effect and wide applicability (regardless of whether they are water-soluble or fat-soluble drugs), a manufacturing process thereof, and a composition containing taste-masking microspheres of vonoprazan fumarate that has a significant anti-Hp infection effect, in order to overcome the deficiencies of the prior art.

[0016] By optimizing the manufacturing process, the present invention has produced taste-masking microspheres with high yield and encapsulation rate, small particle size, good roundness of the product, good flowability, low residual solvent content, and excellent overall performance.

[0017] The present invention has been achieved by the following technical solutions.

[0018] Taste masking microspheres comprising, by weight, 1.5 to 21.2 parts of a drug component, 35 to 110 parts of a drug carrier, 0 to 30 parts of an alkalizing agent, and 0 to 8 parts of a plasticizer.

[0019] Preferably, the taste-masking microspheres comprise, by weight, 5-10 parts of drug component, 50-90 parts of drug carrier, 0-8 parts of alkalizing agent, and 2-8 parts of plasticizer.

[0020] More preferably, the taste-masking microspheres comprise, by weight, 5-10 parts of drug component, 50-90 parts of drug carrier, 2-8 parts of alkalizing agent, and 2-8 parts of plasticizer.

[0021] Preferably, the taste-masking microspheres further comprise at least one of a light-blocking agent and an auxiliary agent, which is used to increase the density of the microspheres, the flowability of the microspheres, improve the stability of the drug component in the microspheres, etc.

[0022] More preferably, the light-blocking agent includes at least one of zinc oxide and titanium dioxide, and even more preferably titanium dioxide.

[0023] More preferably, the auxiliary agent includes at least one of fumaric acid, succinic acid, dibutylhydroxytoluene, magnesium stearate, silica, talc, and povidone, and even more preferably includes at least one of fumaric acid, succinic acid, dibutylhydroxytoluene, silica, and talc.

[0024] Preferably, the drug carrier comprises a carrier A which is a pH-dependent or non-pH-dependent carrier and a carrier B which is a skeletal carrier.

[0025] The pH-dependent carrier has pH dependency, and does not dissolve in aqueous solution (pH 6.8) outside the body, achieving a taste-masking effect. It dissolves inside the body (pH 1-4), allowing the API to be released and exert its medicinal effect.

[0026] The non-pH-dependent carrier is not affected by pH and swells in water to form cells, through which the API is eluted and exerts its medicinal effect.

[0027] More preferably, the carrier A contains at least one of a polyacrylic resin, a methyl methacrylate-diethylaminoethyl methacrylate copolymer, and a polyvinyl acetal diethylaminoacetate.

[0028] More preferably, the polyacrylic resin comprises at least one of Eudragit EPO, Eudragit E100, Eudragit RLPO, Eudragit RL100, Eudragit RSPO and Eudragit RS100.

[0029] More preferably, the methyl methacrylate-diethylaminoethyl methacrylate copolymer is Kollicoat Smartseal 30D100P.

[0030] More preferably, the pH-dependent carrier comprises at least one of Eudragit EPO and Eudragit E100.

[0031] More preferably, the pH-dependent carrier comprises Eudragit EPO.

[0032] More preferably, the non-pH-dependent carrier comprises at least one of Eudragit RLPO, Eudragit RL100, Eudragit RSPO and Eudragit RS100.

[0033] More preferably, the non-pH-dependent carrier comprises at least one of Eudragit RLPO and Eudragit RSPO.

[0034] More preferably, the non-pH-dependent carrier contains Eudragit RLPO and Eudragit RSPO in a mass ratio of 1:1 to 8:1.

[0035] More preferably, the carrier A is used in an amount of 5 to 40 parts, or 10 to 30 parts.

[0036] More preferably, the carrier B (skeleton-type carrier) contains at least one of ethyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, cellulose acetate, polyvinyl acetate, ammonium methacrylate copolymer type A, ammonium methacrylate copolymer type B, crospovidone, and maltodextrin.

[0037] More preferably, the ethyl cellulose includes at least one of N7, N10, N22, and N50, where N represents ethyl cellulose and the subsequent number represents the model number.

[0038] More preferably, the skeletal carrier comprises at least one of N7 and N10.

[0039] More preferably, the skeletal carrier may be used in an amount of 30 to 70 parts, more specifically, 30 to 60 parts, or 40 to 60 parts.

[0040] Preferably, the alkalizing agent comprises at least one of sodium carbonate, sodium bicarbonate, magnesium oxide, meglumine, and trometamol.

[0041] The alkalizing agent can improve the solubility of API (i.e., active pharmaceutical ingredient) raw materials. After adding the alkalizing agent, the reaction stirring time is controlled to 0-12 hours, preferably 0.66-2 hours.

[0042] More preferably, the alkalizing agent comprises at least one of sodium bicarbonate and magnesium oxide.

[0043] The plasticizer can reduce the aggregation and blocking phenomenon during the molding and curing process of the microspheres.

[0044] Preferably, the plasticizer comprises at least one of diethyl phthalate, tributyl citrate, polyethylene glycol 6000, and triethyl citrate.

[0045] More preferably, the plasticizer is triethyl citrate.

[0046] Preferably, the drug component is a compound having a bitter taste or an unpleasant odor, more preferably an alkaloid compound.

[0047] More preferably, the drug component is at least one of an organic amine alkaloid and a nitrogen-containing heterocyclic alkaloid.

[0048] The microsphere formulation of the present invention has an excellent taste-masking effect on APIs with strong bitterness, bitter taste, and specific unpleasant odor. Generally, APIs with bitter taste are alkaloid compounds, such as organic amine alkaloids and nitrogen-containing heterocyclic alkaloids. The alkaloid molecule contains a nitrogen atom, and the outermost electron of the nitrogen atom is connected to a proton (H + ) to form salts. Free alkaloids are generally insoluble or poorly soluble in water, but after forming salts, their water solubility and stability are enhanced. Alkaloids have a bitter or pungent taste, and the bitterness often intensifies after forming salts.

[0049] More preferably, the drug component is selected from the group consisting of vonoprazan, pharmaceutically acceptable salts of vonoprazan, berberine hydrochloride, sildenafil citrate, azithromycin, cefuroxime axetil, vardenafil hydrochloride, metformin hydrochloride, paroxetine hydrochloride, sitagliptin hydrochloride, sertraline hydrochloride, pyridostigmine bromide, lidocaine hydrochloride, famotidine, ibuprofen, tramadol hydrochloride, allicin, beposide, and the like. Tastine besilate, acetaminophen, colchicine, racecadotril, fluoxetine hydrochloride, flucloxacillin sodium, lacosamide, clarithromycin, donepezil hydrochloride, rivaroxaban, linezolid, cefcapene, cefetamet, meropenem, moxifloxacin, fluvoxamine maleate, rebamipide, cefteram pivoxil, verapamil, quetiapine, amisulpride, sulpiride, methope Lorole, pravastatin, atomoxetine, escitalopram, tilidine hydrochloride, ondansetron, vortioxetine hydrobromide, domperidone, zopiclone, roxatidine, loperamide, diphenhydramine, epinastine, mirabegron, solifenacin, irbesartan, vortioxetine hydrobromide, ticagrelor, captopril, colesevelam hydrochloride, rasagiline, nintedanib ethanesulfonate, etanercept The compounds may include at least one of narapril maleate, apremilast, piroxicam, flutamide, varenicline tartrate, pazopanib, pramipexole, ripretinib, tamsulosin hydrochloride, risperidone, linagliptin, teneligliptin, dabigatran etexilate, odebixibat, micafungin, aprepitant, roflumilast, cefprozil, cefpodoxime proxetil, and tenapanol hydrochloride.

[0050] More preferably, the pharmaceutically acceptable salt of vonoprazan is at least one of vonoprazan fumarate, L-malate, succinate, hemi-L-tartrate, dihydrogenphosphate, hydrogensulfate, sulfate, hydrochloride, methanesulfonate, phosphate, acetate, citrate, maleate, tartrate, bitartrate, and hydrobromide, all of which have favorable effects such as taste masking and solubility.

[0051] Preferably, the weight of the drug component is 1.5-21.2% of the total weight of each component of the taste-masking microsphere, and more specifically, it may be 5-15%, 5-10%.

[0052] Vonoprazan is a basic organic amine compound that can form a fumarate, but vonoprazan fumarate has a strong bitter taste. The taste-masking technology of the microspheres of the present invention reduces the strong bitterness to an almost non-bitter level, which is advantageous for the development and use of oral solution (suspension) formulations to meet the administration needs of children, the elderly, and patients with dysphagia.

[0053] Preferably, when the drug component is vonoprazan fumarate, the auxiliary agent comprises at least one of fumaric acid, succinic acid, and dibutylhydroxytoluene. The fumaric acid is added in an amount of 0.08 to 12.42% based on the total mass of the components of the taste-masking microspheres, the succinic acid is added in an amount of 0.08 to 2% based on the total mass of the components of the taste-masking microspheres, and the dibutylhydroxytoluene is added in an amount of 0.08 to 1% based on the total mass of the components of the taste-masking microspheres. Fumaric acid, succinic acid, or dibutylhydroxytoluene can improve the stability of the product.

[0054] More preferably, the fumaric acid may be added in an amount of 0.08 to 10%, more specifically 0.08 to 5%, based on the total mass of each component of the taste-masking microspheres.

[0055] The present invention relates to a process for producing taste-masking microspheres, which comprises the following steps: (1) Preparation of microsphere dispersed phase: Each component of the taste masking microspheres is dissolved in solvent A to form the microsphere dispersed phase. (2) Preparation of microsphere continuous phase: Select solvent B as the microsphere continuous phase; (3) After the microsphere continuous phase is poured into the reactor, the microsphere dispersed phase is fed into the bottom of the reactor and dispersed to form spheres, which are then hardened, filtered, washed, and dried to obtain taste-masking microspheres.

[0056] In the process of preparing the taste-masking microspheres of the present invention, after mixing the dispersed phase and the continuous phase, the steps of forming spherical droplets (abbreviated as droplets), forming soft spheres, hardening the sphere walls, hardening the spheres, filtering the microspheres, and drying are carried out in sequence.

[0057] Preferably, the microspheres are filtered, washed, and dried to obtain the taste-masking microspheres.

[0058] Stages of droplet formation: After the microsphere dispersed phase is fed to the bottom of the microsphere continuous phase, spherical droplets gradually form. The spheronization and dispersibility of each material is controlled to avoid non-dispersed material units (i.e., large spheres) migrating to the liquid surface and exploding to form a film, and materials that are too dispersive, forming an emulsion but not spherical droplets.

[0059] Stages of soft sphere formation: The solvent at the droplet surface rapidly diffuses into the continuous phase, causing the drug carrier at the droplet surface to precipitate and form a relatively thin soft skin, forming soft spheres.

[0060] Sphere wall hardening stage: 1) As the solvent in the soft spheres diffuses into the microsphere continuous phase and the solvent in the microsphere continuous phase diffuses back into the soft spheres, the walls of the soft spheres gradually harden, and the skin of the drug carrier on the surface of the soft spheres gradually thickens, forming core-wrapped balls (the cores of the spheres are still liquid) with a shell of a certain thickness. 2) The solvent in the core-wrapped ball further diffuses over time, and the thickness of the core-wrapped ball shell continues to increase.

[0061] Sphere hardening stages: After the core-wrapped balls are completely cured, they become solid or hollow spheres with small particle sizes.The microspheres have a dense surface and a porous interior, and the drug components exist in the microspheres as molecular dispersions, which is more advantageous for drug delivery and release.

[0062] Microsphere washing steps: Components such as solvents and surfactants on the surface of the microspheres are washed away, preferably with purified water having a pH of 6.5 to 7.5.

