Mirabegron taste-masking preparation as well as preparation method and application thereof

Abstract

The invention relates to a mirabegron taste-masking preparation as well as a preparation method and application thereof, mirabegron or pharmaceutically acceptable salt thereof is taken as an active pharmaceutical ingredient, and a functional auxiliary material glyceryl behenate is added into a prescription, so that various effects of masking taste, lubricating and aiding flow and defoaming are achieved; performance tests show that the mirabegron taste-masking preparation is sufficient in taste masking, better in lubricating performance, better in defoaming performance, more stable in chemical property, less in use variety of preparation auxiliary materials, more stable in product quality and easier to commercially produce and implement. In addition, the preparation method of the mirabegron taste-masking preparation is simple, convenient and economical, a simple three-in-one equipment one-pot compound preparation mode, a fluidized bed granulation mode and a physical mixing mode are adopted in production, and compared with a traditional method, the mirabegron taste-masking preparation is simpler, more convenient and easier to industrialize and has great economic and social benefits.

Description

Technical Field

[0001] The present application relates to the field of biomedicine technology, and in particular to a mirabegron taste-masking preparation and a preparation method and application thereof. Background Art

[0002] Mirabegron is a β-3 adrenergic receptor (AR) agonist that relaxes the detrusor smooth muscle during the storage phase of the bladder filling-vacuolar cycle by activating β-3 AR (increasing bladder capacity). Mirabegron's chemical name is 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide, CAS No. 223673-61-8, molecular formula: C 21 H 24 N4O2S, molecular weight is 396.51g / mol, and its structural formula is as follows:

[0003] .

[0004] Mirabegron was first developed by Astellas Pharma Inc. The clinical dosage form is a sustained-release tablet. It was first launched in Japan in September 2011 with specifications of 25 mg and 50 mg. It was subsequently launched in the United States, Europe, and China. The approved indication in China is the symptomatic treatment of urgency, frequency, and / or urge urinary incontinence in adult patients with overactive bladder (OAB). Its active ingredient, mirabegron, tastes extremely bitter, and patients often find it difficult to accept it when taken directly.

[0005] Currently, the only mirabegron available in China is tablets. For pediatric patients, dry suspensions have better compliance than tablets, are easy to store and adjust dosages, easy to swallow, convenient to take, and have a certain taste-masking effect. The mirabegron sustained-release dry suspension developed by Astellas was approved for marketing in the United States in March 2021 under priority review. It is suitable for children with a specification of 8 mg / mL and a trade name of "Myrbetriq Granules". It is used to treat neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and above.

[0006] The original formulation of mirabegron dry suspension consists of mirabegron, mannitol, sodium polystyrene sulfonate, xanthan gum, hydroxypropyl methylcellulose, magnesium stearate, dilute hydrochloric acid, acesulfame potassium, methyl paraben, ethyl paraben, silicon dioxide and dimethyl silicone oil. Ion exchange resin is mainly used to mask the bitter taste of the drug and control drug release, but it has the following defects: (1) Insufficient taste masking: The taste masking mechanism relies only on a single ion exchange resin technology to form a complex with mirabegron, but since there are also a small amount of ions in the human mouth, these ions will also undergo ion exchange with the drug-loaded resin, thereby releasing a small amount of drug, so there is still a bitter taste in the mouth. (2) The lubricant used in the prescription is magnesium stearate, which is a relatively high risk. Magnesium stearate may cause many problems such as incompatibility with API, over-lubrication, and decreased stability. The oral solid preparations currently on the market, such as Roche's oseltamivir phosphate capsules (trade name: Tamiflu®) and mabaloxavir tablets (trade name: Sufuda®), have obviously excluded traditional magnesium stearate from the lubricant in the product prescriptions. Instead, sodium stearyl fumarate is selected. Sodium stearyl fumarate has the characteristics of good compatibility and excellent lubrication performance. The disadvantage is that it is expensive and increases the material cost of the product. Therefore, there is an urgent need for a lubricant that is better than magnesium stearate and economically suitable to reduce the quality risk and cost of mirabegron preparations. (3) The defoaming agent in the prescription is dimethyl silicone oil, which has limited defoaming ability. A small amount of foam can still be seen during clinical use; these foams will affect the accuracy of the scale reading of the measuring device and the accuracy of the volume of the transferred drug solution, which may cause incorrect dosing and bring potential risks to pediatric patients. Moreover, dimethyl silicone oil is introduced into the preparation in the form of an oily liquid, and the addition and dispersion uniformity during the production process are both difficult to overcome process problems. Summary of the invention

[0007] Based on this, it is necessary to provide a mirabegron taste-masking preparation and its preparation method and application, which has sufficient taste-masking, better lubrication performance, better defoaming performance, higher stability, and is easier to commercialize. The present invention uses glyceryl behenate to replace magnesium stearate through a large number of screening studies, avoids the use of defoaming agent dimethyl silicone oil, and while reducing and replacing the excipients of the original preparation, obtains a product with better taste-masking effect, better lubrication and defoaming performance, more stable chemical properties, and similar in vitro dissolution as the original preparation.

[0008] The technical solution of this application is as follows:

[0009] The first aspect of the present invention provides a mirabegron taste-masking preparation, comprising a pharmaceutically active ingredient and a pharmaceutically acceptable excipient;

[0010] The active pharmaceutical ingredient comprises mirabegron or a pharmaceutically acceptable salt thereof;

[0011] The pharmaceutically acceptable excipients include functional excipients, ion exchange resins, suspending agents, adhesives, fillers, flavoring agents, antibacterial agents and glidants;

[0012] The functional auxiliary material is glyceryl behenate.

[0013] In one embodiment, the ion exchange resin is one or more of sodium polystyrene sulfonate or calcium polystyrene sulfonate;

[0014] The suspending agent is one or more of xanthan gum, gum arabic, guar gum, tragacanth gum, sodium carboxymethyl cellulose or povidone;

[0015] The binder is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or polyethylene oxide;

[0016] The filler is one or more of mannitol, sorbitol, lactose, erythritol or glycerol fructose;

[0017] The flavoring agent is one or more of