[0063] Microsphere drying stage: Preferably, drying is performed using a temperature gradient. More preferably, drying is performed with air at room temperature for 1 hour, followed by heating to 40°C and drying for 2 hours.

[0064] The oral microspheres of the present invention have a diameter of mainly 50 to 380 μm (larger than injectable microspheres). After preforming, the solvent must diffuse into the continuous phase of the microspheres over a certain period of time to harden the microspheres. Blocking aggregation of the microspheres in the continuous phase and the microspheres reaching the surface of the liquid before the shell hardens and exploding to form a membrane both result in failure of sphere formation. These two phenomena are issues that must be resolved first in the microsphere manufacturing process, and the injection method is an important means of resolving these issues.

[0065] The internal liquid supply (conventionally referred to as "top supply") controls the dispersion effect of the injected material in forming spheres and the particle size and uniformity of the formed spheres depending on the supply position into the reactor. The microspheres may be supplied to the bottom, middle, or top of the continuous phase liquid in the reactor, but the bottom supply is preferred.

[0066] Preferably, the solvent A in step (1) is a mixed solvent of organic solvent C and water.

[0067] More preferably, the mass proportion of water in solvent A is 0 to 35%, a preferred range is 0 to 33.5%, even more preferably 0 to 10.5%, or 3.5 to 33.5%, more specifically, a range of 7.5-10.5% may be selected.

[0068] Water can increase the solubility of water-soluble APIs, adjust the diffusion rate of the microsphere dispersed phase in the microsphere continuous phase, and adjust the porosity of the microsphere surface and the hollowness inside the microsphere.

[0069] More preferably, the organic solvent C comprises at least one of methanol, ethanol, isopropanol, methylethylene glycol, acetone, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, acetonitrile, N,N-dimethylacetamide, ethyl acetate, n-butanol, dichloromethane, chloroform, tetrachloroethane, and methylpropylene glycol acetate.

[0070] When preparing the microsphere dispersed phase, the following three factors must be considered for the selection of solvent C: 1) Selection of a solvent capable of forming spheres in the microsphere continuous phase: At least one of ethyl acetate, n-butanol, dichloromethane, chloroform, tetrachloroethane, and methylpropylene glycol acetate is included. From a comprehensive evaluation of sphere-forming properties, recycling economy, drug carrier solubility, and safety of use, at least one of ethyl acetate, n-butanol, and dichloromethane is preferred, and at least one of ethyl acetate and n-butanol is more preferred. 2) Selection of a solvent that has good drug carrier solubility (assuming that it has sphere-forming properties in the microsphere continuous phase): at least one of ethyl acetate, dichloromethane, n-butanol, and methylpropylene glycol acetate is included, with at least one of ethyl acetate and n-butanol being preferred. 3) Selection of a solvent that has good solubility of the API and good diffusibility in the microsphere continuous phase: at least one of methanol, ethanol, isopropanol, methylethylene glycol, acetone, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, acetonitrile, and N,N-dimethylacetamide is included, and at least one of methanol, ethanol, isopropanol, and acetone is preferred.

[0071] More preferably, the solvent C in step (1) comprises at least one of methanol, ethanol, isopropanol, acetone, ethyl acetate, n-butanol, and dichloromethane.

[0072] In another embodiment of the present invention, the solvent C is a mixed solvent of two kinds of solvents, specifically including any of the following mixed solvents: a) an ethyl acetate / ethanol mixed solvent, the volume ratio of which is 4:1 to 1:1, preferably 1.5:1, when the drug carrier comprises a pH-dependent carrier, and the volume ratio of which is 25:1 to 5:1, preferably 20:1, when the drug carrier comprises a non-pH-dependent carrier; b) a mixed solvent of n-butanol / ethanol in a volume ratio of 3:1 to 1.2:1, preferably 1.5:1; c) a dichloromethane / ethanol mixed solvent having a volume ratio of 1.7:1 to 1:1, preferably 1.5:1; d) a mixed solvent of ethyl acetate / methanol in a volume ratio of 3:1 to 1.15:1, preferably 1.5:1; e) a mixed solvent of ethyl acetate / isopropanol in a volume ratio of 4:1 to 1.2:1, preferably 1.5:1; f) a mixed solvent of ethyl acetate / acetone in a volume ratio of 2:1 to 1:1.2, preferably 1.5:1; g) A mixed solvent of ethyl acetate and acetonitrile in a volume ratio of 2:1 to 1:1, preferably 1.5:1.

[0073] In another embodiment of the present invention, the solvent C is a mixed solvent of three kinds of solvents, specifically including any of the following mixed solvents: (a) A mixed solvent of ethyl acetate, ethanol, and n-butanol in the following volume ratios: 60% ethyl acetate, 30 to 10% ethanol, 10 to 30% n-butanol, preferably 60% ethyl acetate, 20% ethanol, 20% n-butanol, (b) A mixed solvent of ethyl acetate, ethanol, and methanol in the following volume ratios: 60% ethyl acetate, 30-10% ethanol, 10-30% methanol, preferably 60% ethyl acetate, 20% ethanol, 20% methanol (c) A mixed solvent of ethyl acetate, ethanol, and isopropanol in the following volume ratios: 60% ethyl acetate, 30-10% ethanol, 10-30% isopropanol, preferably 60% ethyl acetate, 20% ethanol, 20% isopropanol (d) A mixed solvent of ethyl acetate, ethanol, and acetone in the following volume ratios: The solvent is 60% ethyl acetate, 30 to 10% ethanol, and 10 to 30% acetone, and preferably 60% ethyl acetate, 20% ethanol, and 20% acetone.

[0074] Preferably, the solvent B in step (2) contains water or a mixed solvent of water and at least one of ethyl acetate, ethanol, liquid paraffin, and dichloromethane.

[0075] More preferably, the solvent B in step (2) is water.

[0076] Preferably, the microsphere continuous phase in step (2) further comprises a surfactant to improve the surface tension of the continuous phase.

[0077] More preferably, the surfactant is used in the microsphere continuous phase at 0.01 to 2 wt %, preferably 0.05 wt % to 0.8 wt %.

[0078] More preferably, the surfactant comprises at least one of sodium oleate, a Tween surfactant, polyvinyl alcohol, sodium lauryl sulfate, and sodium carboxymethylcellulose.

[0079] More preferably, the Tween surfactant includes at least one of Tween 20, Tween 40, Tween 60 and Tween 80, and preferably Tween 80.

[0080] Regarding preferred embodiments of the surfactant, 1) The mass percentage of sodium oleate in the microsphere continuous phase is in the range of 0.01 to 0.05%. 2) The mass percentage of Tween 80 in the microsphere continuous phase is in the range of 0.02 to 2%. 3) Polyvinyl alcohol surfactants include model numbers 03-88, 05-88, 17-88, 20-88, and 25-88, and preferably 05-88, and the polyvinyl alcohol aqueous phase concentration is in the range of 0.05 to 2.0%, preferably 0.2 to 0.4%. 4) The mass percentage of sodium lauryl sulfate (SDS) surfactant in the microsphere continuous phase is controlled to be in the range of 0.02 to 0.2%, preferably 0.05%. 5) The mass percentage of the carboxymethylcellulose sodium (CMC-Na) surfactant in the microsphere continuous phase is controlled to be in the range of 0.02 to 0.25%, preferably 0.05%.

[0081] Preferably, the temperature of the microsphere continuous phase in step (2) is 2 to 30°C.

[0082] Under this temperature condition, the API has higher quality stability and spheronization yield during the spheronization process.

[0083] More preferably, the temperature of the microsphere continuous phase in step (2) is 2 to 10°C.

[0084] Preferably, the pH of the microsphere continuous phase in step (2) is 6 to 11.

[0085] Under this pH condition, the diffusion of the dispersed phase into the continuous phase and the sphere formation quality are more stable.

[0086] More preferably, the pH of the microsphere continuous phase in step (2) is 6-8, and more specifically, it may be 7-8.

[0087] Preferably, the mass ratio of the microsphere continuous phase to the microsphere dispersed phase is 14.7 to 123.5:1.

[0088] More preferably, the mass ratio of the microsphere continuous phase to the microsphere dispersed phase is 20 to 50:1.

[0089] Preferably, the ratio of the total mass of each component of the taste-masking microsphere to the mass of solvent A is 6.5 to 21.5:100.

[0090] More preferably, the mass ratio of the total mass of each component of the taste-masking microsphere to solvent A is 6.5 to 17:100, and more specifically, it may be 6.5 to 15:100, 12 to 17:100, or 12 to 15:100.

[0091] Preferably, the reactor in step (3) has an inverted triangular pyramid shape, and the feed port is installed at the bottom of the reactor.

[0092] More preferably, the cross section of the inverted truncated pyramid is an isosceles triangle.

[0093] More preferably, the base angle β of said isosceles triangle is in the range of 45° to 75°, preferably 60°.

[0094] More preferably, the height of the reactor is from 10 cm to 200 cm.

[0095] More preferably, the angle α between the ridge line of the side plane of the inverted triangular pyramid and the base is in the range of 30°≦α<90°, preferably 60°≦α<90°, and even more preferably α=79° to 85°.

[0096] Preferably, two to four layers of stirring blades are installed in the reactor, and the stirring rotation speed is 50 to 900 rpm.

[0097] More preferably, the blade is a push-down type stirring blade.

[0098] Preferably, in step (3), a washing operation is carried out after filtration.

[0099] The present invention develops a novel microsphere reactor and microsphere process in which the spiral ascending path and ascending speed of the spherical droplets after their formation are controlled, and the ascending time of the spherical droplets in the aqueous phase is rationally controlled, so as to prevent the spherical droplets from rising to the liquid surface and imploding at the air / water interface to form an organic film before forming soft spheres.

[0100] The principle of producing taste-masking microspheres by the bottom diffusion method of the present invention is as follows.

[0101] The drug component and drug carrier are dissolved in a solvent, and the sphericity and dispersibility of the drug-containing microsphere dispersed phase in the microsphere continuous phase are adjusted by carefully adjusting the lipid solubility and water-solubility partition coefficient of the solvent. The drug-containing microsphere dispersed phase is dispersed at the bottom of the microsphere continuous phase, uniformly forming spheres. Due to the density difference between the microsphere dispersed phase and the microsphere continuous phase, the droplets that formed the spheres move to the upper layer of the liquid surface as the solvent hardens, and before reaching the liquid surface, they harden into semi-hardened (sphere wall hardened) microspheres with a certain hardness and mechanical strength.

[0102] Furthermore, the fluid formed by the inverted triangular pyramid reactor and multi-stage push-down agitation simultaneously has the effects of planar folding (as shown in Figure 1) and vertical vortex flow (designated by symbol A in Figures 2 and 3), causing the microspheres to rise in a curved line from the bottom of the reactor, as shown in Figure 4. By controlling the curing and rising time of the microspheres, it is possible to prevent the microspheres from exploding and forming a film when they reach the liquid surface. The horizontal folding effect of the inverted triangular pyramid reactor prevents the microspheres from agglomerating and blocking during the curing process, achieving the favorable effect of uniform microsphere particle size.

[0103] To control the stable and sustained diffusion of the microsphere-dispersed phase into the microsphere-continuous phase, the solvent used for the microsphere-dispersed phase is initially added to the microsphere-continuous phase in the amount required, and the solvent is then used as the mother liquid for the continuous phase when the microsphere-dispersed phase is added to the microsphere-continuous phase or when the microsphere-dispersed phase is added to the continuous phase. This controls the differences between and within lots.

[0104] Preferably, the filtrate obtained in step (3) (i.e., the mother liquor of the continuous phase) is applied to the next reaction in an amount of 10 to 80%, preferably 30 to 50% (i.e., the mass ratio of the filtrate to the microsphere continuous phase to be added next), or the solvent is recovered from the filtrate obtained in step (3), and the recovered solvent is used to prepare solvent A or solvent B.

[0105] The solvent recovered in step (3) contains ethanol, and when used to prepare solvent A, the ethanol is used at a mass concentration of 42.3% to 99.9%, more preferably 75% to 80%, by mass.

[0106] By circulating the continuous phase mother liquor, the solvent diffusion rate at the initial stage of microsphere formation can be controlled, the encapsulation rate can be improved, and the recovery and discharge of organic solvents can be reduced.

[0107] Preferably, before recycling the continuous phase mother liquor, a vacuum system is used to first form an evaporation membrane on the surface of the organic membrane, and the pressure difference between both sides of the membrane causes the evaporated organic solvent to pass through the organic membrane, condense, and cool, resulting in a mixed organic solvent liquid with a content of 90% or more. After recovery, the mixed solvent can be directly used in production after content measurement and secondary blending, thereby reducing the input of large solvent recovery tower equipment, reducing energy consumption, and realizing a circular economy and a green economy.

[0108] Preferably, the manufacturing process is a continuous process, in which a microsphere continuous phase (new microsphere continuous phase and continuous phase mother liquor are prepared and mixed in proportion) is continuously replenished at the bottom of the reactor by a feed pump, and a microsphere-containing suspension is continuously discharged to the middle of the microsphere reactor by a liquid level controller, filtered, and washed to obtain wet microspheres, and the filtered mother liquor is recovered and reused by an organic membrane.

[0109] Therefore, the microsphere manufacturing process of the present invention is clean and environmentally friendly, and can realize a circular economy and continuous production.

[0110] The present invention relates to a composition comprising the above-described taste-masking microspheres containing vonoprazan fumarate, or the taste-masking microspheres containing vonoprazan fumarate produced by the above-described production process.

[0111] Preferably, the composition comprises, by weight, 10-20 parts taste-masking microspheres, 500-1500 parts amoxicillin, and 50-150 parts rifabutin.

[0112] More preferably, the mass ratio of the taste masking microspheres to amoxicillin to rifabutin is 20:1000:50, 20:1000:75, 20:1000:100, 20:1000:125 or 20:1000:150.

[0113] More preferably, the amoxicillin and / or rifabutin are particles, micropellets or microspheres.

[0114] The present invention further relates to the use of the above composition for the manufacture of a medicament for a disease associated with H. pylori infection.

[0115] The present invention further relates to a formulation comprising the above-described taste-masking microspheres, or the taste-masking microspheres produced by the above-described production process, or the above-described composition.

[0116] Preferably, the formulation is a dry suspension, granules, capsules, tablets or films.

[0117] The beneficial effects of the present invention are as follows: Excellent taste-masking effect: When prepared as a suspension (pH 6.8) in an in vitro environment, the taste-masking microspheres of vonoprazan fumarate of the present invention have an API release rate of less than 0.5%, and in taste tests, the bitterness / off-flavor level was reduced by more than 90%, and in electronic tongue tests, the bitterness of basic salts was reduced by more than 85%, reaching 100%, demonstrating an excellent taste-masking effect. This will enable the development of single-component and multiple-component dry suspension formulations of drug ingredients, providing new dosage forms that are easy to take and have high compliance for children, the elderly, and patients with dysphagia. The microspheres have a small particle size, so the suspension is not rough when taken orally: Products manufactured using conventional granulation or micropellet coating techniques have a particle size of 300-1200 μm, which causes obvious roughness, whereas the taste-masking microspheres of the present invention have a small particle size, a concentrated particle size distribution, and a particle size of mainly 50-380 μm, which causes no roughness. The present invention solves the problem of roughness when taking dry suspensions orally, improves patient comfort and compliance, and is more suitable for children and elderly patients with swallowing difficulties. The present invention has an excellent taste-masking effect on many alkaloid drugs that have a strong bitter taste or unpleasant odor: The present invention has an excellent taste-masking effect on all compounds that have a bitter taste or unpleasant odor, with an in vitro release rate of 0.5% or less, a reduction in bitterness / unpleasant odor levels in taste tests of more than 85%, and no roughness, a significant texture effect, and improved medication compliance. High yield and encapsulation rate of microsphere products: The present invention uses a bottom diffusion method to produce microspheres, optimizing the composition of the dispersed and continuous phases to obtain a dispersed phase with solubility, sphericity, and diffusibility. The yield and encapsulation rate of the microsphere production process are generally above 60%. The encapsulation rate at room temperature is usually 60%-80%. After optimizing the compounding process, the encapsulation rate can reach above 90%, with the encapsulation rate of the microspheres reaching a maximum of 94.6%. The microsphere process allows for continuous, automated production: both water-soluble and fat-soluble drugs produced by the manufacturing process of the present invention can achieve excellent encapsulation and taste-masking effects. The present invention has a wide range of applications because the process is simple, does not require complex equipment, raw materials are easily available, and is suitable for continuous, automated, and scaled-up production. The taste-masking microspheres produced by the present invention have high integrity and roundness, with smooth and dense outer surfaces. The drug components are encapsulated in the microspheres so that they are uniformly dispersed as molecular dispersions within the microspheres, resulting in a good encapsulation effect and a fast drug dissolution rate in the stomach.

[0118] The present invention innovatively designs the reactor in an inverted triangular pyramid shape and employs a push-down stirring blade, thereby realizing the effects of hydrodynamic lateral folding and vertical vortex flow, and solving the problems of blocking (agglomeration) and explosion to form a membrane during the microsphere molding and hardening process.

[0119] The present invention solves the problems of combination preparations, such as API compatibility and mixed powder uniformity in a triple-drug compound dry suspension composition, by dissolving the problem of compatibility between API drugs and accessory materials during storage by having different APIs present as separate microspheres or particles in the mixed powder.

[0120] The composition of the present invention comprises taste-masking microspheres containing vonoprazan fumarate, amoxicillin, and rifabutin, and is intended for treating anti-H. pylori (H. pylori) infection, achieving clinical efficacy and safety and resolving the difficult problem of clinical drug resistance to anti-H. pylori infection.

[0121] The composition of the present invention has a consistent composition, replaces clinically-proven treatments, greatly simplifies the administration process, and can be taken twice a day after dissolving in water, without dietary restrictions, thereby improving patient compliance. [Brief explanation of the drawings]

[0122] [Figure 1] FIG. 1 is a schematic diagram showing the lateral folding effect of a reactor whose cross section is an equilateral triangle. [Figure 2] FIG. 2 is a schematic diagram showing the vertical vortex flow effect of an inverted triangular pyramid containing a push-down type stirring blade. [Figure 3] FIG. 3 is a side view photograph showing the effect of longitudinal vortex flow in the microsphere manufacturing process. [Figure 4] FIG. 4 is a schematic diagram showing the ascending trajectory of a microsphere. [Figure 5] FIG. 5 is a schematic diagram showing the structure of the inverted triangular pyramid reactor of the present invention. [Figure 6] Figure 6 is a diagram of the 1# reactor. [Figure 7] Figure 7 is a diagram of the 2# reactor. [Figure 8] FIG. 8 is a schematic diagram showing the structure of a syringe with upper and lower openings. [Figure 9] FIG. 9 is an electronic tongue test radar diagram of taste masking microspheres with lot number FC509-2. [Figure 10] FIG. 10 is a scanning electron microscope image of the appearance of vonoprazan fumarate microspheres. [Figure 11] FIG. 11 is a cross-sectional view of vonoprazan fumarate microspheres taken by a scanning electron microscope. [Figure 12] FIG. 12 is a microscopic view of vonoprazan fumarate microspheres. [Figure 13] FIG. 13 is a view of the appearance of the extruded spheroidized particles of Comparative Example 4 taken by a scanning electron microscope. [Figure 14] FIG. 14 is a cross-sectional view of the extruded spheroidized particles of Comparative Example 4 taken by a scanning electron microscope. [Figure 15] FIG. 15 is a view of the appearance of the wet-granulated fluidized-bed coated particles of Comparative Example 5 taken by a scanning electron microscope. [Figure 16] FIG. 16 is a cross-sectional view of the wet-granulated fluidized-bed coated particles of Comparative Example 5 taken by a scanning electron microscope. [Figure 17] FIG. 17 is a scanning electron microscope view of the appearance of the fluidized bed sprayed micropellet coating of Comparative Example 6. [Figure 18] FIG. 18 is a cross-sectional view of the fluidized bed sprayed micropellet coating of Comparative Example 6 taken by a scanning electron microscope. DETAILED DESCRIPTION OF THE INVENTION

[0123] The present invention will be further described below with reference to specific examples, and the advantages and features of the present invention will become more apparent from the description. However, these examples are merely illustrative and do not limit the scope of the present invention. Those skilled in the art may modify or replace the details and forms of the technical solutions of the present invention without departing from the spirit and scope of the present invention, and it should be understood that all such modifications and replacements are within the scope of the claims of the present invention.

[0124] A schematic diagram of the structure of the inverted triangular pyramid reactor of the present invention is shown in Figure 5. Here, the angle between the ridge of the side plane and the bottom surface is α, and the base angle of the isosceles triangle of the bottom surface is β.

[0125] The reactor #1 of the present invention is a 3L visual triangular pyramid reactor, with ∠α=84.2°, ∠β=60°, a volume of 3L, and equipped with a three-stage push-down stirring blade, as specifically shown in Figure 6.

[0126] The reactor #2 of the present invention is an 8L visual triangular pyramid reactor, with ∠α=79.1°, ∠β=60°, a volume of 8L, and equipped with a three-stage push-down stirring blade, as specifically shown in Figure 7.

[0127] In each of the following examples, the API is a type of raw material drug such as vonoprazan fumarate, and all except for Example 36 are vonoprazan fumarate.

[0128] In the following examples, "N7, N10, N22, N50" are the model numbers of ethyl cellulose, which are obtained from Shenzhen Youpuhui Pharmaceutical Co., Ltd.

[0129] In each of the following examples, the plasticizer is triethyl citrate.

[0130] In the following examples, EPO is Eudragit EPO (polyacrylic resin IV powder), E100 is Eudragit E100 (polyacrylic resin IV particles), RSPO is Eudragit RSPO (quaternary ammonium group methacrylate copolymer type B powder), and RLPO is Eudragit RLPO (quaternary ammonium group methacrylate copolymer type A powder).

[0131] In the following examples, 30D100P is Kollicoat Smartseal 30D100P (methyl methacrylate-diethylaminoethyl methacrylate copolymer).

[0132] In each of the following examples, AEA is Sankyo's polyvinyl acetal diethylaminoacetate.

[0133] In the following examples, BHT is dibutylhydroxytoluene, obtained from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.

[0134] In each of the following examples, ethanol is absolute ethanol. When aqueous ethanol is used, the amount of water to be replenished in solvent A in step (1) can be calculated based on the amount of aqueous ethanol used.

[0135] Basic implementation example Manufacturing process: The dispersed phase is fed into the bottom of the reactor by needle injection, and the number of feeding ports is 1-2 on each side, totaling 3-6. The feed stirring speed is 100-180 rpm, and the feed time is 10-20 min (peristaltic pump model: iPump 2S, feed rotation speed is 2-15 rpm). The post-feed stirring speed is 80-120 rpm, and the stirring time is 10-60 min. After filtering, washing, and drying, the taste-masking microspheres are obtained. Specifically, the washing process involves adjusting the pH of purified water to 6.5 to 7.5 and washing twice with 50 mL of water each. Specifically, the drying process involved drying with air at room temperature for 1 hour, then heating to 40°C and drying for 2 hours.

[0136] The taste-masking microspheres in each of the following examples were all manufactured based on this basic example. [Example]

[0137] Example 1 Purpose of the experiment: Check and select the possible models of Tween (0.2%) aqueous solution Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solutes:API, EPO, N10, magnesium oxide, triethyl citrate, magnesium stearate, silica, titanium dioxide, and talc was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g). Continuous phase: 0.2% Tween series aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: In the basic example, the number of supply ports is three, one on each side, the supply stirring speed is 150 rpm, and the supply time is 15 min (peristanic pump model number: iPump2S, supply rotation speed is 10 rpm), the stirring speed after supply is 100 rpm, and the stirring time is 30 min.

[0138] The indices of the produced taste-masking microspheres are shown in Table 1.

[0139] [Table 1] Note: The "content" indicated by a refers to the content of API in the final taste-masking microspheres, and the same applies to the following examples. b represents the test method for the 30-minute dissolution rate. The dissolution medium is a pH 4.5 acetate buffer solution, the volume is 900 mL, the paddle method is 50 rpm, and the temperature is 37°C. The test method for each of the following examples is the same. [Example]

[0140] Example 2 Experimental objective: To confirm and optimize the range of possible concentrations of Tween 80 aqueous solution Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, triethyl citrate, and titanium dioxide was 5.6:15:37:15:5:1 (total amount 7.86 g). Continuous phase: Tween 80 aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0141] The indices of the produced taste-masking microspheres are shown in Table 2.

[0142] [Table 2] [Example]

[0143] Example 3 Purpose of the experiment: To confirm and select the possible models of polyvinyl alcohol (0.4%) aqueous solution. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, triethyl citrate, and titanium dioxide was 5.6:15:37:15:1:1 (total amount 7.46 g). Continuous phase: 0.4% aqueous solution of polyvinyl alcohol series of different model numbers, continuous phase temperature: room temperature, continuous phase pH: 7. Manufacturing process: same as in Example 1.

[0144] The indices of the produced taste-masking microspheres are shown in Table 3.

[0145] [Table 3] [Example]

[0146] Example 4 Experimental objective: To identify and optimize the range of possible concentrations for aqueous polyvinyl alcohol (05-88) solutions. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, titanium dioxide, and triethyl citrate was 5.6:15:37:15:1:1 (total amount 7.46 g). Continuous phase: Polyvinyl alcohol (05-88) series aqueous solution of different concentrations, continuous phase temperature: room temperature, continuous phase pH: 7. Manufacturing process: In the basic example, the number of supply ports is three, one on each side, the supply stirring speed is 120 rpm, and the supply time is 20 min (peristanic pump model: iPump2S, supply rotation speed is 4 rpm), the stirring speed after supply is 80 rpm, and the stirring time is 10 min.

[0147] The indices of the produced taste-masking microspheres are shown in Table 4.

[0148] [Table 4] [Example]

[0149] Example 5 Experimental objective: To confirm the feasibility of the concentration range of sodium oleate solution and to select the optimum one. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solutes:API, EPO, N10, magnesium oxide, triethyl citrate, magnesium stearate, silica, titanium dioxide, and talc was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g). Continuous phase: different low concentration sodium oleate series aqueous solution, continuous phase temperature: room temperature, continuous phase pH: 7. Manufacturing process: same as in Example 1.

[0150] The indices of the produced taste-masking microspheres are shown in Table 5.

[0151] [Table 5] [Example]

[0152] Example 6 Experimental objective: To confirm and optimize the range of possible concentrations of SDS (sodium lauryl sulfate) aqueous solution. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solutes:API, EPO, N10, magnesium oxide, triethyl citrate, magnesium stearate, silica, titanium dioxide, and talc was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g). Continuous phase: SDS series aqueous solution of different concentrations, continuous phase temperature: room temperature, continuous phase pH: 7. Manufacturing process: In the basic example, the number of supply ports is three, one on each side, the supply stirring speed is 180 rpm, and the supply time is 10 min (peristanic pump model: iPump2S, supply rotation speed is 15 rpm), the stirring speed after supply is 120 rpm, and the stirring time is 60 min.

[0153] The indices of the produced taste-masking microspheres are shown in Table 6.

[0154] [Table 6] [Example]

[0155] Example 7 Experimental objective: To confirm and optimize the range of possible concentrations of CMC-Na (carboxymethylcellulose sodium) aqueous solution. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solutes:API, EPO, N10, magnesium oxide, triethyl citrate, silica, povidone, titanium dioxide, and talc was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g). Continuous phase: aqueous solutions of different CMC-Na concentrations, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0156] The indices of the produced taste-masking microspheres are shown in Table 7.

[0157] [Table 7] [Example]

[0158] Example 8 Experimental objective: To confirm the possibility of a surfactant-free continuous phase. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, triethyl citrate, and titanium dioxide was 5.6:15:37:15:5:1 (total amount 7.86 g). Continuous phase: shown in Table 8. Temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0159] The indices of the produced taste-masking microspheres are shown in Table 8.

[0160] [Table 8] [Example]

[0161] Example 9 Experimental objective: To confirm the possible range of test temperatures for 0.4% polyvinyl alcohol aqueous solution and to select the optimum one. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, E100, N10, magnesium oxide, triethyl citrate, povidone, silica, talc, and titanium dioxide was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: the temperature shown in Table 9, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0162] The indices of the produced taste-masking microspheres are shown in Table 9.

[0163] [Table 9] [Example]

[0164] Example 10 Experimental objective: To confirm and optimize the process feasibility range for the application rate of the continuous phase. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, triethyl citrate, and titanium dioxide was 5.6:15:37:15:5:1 (total amount 7.86 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution applied in the proportions shown in Table 10, continuous phase temperature: room temperature, continuous phase pH: 7. Manufacturing process: same as in Example 1.

[0165] The indices of the produced taste-masking microspheres are shown in Table 10.

[0166] [Table 10] [Example]

[0167] Example 11 Purpose of the experiment: To identify and optimize the possible range of pH values for a 0.4% aqueous solution of polyvinyl alcohol. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, E100, N10, magnesium oxide, triethyl citrate, povidone, magnesium stearate, talc, and titanium dioxide was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: value shown in Table 11. Manufacturing process: same as in Example 1.

[0168] The indices of the produced taste-masking microspheres are shown in Table 11.

[0169] [Table 11] [Example]

[0170] Example 12 Experimental purpose: To confirm and select the process feasible range for the blending ratio of ethyl acetate and ethanol. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate + ethanol total 65 mL, water added amount 6.5 mL. The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide was 1:2.68:6.61:2.68 (total amount 7.26 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0171] The indices of the produced taste-masking microspheres are shown in Table 12.

[0172] [Table 12] [Example]

[0173] Example 13 Purpose of the experiment: To confirm and select the range of possibilities for the process (non-pH value dependent carrier) regarding the blending ratio of ethyl acetate and ethanol. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate + ethanol, total 66 mL. The mass ratio of dispersed phase solute:API, RSPO, RLPO, N10, fumaric acid, succinic acid, BHT, titanium dioxide, and TEC was 1:0.6:2.4:6:0.6:0.1:0.02:0.05:0.2 (total amount 5.48 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (5°C), continuous phase pH: 6. Manufacturing process: same as in Example 1.

[0174] The indices of the produced taste-masking microspheres are shown in Table 13.

[0175] [Table 13] [Example]

[0176] Example 14 Experimental objective: To confirm the process feasibility of different two-phase mixed solvents. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The volume ratio of dispersed phase solvent to two-phase mixed solvent (shown in Table 14) was 1.5:1, totaling 65 mL, and 6.5 mL of water. The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide was 1:2.68:6.61:2.68 (total amount 7.26 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0177] The indices of the produced taste-masking microspheres are shown in Table 14.

[0178] [Table 14] [Example]

[0179] Example 15 Experimental objective: To confirm the process feasibility range for the amount of water added and to select the optimum one. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The mass ratio of dispersed phase solvent: ethyl acetate, ethanol (anhydrous) was 1.69:1 (total 55.5 g), and water was added in the amounts shown in Table 15. The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, triethyl citrate, and titanium dioxide was 5.6:15:37:15:5:1 (total amount 7.86 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0180] The indices of the produced taste-masking microspheres are shown in Table 15.

[0181] [Table 15] remarks: ※ The corresponding percentage content of hydrous ethanol refers to the amount of hydrous ethanol added (which can reduce the cost of ethanol procurement and recovery) to achieve the minimum ethanol content required for the blending ratio of ethyl acetate, ethanol, and water. For example, if 6.5 mL of water is required for blending, the mass concentration of the corresponding added (or recovered) hydrous ethanol must be 75.9% or more. If the mass concentration of the newly purchased or recovered ethanol is 80%, then the amount of 80% hydrous ethanol to be added can be calculated based on the blending ratio of anhydrous ethanol, and the difference between the amount of water in the calculated process blending ratio can be added. [Example]

[0182] Example 16 Experimental objective: To confirm the process feasibility of using a water-free dispersed phase solvent. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The mass ratio of dispersed phase solvent: ethyl acetate, ethanol (anhydrous) was 4.56:1 (57.1 g in total). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, triethyl citrate, and titanium dioxide was 5.6:22:37:15:7:1 (total amount 8.76 g). Continuous phase: 0.2% Tween 80 aqueous solution, temperature of continuous phase: low temperature (3.5°C), pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0183] The indices of the produced taste-masking microspheres are shown in Table 16.

[0184] [Table 16] [Example]

[0185] Example 17 Experimental objective: To confirm the processability of three-phase mixed solvents with different blend ratios. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The volume ratio of dispersed phase solvent: three-phase mixed solvent (shown in Table 17) was 1.5:0.5:0.5, totaling 65 mL, and water was 6.5 mL. The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide was 1:2.68:6.61:2.68 (total amount 7.26 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0186] The indices of the produced taste-masking microspheres are shown in Table 17.

[0187] [Table 17] [Example]

[0188] Example 18 Experimental objective: To verify and optimize the processability of different types of pH-dependent carriers. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 7.8:3.9:1 (total amount 57.1 g). The mass ratio of dispersed phase solute:API, different types of carrier, N10, magnesium oxide, and triethyl citrate was 1.12:3:9.24:1.16:1 (total amount 7.76 g). The type of each carrier is shown in Table 18. Continuous phase: 0.4% polyvinyl alcohol (05-88) solution, temperature of continuous phase: 9°C, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0189] The indices of the produced taste-masking microspheres are shown in Table 18.

[0190] [Table 18] [Example]

[0191] Example 19 Experimental objective: To verify and optimize the processability of different types of non-pH dependent carriers. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous) mass ratio was 20:1 (total amount 59 g). The mass ratio of dispersed phase solute:API, different types of carriers, N10, fumaric acid, succinic acid, BHT, titanium dioxide, and TEC was 1:3:6:0.6:0.1:0.02:0.05:0.2 (total amount 5.48 g). The type of each carrier is listed in Table 19. Continuous phase: 0.4% polyvinyl alcohol (05-88) solution, continuous phase temperature: low temperature (5°C), continuous phase pH: 6. Manufacturing process: same as in Example 1.

[0192] The indices of the produced taste-masking microspheres are shown in Table 19.

[0193] [Table 19] [Example]

[0194] Example 20 Experimental objective: To confirm and optimize the process feasibility of combining different types of non-pH dependent carriers. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous) mass ratio was 20:1 (total amount 59 g). The mass ratio of dispersed phase solute:API, different types of carriers, N10, fumaric acid, succinic acid, BHT, titanium dioxide, and TEC was 1:3:6:0.6:0.1:0.02:0.05:0.2 (total amount 5.48 g). The type of each carrier is listed in Table 20. Continuous phase: 0.4% polyvinyl alcohol (05-88) solution, continuous phase temperature: low temperature (6°C), continuous phase pH: 6. Manufacturing process: same as in Example 1.

[0195] The indices of the produced taste-masking microspheres are shown in Table 20.

[0196] [Table 20] [Example]

[0197] Example 21 Experimental objective: To confirm and select the processability range for the ratio of pH-dependent carrier (EP0) and skeletal carrier (N10). Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, magnesium oxide was 1:2.68 (charge amount 2.06 g), and the amounts of EPO and N10 used were added according to the charge ratios in Table 21 (total charge amount of solute: 7.26 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0198] The indices of the produced taste-masking microspheres are shown in Table 21.

[0199] [Table 21] [Example]

[0200] Example 22 Experimental objective: To confirm and optimize the process feasibility of N series skeletal carriers and pH-dependent carrier models. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, magnesium oxide was 1:2.68:2.68 (total amount 3.56 g), and the amounts of ethyl cellulose of different models added are shown in Table 22. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0201] The indices of the produced taste-masking microspheres are shown in Table 22.

[0202] [Table 22] [Example]

[0203] Example 23 Experimental objective: To confirm and optimize the process feasibility of N series skeletal carriers, non-pH dependent carrier models. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The mass ratio of dispersed phase solvent: ethyl acetate, ethanol (anhydrous) was 20:1 (total amount 59 g). The mass ratio of dispersed phase solutes (API, RSPO, RLPO, ethyl cellulose type, fumaric acid, succinic acid, BHT, titanium dioxide, and TEC) was 1:0.6:2.4:6:0.6:0.1:0.02:0.05:0.2 (total amount: 5.48 g). The type of each skeletal carrier is shown in Table 23. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (5°C), continuous phase pH: 6. Manufacturing process: same as in Example 1.

[0204] The indices of the produced taste-masking microspheres are shown in Table 23.

[0205] [Table 23] [Example]

[0206] Example 24 Experimental objective: To confirm the process feasibility range of magnesium oxide addition percentage and to select the optimum one. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, E100 was 1:2.68 (charge amount 2.06 g), and magnesium oxide was added in the proportions shown in Table 24 (total charge amount of solute 7.26 g, total amount of N7 and magnesium oxide used 5.2 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0207] The indices of the produced taste-masking microspheres are shown in Table 24.

[0208] [Table 24] [Example]

[0209] Example 25 Experimental objective: To confirm and optimize the process feasibility range for the addition and stirring time of magnesium oxide. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, E100, N7, magnesium oxide was 1:2.68:6.61:2.68 (total amount 7.26 g). The stirring time after adding magnesium oxide was controlled in Table 25. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0210] The indices of the produced taste-masking microspheres are shown in Table 25.

[0211] [Table 25] As can be seen from Table 25, the addition and stirring time of magnesium oxide has little effect on the yield, content, encapsulation rate and dissolution rate of the product. [Example]

[0212] Example 26 Experimental objective: To verify and optimize the process feasibility for different types of alkalizing agents. Process conditions: reactor model number is -1#, continuous phase volume is 3L. Stirring type: three-stage push-down paddle stirring. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, N10, alkalizing agent, triethyl citrate, silica, povidone, titanium dioxide, and talc was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g), and the type of alkalizing agent is shown in Table 26. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0213] The indices of the produced taste-masking microspheres are shown in Table 26.

[0214] [Table 26] [Example]

[0215] Example 27 Experimental objective: To confirm the process feasibility without adding alkalizing agents. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: the mass ratio of ethyl acetate, ethanol (anhydrous), and water was 7.2:1.58:1 (total amount 63.6 g). The mass ratio of dispersed phase solute:API, EPO, N10, triethyl citrate, and titanium dioxide was 5.6:18:53:5:1 (charge amount: 8.26 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (4.5°C), continuous phase pH: 7. Manufacturing process: same as in Example 1.

[0216] The indices of the produced taste-masking microspheres are shown in Table 27.

[0217] [Table 27] [Example]

[0218] Example 28 Experimental objective: To verify and optimize the process feasibility of different types of sunscreens. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, and light-blocking agent was 5.6:15:40:10:1 (total amount 7.2 g), and the type of light-blocking agent is shown in Table 28. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0219] The indices of the produced taste-masking microspheres are shown in Table 28.

[0220] [Table 28] [Example]

[0221] Example 29 Experimental objective: To verify and optimize the processability for different types of plasticizers. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, E100, N7, magnesium oxide, and plasticizer was 1.12:3:7.40:3:1 (total amount 7.76 g). The type of plasticizer is listed in Table 29. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0222] The indices of the produced taste-masking microspheres are shown in Table 29.

[0223] [Table 29] [Example]

[0224] Example 30 Purpose of the experiment: To confirm the process feasibility range for the external addition ratio of fumaric acid. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, E100, N7, magnesium oxide, triethyl citrate, and titanium dioxide was 3.7:10:24.7:10:3.3:1 (charge amount 7.91 g), and fumaric acid was added externally in the proportions shown in Table 30. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0225] The indices of the produced taste-masking microspheres are shown in Table 30.

[0226] [Table 30] [Example]

[0227] Example 31 Experimental objective: To confirm the process feasibility range of the proportion of API in the solid charge and to select an optimal one. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The mass ratio of dispersed phase solvent: ethyl acetate, ethanol (anhydrous) was 1.71:1 (the total amount of the FC511-1, FC511-2, and FC511-3 batches was 55.6 g, and the total amount of the FC511-7 batch was 27.8 g), and the amount of water added is shown in Table 31. The mass ratio of dispersed phase solute: E100, magnesium oxide, and N7 was 1:1:2.47 (the three components were charged in the FC511-7 batch in Table 27 at 3.35 g, and in the other batches at 6.7 g), and the amounts of API added are shown in Table 27. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0228] The indices of the produced taste-masking microspheres are shown in Table 31.

[0229] [Table 31] [Example]

[0230] Example 32 Purpose of the experiment: To confirm and optimize the process range for the ratio of the total amount of dispersed phase solute to the total amount of dispersed phase solvent. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: the mass ratio of ethyl acetate, ethanol (anhydrous), and water was 7.8:4.6:1 (total amount of solvent A: 60.2 g). The mass ratio of dispersed phase solute:API, E100, magnesium oxide, and N7 was 1:2.68:1.04:8.25, and the amount of API charged is shown in Table 32. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0231] The indices of the produced taste-masking microspheres are shown in Table 32.

[0232] [Table 32] [Example]

[0233] Example 33 Experimental objective: To confirm the process feasibility range of the blending ratio of the continuous phase and the dispersed phase and to select the optimum one. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 7.0:4.1:1. The mass ratio of dispersed phase solute:API, E100, magnesium oxide, and N7 was 1:2.68:1.04:8.25, and the total amount of dispersed phase solvent and dispersed phase solute added is shown in Table 33. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0234] The indices of the produced taste-masking microspheres are shown in Table 33.

[0235] [Table 33] [Example]

[0236] Example 34 Experimental objective: To confirm and optimize the process feasibility of the injection location of the microsphere reactor. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 8.8:3.9:1 (total amount 61.5 g). The mass ratio of dispersed phase solute:API, E100, N7, magnesium oxide, triethyl citrate, povidone, magnesium stearate, titanium dioxide, and talc was 5.6:15:46.2:5.8:5:2:2:1:1 (total amount 8.36 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: The only difference in the manufacturing process of the taste-masking microspheres in Example 1 was the injection position, while the other conditions were the same. The injection position was as shown in Table 34.

[0237] The indices of the produced taste-masking microspheres are shown in Table 34.

[0238] [Table 34] [Example]

[0239] Example 35 Experimental objective: To confirm and optimize the process feasibility for ethyl acetate, acetone and water. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The mass ratio of dispersed phase solvent: ethyl acetate, acetone, and water was 7.8:3.9:1 (total amount: 57.1 g). The mass ratio of dispersed phase solutes:API, EPO, N7, magnesium oxide, triethyl citrate, povidone, magnesium stearate, titanium dioxide, and talc was 5.6:15:37:15:5:2:2:1:1 (total amount 8.36 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (9°C), continuous phase pH: 7. Manufacturing process: In the basic example, the number of supply ports is three, one on each side, the supply stirring speed is 140 rpm, and the supply time is 18 min (peristanic pump model: iPump2S, supply rotation speed is 12 rpm), the stirring speed after supply is 100 rpm, and the stirring time is 30 min.

[0240] The indices of the produced taste-masking microspheres are shown in Table 35.

[0241] [Table 35] [Example]

[0242] Example 36 Experimental objective: To confirm and optimize the process feasibility for ethyl acetate, ethanol and water. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 7.8:3.9:1 (total amount 57.1 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, and triethyl citrate was 1.12:3.2:7.2:3.0:1 (total amount 7.76 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: low temperature (10°C), pH of continuous phase: 7. Manufacturing process: In the basic example, the number of supply ports is three, one on each side, the supply stirring speed is 150 rpm, and the supply time is 16 min (peristanic pump model number: iPump2S, supply rotation speed is 10 rpm), the stirring speed after supply is 100 rpm, and the stirring time is 30 min.

[0243] The indices of the produced taste-masking microspheres are shown in Table 36.

[0244] [Table 36] [Example]

[0245] Example 37 Experimental purpose: To confirm the process feasibility for the application of ethyl acetate and ethanol mixed solvent recovery. Process conditions: reactor model number is -1#, continuous phase volume is 3L. The organic solvent is recycled and used, and the content of ethyl acetate in the recycled solvent is 58.55%, and the content of ethanol is 30.22%. Dispersed phase solvent: 60 g of the recovered mixed solvent was supplemented with 2.4 g of absolute ethanol. The mass ratio of ethyl acetate, ethanol, and water was 5.3:3.1:1. The mass ratio of dispersed phase solute:API, E100, N7, magnesium oxide, triethyl citrate, and titanium dioxide was 3.7:10:24.7:10:3.3:1 (charge amount: 7.91 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0246] The indices of the produced taste-masking microspheres are shown in Table 37.

[0247] [Table 37] [Example]

[0248] Example 38 Experimental purpose: To confirm the process feasibility for the application of ethyl acetate and acetone mixed solvent recovery. Process conditions: reactor model number is -1#, continuous phase volume is 3L. The organic solvent is recycled and used, and the content of ethyl acetate in the recycled solvent is 58.26%, and the content of acetone is 29.40%. Dispersed phase solvent: The recovered mixed solvent was 60 g, supplemented with 3.0 g of acetone. The mass ratio of ethyl acetate, acetone, and water was 4.7:2.8:1. The mass ratio of dispersed phase solute:API, E100, N7, magnesium oxide, and triethyl citrate was 1.12:3:9.24:1.16:1 (total amount 7.76 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 1.

[0249] The indices of the produced taste-masking microspheres are shown in Table 38.

[0250] [Table 38] [Example]

[0251] Example 39 Experimental objective: To evaluate the reactor equipment and confirm the process feasibility. Process conditions: reactor model number is -2#, continuous phase 6L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 9.8:3.8:1 (total amount 99.6 g). The mass ratio of dispersed phase solute:API, E100, N7, magnesium oxide, triethyl citrate, povidone, magnesium stearate, titanium dioxide, and talc was 5.6:15:46.2:5.8:3.3:2:2:1:1 (total amount 12.29 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (9°C), continuous phase pH: 7. Injection parameters: There were two injection points on each side, for a total of six, and one outlet on the central side. A syringe with two openings at the top and bottom (Figure 8) was used for injection. The continuous phase and dispersed phase were supplied synchronously. The rotation speed of the continuous phase was 65 rpm (peristaltic pump model: iPump BS100-1A), and the rotation speed of the dispersed phase was 15 rpm (peristaltic pump model: iPump 2S). The injection time was 17 minutes.

[0252] The indices of the produced taste-masking microspheres are shown in Table 39.

[0253] [Table 39] [Example]

[0254] Example 40 Purpose of the experiment: To investigate the feasibility of producing taste-masking microspheres using API drug substances such as berberine hydrochloride and to verify the experimental results. Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. The mass ratio of dispersed phase solvent: ethyl acetate, ethanol, and water was 7.8:3.9:1 (total amount: 57.1 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, and triethyl citrate was 1.12:3:9.24:1.16:1 (total amount 7.76 g). Specific APIs are shown in Table 40. Continuous phase: 0.4% polyvinyl alcohol (05-88), continuous phase temperature: low temperature (9°C), continuous phase pH: 7. Manufacturing process: same as in Example 1.

[0255] The efficacy evaluation of taste masking microspheres made with different APIs is shown in Table 40.

[0256] [Table 40] TIFF2025527357000042.tif254170TIFF2025527357000043.tif253170Note: The test methods for the content and in vitro release rate of the taste-masking microspheres prepared with other APIs in Example 40 are the same as those for the vonoprazan fumarate taste-masking microspheres.

[0257] Note: The in vitro API release rate (pH = 6.8) refers to the percentage of the amount of API dissolved during the in vitro preparation process relative to the total amount of API in the formulation, in a simulation in which water (neutral water) is added to dry suspensions, granules, etc. to prepare a suspension solution or suspended particles before administration.

[0258] Cefcapene, cefetamet, meropenem, moxifloxacin, linezolid, fluvoxamine maleate, rebamipide, cefteram pivoxil, verapamil, quetiapine, amisulpride, sulpiride, metoprolol, pravastatin, atomoxetine, escitalopram, tilidine hydrochloride, ondansetron, vortioxetine hydrobromide, domperidone, zopiclone, roxatidine, loperamide, diphenhydramine, epinastine, mirabegron, solifenacin, irbesartan, vortioxetine hydrobromide, ticagrelor, captopril, colesevelam hydrochloride, rasagiline, nintedanib ethanesulfonate, enaraprazole For drugs such as rilmaleate, apremilast, piroxicam, flutamide, varenicline tartrate, pazopanib, pramipexole, ripretinib, tamsulosin hydrochloride, linagliptin, micafungin, aprepitant, tigecycline, roflumilast, tenapanol hydrochloride, tulobuterol, tramadol hydrochloride, acetaminophen, colchicine, rivaroxaban, lacosamide, teneligliptin, dabigatran etexilate, and odebixibat, the API content of the microspheres reached 3% or more, the in vitro release rate was less than 0.5%, and the percentage reduction in bitterness / off-flavor levels was greater than 85% without any grittiness.

[0259] Test Example 1 In vitro release rate test of taste masking microspheres Test method for Vonoprazan fumarate taste-masking microspheres: Measurement method: Performed according to high-performance liquid chromatography (Chinese Pharmacopoeia 2020, Part 4 General Rule 0512). Chromatography conditions: C18, 4.6 mm x 150 mm, 5 μm, 0.02 M dipotassium hydrogen phosphate buffer (pH 5.0)-acetonitrile (65:35) as the mobile phase, detection wavelength 230 nm, column temperature 35 °C. Sample solution for measuring in vitro release rate: 400 mg of vonoprazan fumarate taste-masking microspheres (containing approximately 20 mg of vonoprazan) prepared in each example was taken, precisely weighed, placed in a beaker, 20 mL of water (pH 6.8) was added, stirred for 30 seconds, allowed to stand for 30 minutes, and then sampled. When filtered through nylon 0.45 μm and nylon 0.22 μm filter membranes, respectively, the first 2 mL of filtrate was discarded and the remaining filtrate was taken as the sample solution. Sample solution for content measurement: 10 mg of the vonoprazan fumarate taste-masking microspheres (containing approximately 0.5 mg of vonoprazan) prepared in each example was taken and precisely weighed, placed in a 10 mL volumetric flask, 1 mL of acetonitrile was added, ultrasonicated for 3 minutes, diluted to the mark with diluent, shaken uniformly, and filtered through a 0.45 μm nylon filter membrane. The first 2 mL of the filtrate was discarded, and the remaining filtrate was taken as the sample solution.

[0260] The results for vonoprazan fumarate taste-masking microspheres are shown in Table 41.

[0261] [Table 41] TIFF2025527357000045.tif56170 In each example of the present invention, the taste-masking microspheres prepared using vonoprazan fumarate have an in vitro release rate of 0.5% or less.

[0262] Remarks: For FCC lot numbers, the microspheres were manufactured using a non-pH-dependent carrier, and the preparation method for the in vitro release rate test was as follows: 400 mg of the taste-masking microspheres of vonoprazan fumarate manufactured in each example (containing approximately 20 mg of vonoprazan) was taken, precisely weighed, placed in a beaker, 20 mL of water (pH 6.8) was added, stirred for 30 seconds, allowed to stand for 3 minutes, sampled, and filtered through nylon 0.45 μm and nylon 0.22 μm filter membranes, respectively; the first 2 mL of filtrate was discarded, and the latter filtrate was obtained.

[0263] Test Example 2 Taste masking effect test of taste masking microspheres 1. Taste test The taste-masking texture test method is the same for the taste-masking microspheres of the present invention produced by each API, and will be specifically explained below using the taste-masking microspheres of vonoprazan fumarate as an example. (1) Preparation of bitterness standard solution Approximately 0.25 g of raw drug (vonoprazan) was taken and diluted to a 0.1% aqueous solution of vonoprazan to obtain a solution with four bitterness levels. The above solution was then diluted 100, 20, 10, and 5 times to obtain standard solutions with bitterness levels of 0, 1, 2, and 3. The bitterness standards are shown in Table 42.

[0264] [Table 42] (2) Preparation of standard solutions of samples Four batches of vonoprazan microspheres were weighed to prepare suspensions containing vonoprazan at 1 mg / mL (0.1%), which were then stirred for 30 seconds and allowed to stand for 30 minutes. These suspensions were used as test samples. The sample numbers are shown in Table 43.

[0265] [Table 43] Two healthy volunteers (six males and six females) aged 22 to 35 years old rinsed their mouths with water three times before the test. They then tested 1 mL of the standard solution in the following order: purified water, bitter standard solutions 0, 1, 2, 3, and 4. The bitter standard solutions were dropped onto the center of the tongue and allowed to remain in the mouth for approximately 30 seconds to create a bitterness standard for individual differences. Samples should be tested at intervals of at least 15 minutes. For the sample test, each subject texture-tested the sample according to the individualized standard and method using the bitterness standard solution and recorded the bitterness level. (4) Bitterness experiment results 1. Results of bitterness test of standard solution The results of the bitterness test of the standard solution are shown in Table 44.

[0266] [Table 44] 2. Results of the bitterness experiment on the sample solution The test results for the taste-masking microspheres produced in each example are shown in Table 45.

[0267] [Table 45] 3. Results of the roughness test for the sample solution: presence of roughness was scored as 1, and absence of roughness was scored as 0. The results are shown in Table 46.

[0268] [Table 46] In the present invention, the taste masking microspheres produced by each API in each Example were tested for texture effects. As a result, each taste masking microsphere had a significant effect in terms of bitterness reduction, with a bitterness reduction level of 85% or more, and was not rough.

[0269] 2. Taste recognition test Device model number: SA402B taste recognition device (electronic tongue) manufactured by Japan Insent Co., Ltd., a lipid membrane potential-type electronic tongue. The lipid membrane consists of multiple potential-type electrodes and can sense and distinguish the taste of different sample solutions, just like the lipid membrane of the cell wall of human taste cells. Bitterness analysis system sensor and performance description: AN0: Bitterness of base salts (B-bitterness2) BT0: Basic bitterness (H-bitterness) Sample preparation method: API solution: Approximately 27 mg of API sample was weighed and placed in a 40 mL volumetric flask, and water was added up to the scale to dissolve, followed by shaking to homogenize. Taste masking microsphere solution: Approximately 400 mg of taste masking microspheres (lot number: FC509-2) was weighed out and placed in a 40 mL volumetric flask. Water was added up to the scale, the flask was shaken for 30 seconds, allowed to stand for 10 minutes, and then filtered through filter paper. The filtrate was used as the sample solution. Both concentrations are approximately 0.5 mg / mL as vonoprazan. Test Method Equilibration: The sensor was first washed with the cleaning solution for 90 s, then washed with the reference solution for 120 s, then washed with another reference solution for 120 s, and the sensor was zeroed in the equilibration position for 30 s. Test: A 35 mL sample was taken, placed in the specific sample cup of the electronic tongue, and tested for 30 seconds, after which the test value was output. After that, the sensor was washed with the reference solution for 3 seconds, and then inserted into a new reference solution and left for 30 seconds, and the cycle test was repeated four times. The average data of the last three tests was used as the test result, excluding the first test value. The test results are shown in Table 47.

[0270] [Table 47] Note: If the reference is 0 and the test value > 0, bitterness is detected, if the test value < 0, no bitterness is detected. The radar diagram obtained in the test is shown in Figure 9, where k1 is the API and k2 is the taste-masking microspheres F509-2 of vonoprazan fumarate.

[0271] Test Example 3 Examination of substances related to taste-masking microspheres of vonoprazan fumarate Testing method: Octadecylsilane-bonded silica gel was used as the packing material. Mobile phase A was 0.025 mol / L dipotassium hydrogen phosphate solution (adjusted to pH 6.0 with phosphoric acid)-acetonitrile (80:20), and mobile phase B was 0.025 mol / L dipotassium hydrogen phosphate solution (adjusted to pH 6.0 with phosphoric acid)-acetonitrile (30:70). The column temperature was 30°C, the flow rate was 1.0 mL / min, and 10 μL was injected. The test wavelength was 230 nm. Linear gradient elution was performed as shown in Table 48.

[0272] [Table 48] The results are shown in Table 49. The impurities G and F were both about 0.1%, the total impurities were both less than 0.4%, the number of impurities was 7, the purity of the liquid phase was greater than 99.6%, and the mass of microsphere-related substances complied with the formulation specifications.

[0273] [Table 49] Test Example 4 The results of the particle size distribution test for vonoprazan fumarate microspheres (FC606-1) are shown in Table 50. Here, Dv(10) was 159 μm, Dv(50) was 249 μm, and Dv(90) was 379 μm, and "Dv(50) is 249 μm" means that 50% of the microspheres had a particle size of 250 μm or less.

[0274] [Table 50] *: 2020 Chinese Pharmacopoeia, Part 4 General Provisions 0982, Method 3, Light Scattering Method Test Example 5 Observation of the appearance and morphology of taste-masking microspheres The results of observing the external morphology of vonoprazan fumarate microspheres using a scanning electron microscope are shown in Figures 10 and 11. In Figure 10, the vonoprazan fumarate microspheres were perfect spheres with smooth, hole-free surfaces, no surface impurities, and high roundness. In Figure 11, the microspheres had many nanoscale voids inside and were uniform, consistent spheres (no coating layer). In Figure 10, the microspheres were perfect spheres with particle sizes uniformly ranging from 50 to 280 μm.

[0275] The microspheres of vonoprazan fumarate (Lot No. FC606-1) produced according to the present invention were observed using a microscope, and the results are shown in FIG.

[0276] Test Example 6 Dissolution rate test of vonoprazan fumarate microspheres Dissolution scheme: In accordance with the provisions of the Chinese Pharmacopoeia 2020, Part 4 General Provisions 0931, Method 2 of the Dissolution Rate and Release Rate Determination Method, dissolution tests were conducted on the taste masking microspheres produced in each example under the following dissolution conditions: Elution medium: pH 1.0, buffer 900 mL, rotation speed: 50 rpm. Measurement method: high performance liquid chromatography. The results are shown in Table 51.

[0277] [Table 51] Test Example 7 Density and flowability studies of vonoprazan fumarate microspheres The results of powder measurement of vonoprazan fumarate microspheres with lot number FC527-3 are shown in Table 52.

[0278] [Table 52] Test Example 8 Crystallinity test of vonoprazan fumarate microspheres XRD (X-ray diffraction) analysis was performed on vonoprazan fumarate drug-containing microspheres and blank microspheres made of the same secondary materials, and the results are shown in Table 53. The analysis data in Table 53 showed that the deviations of all four diffraction peaks were within ±0.2°. This indicates that the crystallinity of the vonoprazan fumarate drug-containing microspheres of the present invention is mainly due to the secondary materials in the blank microspheres, and therefore vonoprazan fumarate in the drug-containing microspheres has almost no crystallinity and exists as a molecular dispersion rather than a crystalline dispersion.

[0279] [Table 53] The drug vonoprazan fumarate is present in the taste-masking microspheres as an amorphous molecular dispersion, which is advantageous for the drug's release in the body. This is because the drug is first released in the amorphous region and then in the crystalline region, and therefore, the drug's presence in the microspheres as a molecular dispersion is more advantageous for drug delivery and release than the presence in a particle dispersion.

[0280] Application example 1 A compound formulation of vonoprazan fumarate (microsphere type), amoxicillin, and rifabutin dry suspension was prepared. (1) Manufacturing method of amoxicillin particles (1.0 g) in compound preparation Amoxicillin granules are manufactured according to the formulation shown in Table 54, through the steps of pre-processing of raw materials and auxiliary materials, pre-mixing, soft material production, extrusion, spheronization, drying, and granulation.

[0281] [Table 54] The key test results for amoxicillin particles are shown in Table 55.

[0282] [Table 55] (2) Manufacturing method of rifabutin particles in compound preparations (labeled amounts: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg) Rifabutin particles are manufactured according to the formulation shown in Table 56, through the steps of pre-treatment, pre-mixing, extrusion, spheronization, drying, and sizing of raw materials and auxiliary materials.

[0283] [Table 56] Note: The amount used is 1600g for a formulation unit of 1000 pieces.

[0284] The results of the rifabutin particle measurement items are shown in Table 57.

[0285] [Table 57] (3) According to the formulation shown in Table 58, a compound preparation of vonoprazan fumarate microspheres, amoxicillin, and rifabutin dry suspension was prepared.

[0286] [Table 58] *Note: HFC613-2 was a mixture of birch FC407-1, FC526-1, FC526-2, FC611-1, FC611-2, and FC611-3 so that the content after mixing was 7.3%.

[0287] The total particle count data for the compound formulation are shown in Table 59.

[0288] [Table 59] The total particles in this compound preparation contain 20 mg of vonoprazan, 1000 mg of amoxicillin, and 50-150 mg of rifabutin, and can be made into a dry suspension for oral administration in the amount of 4.81 g per bag for clinical eradication of Hp infection.

[0289] The test results of the compound formulation are shown in Table 60.

[0290] [Table 60] * Note: F stands for vonoprazan, A stands for amoxicillin, and L stands for rifabutin.

[0291] Application example 2 Preparation of vonoprazan fumarate (microsphere type) dry suspension The formulation is shown in Table 61.

[0292] [Table 61] Microsphere production → weighing according to the compounding ratio → mixing → intermediate inspection → particle dispensing → finished product, specifications are 10 mg or 20 mg (with vonoprazan). The product inspection results are shown in Table 62.

[0293] [Table 62] Application example 3 Manufacture of Vonoprazan fumarate tablets, capsules and granules The formulation is shown in Table 63.

[0294] [Table 63] The dosage is 10 mg or 20 mg (with vonoprazan) Granules: Microsphere production → weighing according to the compounding ratio → mixing → inspection of intermediates → dispensing of particles → finished product. Tablets: Microsphere production → weighing according to the compounding ratio → mixing → inspection of intermediates → tableting → finished product. Capsules: Manufacture of microspheres → weighing according to the compounding ratio → mixing → inspection of intermediates → filling into capsules → finished product. 3. The product inspection results are shown in Table 64.

[0295] [Table 64] Comparative Example 1 Comparison of dripping onto the reactor liquid surface Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 7.8:3.9:1 (total amount 57.1 g). The mass ratio of dispersed phase solute:API, EPO, N10, magnesium oxide, and triethyl citrate was 1.12:3.2:7.2:3.0:1 (total amount 7.76 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (10°C), continuous phase pH: 7. Manufacturing process: The process is the same as in Example 36 except that the method of dropping the solution onto the reactor liquid surface is used.

[0296] The indices of the produced taste-masking microspheres are shown in Table 65.

[0297] [Table 65] As can be seen from Table 61, when the dispersed phase material was dropped onto the liquid surface, a film formation phenomenon occurred and the encapsulation rate was low (less than 60%).

[0298] Comparative Example 2 Alkalizing agent with low microsphere content and encapsulation rate Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solutes: API, EPO, N10, alkalizing agent, triethyl citrate, magnesium stearate, talc, and titanium dioxide was 5.6:15:37:15:5:2:1:1 (total amount 8.16 g). The type of alkalizing agent is listed in Table 66. Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 26.

[0299] The indices of the produced taste-masking microspheres are shown in Table 66.

[0300] [Table 66] In Table 66, the taste masking microspheres produced using an alkalizing agent such as sodium citrate had low yields and contents, and the encapsulation rate was less than 30%.

[0301] Comparative Example 3 Sub-carrier material to replace skeletal carrier N7 or N10 Process conditions: the reactor model number is -1#, and the volume of the continuous phase is 3L. Dispersed phase solvent: ethyl acetate, ethanol (anhydrous), water in a mass ratio of 5.4:3.2:1 (total amount 62 g). The mass ratio of dispersed phase solute:API, E100, celluloses (shown in Table 67), magnesium oxide was 1:2.68:6.61:2.68 (total amount 7.26 g). Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, temperature of continuous phase: room temperature, pH of continuous phase: 7. Manufacturing process: same as in Example 25.

[0302] The indices of the produced taste-masking microspheres are shown in Table 67.

[0303] [Table 67] When the skeletal carriers N7 and N10 in Table 67 were replaced with microcrystalline cellulose, crospovidone, or other series cellulose, the encapsulation rates in the tests were all less than 40%.

[0304] Comparative Example 4 Extrusion-spheronization manufacturing process for vonoprazan fumarate particles 1.Blend composition:

[0305] [Table 68] 2. Manufacturing process: Material mixing (direct mixing of pH-dependent auxiliary materials) - Wetting - Extrusion into strands - Cutting into cylindrical shapes - Spheronizing into pellets in a spheronizing machine - Drying - Manufacturing into extrusion-spheronized pellets (if sticking occurs during the extrusion-spheronization process, resulting in strands or blocks, the material is dried and crushed into particles). 3. Product inspection:

[0306] [Table 69] Note: The taste test standards and tests in Table 69 are the same as those in Test Example 2. Other inspection data: (1) Particle size distribution

[0307] [Table 70] (2) Scanning electron microscope The appearance of the extruded spheroidized particles taken under a scanning electron microscope is shown in FIG. 13, and a cross-sectional view is shown in FIG.

[0308] The particles of vonoprazan fumarate produced by the extrusion-spheronization process were not round in appearance, had a large particle size, and the Dv(90) reached 468 μm. In the taste test, the bitterness was reduced by 31.25% and the roughness was 0.33, indicating a poor taste-masking effect.

[0309] Comparative Example 5 Wet Granulation Fluid Coating Manufacturing Process Mixture composition

[0310] [Table 71] Manufacturing process: material mixing-wetting-granulation--drying--fluid coating--coating particles.

[0311] The technical specifications of the coated particles are shown in Table 72.

[0312] [Table 72] 3. Product inspection

[0313] [Table 73] Other inspection data: Particle size distribution

[0314] [Table 74] (2) Scanning electron microscope The appearance of the wet-granulated fluidized-bed coated particles taken under a scanning electron microscope is shown in FIG. 15, and a cross-sectional view is shown in FIG.

[0315] The particles of vonoprazan fumarate produced by wet granulation fluidized coating had a non-round appearance and large particle size, with a Dv(50) of 358 μm and a Dv(90) of 502 μm. In a taste test, the bitterness was reduced by 52% and the roughness was measured to be 0.58, indicating poor taste masking effect and roughness.

[0316] Comparative Example 6 Fluidized Bed Spray Micropellet Coating Manufacturing Process Formula composition:

[0317] [Table 75] Manufacturing process: blank round core - feeding into fluidized bed - spray coating - drying - micro pellet coating.

[0318] Micropellet technical indicators are shown in Table 76.

[0319] [Table 76] 3. Product inspection

[0320] [Table 77] 4. Other test data: (1) Particle size distribution

[0321] [Table 78] (2) Scanning electron microscope The appearance of the fluidized bed sprayed micropellet coating was shown by scanning electron microscope in FIG. 17, and a cross section was shown in FIG.

[0322] Vonoprazan fumarate was added to a fluidized bed and spray-coated to produce micropellets. The results showed that the pellets had a round appearance, large particle size, Dv(50) of 349 μm, Dv(90) of 522 μm, a 62.5% reduction in bitterness, and a roughness of 1. This indicated a poor taste-masking effect and obvious roughness.

[0323] The above detailed description is a specific description of one of the possible embodiments of the present invention, and this embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification made without departing from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A taste-masking microsphere comprising, by weight, 1.5 to 21.2 parts of a drug component, 35 to 110 parts of a drug carrier, 0 to 30 parts of an alkalizing agent, and 0 to 8 parts of a plasticizer.

2. 2. The taste-masking microspheres of claim 1, comprising, by weight, 5-10 parts of a drug component, 50-90 parts of a drug carrier, 0-8 parts of an alkalizing agent, and 2-8 parts of a plasticizer.

3. 2. The taste-masking microsphere of claim 1, further comprising at least one of a light-blocking agent and an auxiliary agent, wherein the light-blocking agent comprises at least one of zinc oxide and titanium dioxide, and the auxiliary agent comprises at least one of fumaric acid, succinic acid, dibutylhydroxytoluene, magnesium stearate, silica, talc, and povidone.

4. The taste-masking microspheres according to claim 1, characterized in that the drug carrier comprises a carrier A which is a pH-dependent or non-pH-dependent carrier and a carrier B which is a skeletal carrier, and the carrier A is used in an amount of 5 to 40 parts and the carrier B is used in an amount of 30 to 70 parts.

5. 5. The taste-masking microspheres of claim 4, wherein the carrier A is used in an amount of 10 to 30 parts and the carrier B is used in an amount of 30 to 60 parts.

6. 5. The taste-masking microspheres according to claim 4, wherein the carrier A comprises at least one of a polyacrylic resin, a methyl methacrylate-diethylaminoethyl methacrylate copolymer, and a polyvinyl acetal diethylaminoacetate, and the skeletal carrier comprises at least one of ethyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, cellulose acetate, polyvinyl acetate, ammonium methacrylate copolymer type A, ammonium methacrylate copolymer type B, crospovidone, and maltodextrin.

7. 7. The taste-masking microspheres of claim 6, wherein the polyacrylic resin comprises at least one of Eudragit EPO, Eudragit E100, Eudragit RLPO, Eudragit RL100, Eudragit RSPO, and Eudragit RS100, the methyl methacrylate-diethylaminoethyl methacrylate copolymer is Kollicoat Smartseal 30D100P, and the ethyl cellulose comprises at least one of N7, N10, N22, and N50.

8. The taste-masking microspheres according to claim 7, characterized in that the pH-dependent carrier comprises at least one of Eudragit EPO and Eudragit E100, the non-pH-dependent carrier comprises at least one of Eudragit RLPO and Eudragit RSPO, preferably a mixture of Eudragit RLPO and Eudragit RSPO, in a mass ratio of 1:1 to 8:1, and the skeletal carrier comprises at least one of N7 and N10.

9. 2. The taste-masking microspheres of claim 1, wherein the alkalinizing agent comprises at least one of sodium carbonate, sodium bicarbonate, magnesium oxide, meglumine, and trometamol, and the plasticizer comprises at least one of diethyl phthalate, tributyl citrate, polyethylene glycol 6000, and triethyl citrate.

10. 10. The taste-masking microspheres of claim 9, wherein the alkalizing agent comprises at least one of sodium bicarbonate and magnesium oxide, and the plasticizer is triethyl citrate.

11. The drug component is a compound having a bitter taste or an unpleasant odor, preferably an alkaloid compound, more preferably at least one of organic amine alkaloids and nitrogen-containing heterocyclic alkaloids, and more preferably vonoprazan, a pharmaceutically acceptable salt of vonoprazan, berberine hydrochloride, sildenafil citrate, azithromycin, cefuroxime axetil, vardenafil hydrochloride, metformin hydrochloride, paroxetine hydrochloride, sitagliptin hydrochloride, celite hydrochloride, cefolia ... Traline hydrochloride, pyridostigmine bromide, lidocaine hydrochloride, famotidine, ibuprofen, tramadol hydrochloride, allicin, bepotastine besilate, acetaminophen, colchicine, racecadotril, fluoxetine hydrochloride, flucloxacillin sodium, lacosamide, clarithromycin, donepezil hydrochloride, rivaroxaban, linezolid, cefcapene, cefetamet, meropenem, moxifloxacin, fluvoxamine maleate, rebamipide, Cefteram pivoxil, verapamil, quetiapine, amisulpride, sulpiride, metoprolol, pravastatin, atomoxetine, escitalopram, tilidine hydrochloride, ondansetron, vortioxetine hydrobromide, domperidone, zopiclone, roxatidine, loperamide, diphenhydramine, epinastine, mirabegron, solifenacin, irbesartan, vortioxetine hydrobromide, ticagrelor, captopril, colesevelam hydrochloride, rasagi at least one of nintedanib ethanesulfonate, enalapril maleate, apremilast, piroxicam, flutamide, varenicline tartrate, pazopanib, pramipexole, ripretinib, tamsulosin hydrochloride, risperidone, linagliptin, teneligliptin, dabigatran etexilate, odebixibat, micafungin, aprepitant, roflumilast, cefprozil, cefpodoxime proxetil, and tenapanor hydrochloride; The taste-masking microspheres according to claim 1, characterized in that the pharmaceutically acceptable salt of vonoprazan is preferably fumarate, L-malate, succinate, hemi-L-tartrate, dihydrogenphosphate, hydrogensulfate, sulfate, hydrochloride, methanesulfonate, phosphate, acetate, citrate, maleate, tartrate, bitartrate, or hydrobromide of vonoprazan.

12. The taste-masking microspheres of claim 3, wherein when the drug component is vonoprazan fumarate, the auxiliary agent comprises at least one of fumaric acid, succinic acid, and dibutylhydroxytoluene, wherein the fumaric acid is added in an amount of 0.08 to 12.42% of the total weight of the components of the taste-masking microspheres, the succinic acid is added in an amount of 0.08 to 2% of the total weight of the components of the taste-masking microspheres, and the dibutylhydroxytoluene is added in an amount of 0.08 to 1% of the total weight of the components of the taste-masking microspheres.

13. 13. The taste-masking microspheres of claim 12, wherein the fumaric acid is added in an amount of 0.08 to 10% of the total mass of each component of the taste-masking microspheres.

14. A process for producing the taste-masking microspheres of any one of claims 1 to 13, comprising: (1) Preparation of microsphere dispersed phase: Each component of the taste masking microspheres is dissolved in solvent A to form a microsphere dispersed phase. (2) Preparation of microsphere continuous phase: Select solvent B as the microsphere continuous phase; (3) After the microsphere continuous phase is poured into the reactor, the microsphere dispersed phase is fed into the bottom of the reactor and dispersed to form spheres, which are then hardened, filtered, washed, and dried to obtain taste-masking microspheres. A manufacturing process comprising the steps of:

15. 15. The production process according to claim 14, wherein the solvent A in step (1) is a mixed solvent of an organic solvent C and water, the mass ratio of the water in the solvent A is 0 to 35%, and the organic solvent C contains at least one of methanol, ethanol, isopropanol, methylethylene glycol, acetone, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, acetonitrile, N,N-dimethylacetamide, ethyl acetate, n-butanol, dichloromethane, chloroform, tetrachloroethane, and methylpropylene glycol acetate.

16. 16. The production process according to claim 15, wherein in step (1), the mass ratio of water in solvent A is 0 to 33.5%, preferably 0 to 10.5%, and solvent C contains at least one of methanol, ethanol, isopropanol, acetone, ethyl acetate, n-butanol, and dichloromethane.

17. In step (1), the solvent C is a mixed solvent of two types of solvents, specifically, the following mixed solvent: a) an ethyl acetate / ethanol mixed solvent, the volume ratio of which is 4:1 to 1:1, preferably 1.5:1, when the drug carrier comprises a pH-dependent carrier, and the volume ratio of which is 25:1 to 5:1, preferably 20:1, when the drug carrier comprises a non-pH-dependent carrier; b) a mixed solvent of n-butanol / ethanol in a volume ratio of 3:1 to 1.2:1, preferably 1.5:1; c) a dichloromethane / ethanol mixed solvent with a volume ratio of 1.7:1 to 1:1, preferably 1.5:1; d) a mixed solvent of ethyl acetate / methanol in a volume ratio of 3:1 to 1.15:1, preferably 1.5:1; e) a mixed solvent of ethyl acetate and isopropanol in a volume ratio of 4:1 to 1.2:1, preferably 1.5:1; f) a mixed solvent of ethyl acetate / acetone in a volume ratio of 2:1 to 1:1.2, preferably 1.5:1; g) a mixed solvent of ethyl acetate / acetonitrile in a volume ratio of 2:1 to 1:1, preferably 1.5:1; 15. The manufacturing process of claim 14, comprising either

18. In step (1), the solvent C is a mixed solvent of three types of solvents, specifically the following mixed solvent: (a) A mixed solvent of ethyl acetate, ethanol, and n-butanol in the following volume percentages: 60% ethyl acetate, 30 to 10% ethanol, 10 to 30% n-butanol, preferably 60% ethyl acetate, 20% ethanol, 20% n-butanol, (b) a mixed solvent of ethyl acetate, ethanol, and methanol in the following volume percentages: 60% ethyl acetate, 30-10% ethanol, and 10-30% methanol, preferably 60% ethyl acetate, 20% ethanol, and 20% methanol; (c) a mixed solvent of ethyl acetate, ethanol, and isopropanol in the following volume percentages: 60% ethyl acetate, 10-30% ethanol, and 10-30% isopropanol, preferably 60% ethyl acetate, 20% ethanol, and 20% isopropanol; (d) A mixed solvent of ethyl acetate, ethanol, and acetone in the following volume percentages: 60% ethyl acetate, 30-10% ethanol, and 10-30% acetone, preferably 60% ethyl acetate, 20% ethanol, and 20% acetone.

15. The manufacturing process of claim 14, comprising either

19. 15. The production process according to claim 14, wherein the solvent B in step (2) comprises water or a mixed solvent of water and at least one of ethyl acetate, ethanol, liquid paraffin, and dichloromethane.

20. 20. The manufacturing process of claim 19, wherein the solvent B in step (2) is water.

21. 21. The manufacturing process according to claim 19 or 20, wherein the microsphere continuous phase in step (2) further comprises a surfactant, and the surfactant in the microsphere continuous phase is used in an amount of 0.01 to 2 wt %, preferably 0.05 to 0.8 wt %.

22. 22. The process of claim 21, wherein the surfactant comprises at least one of sodium oleate, Tween, polyvinyl alcohol, sodium lauryl sulfate, and sodium carboxymethylcellulose.

23. When the surfactant is sodium oleate, the mass percentage of sodium oleate in the microsphere continuous phase is in the range of 0.01 to 0.05%; When the surfactant is Tween 80, the mass percentage of Tween 80 in the microsphere continuous phase is in the range of 0.02 to 2%; When the surfactant is polyvinyl alcohol, the polyvinyl alcohol includes at least one of model numbers 03-88, 05-88, 17-88, 20-88, and 25-88, and the weight percentage of the microspheres in the continuous phase is in the range of 0.05 to 2.0%, preferably in the range of 0.2 to 0.4%; When the surfactant is sodium lauryl sulfate, the mass percentage of sodium lauryl sulfate in the microsphere continuous phase is in the range of 0.02 to 0.2%, preferably 0.05%; 22. The manufacturing process according to claim 21, wherein when the surfactant is sodium carboxymethylcellulose, the mass percentage of sodium carboxymethylcellulose in the microsphere continuous phase is in the range of 0.02-0.25%, preferably 0.05%.

24. 15. The manufacturing process of claim 14, wherein the microsphere continuous phase in step (2) has a temperature of 2-30°C and a pH of 6-11.

25. 25. The manufacturing process of claim 24, wherein the microsphere continuous phase in step (2) has a temperature of 2-10°C and a pH of 6-8.

26. 15. The process of claim 14, wherein the mass ratio of the microsphere continuous phase to the microsphere dispersed phase is 14.7-123.5:1, and the ratio of the total mass of the taste-masking microsphere components to the mass of Solvent A is 6.5-21.5:

100.

27. 27. The process of claim 26, wherein the mass ratio of the microsphere continuous phase to the microsphere dispersed phase is 20-50:1, and the ratio of the total mass of the taste-masking microsphere components to the mass of solvent A is 6.5-15:

100.

28. 15. The manufacturing process according to claim 14, wherein the reactor in step (3) has an inverted triangular pyramid shape, and the feed port is installed at the bottom of the reactor.

29. 30. The manufacturing process of claim 28, wherein the cross section of the inverted truncated pyramid is an isosceles triangle.

30. 30. The process according to claim 29, wherein the base angle β of the isosceles triangle is in the range of 45° to 75°, preferably 60°, the height of the reactor is 10 cm to 200 cm, and the angle α between the edge of the side plane of the inverted triangular pyramid and the base is in the range of 30°≦α<90°, preferably 60°≦α<90°, more preferably α=79° to 85°.

31. Two to four layers of stirring blades are installed in the reactor, the blades are push-down type stirring blades, and the stirring rotation speed is 50 to 900 rpm; The production process according to claim 14, wherein in step (3), the filtrate obtained by filtration is applied to a subsequent reaction at a ratio of 10 to 80%, or the filtrate obtained by filtration in step (3) is subjected to solvent recovery, and the recovered solvent is used in the production of solvent A or solvent B.

32. A composition comprising the taste-masking microspheres of claim 12 or 13.

33. 33. The composition of claim 32, comprising, in parts by weight, 10-20 parts taste-masking microspheres, 500-1500 parts amoxicillin, and 50-150 parts rifabutin.

34. 34. The composition of claim 33, wherein the mass ratio of the taste-masking microspheres to amoxicillin to rifabutin is 20:1000:50, 20:1000:75, 20:1000:100, 20:1000:125, or 20:1000:

150.

35. 34. The composition of claim 33, wherein the amoxicillin and / or rifabutin are in the form of particles, micropellets, or microspheres.

36. Use of the composition according to any one of claims 32 to 35 for the manufacture of a medicament for a disease associated with Helicobacter pylori infection.

37. A formulation comprising taste-masking microspheres according to any one of claims 1 to 13, or taste-masking microspheres obtained by the manufacturing process according to any one of claims 14 to 31, or a composition according to any one of claims 32 to 35.

38. 38. The formulation of claim 37, which is a dry suspension, a film, a granule, a capsule or a tablet.

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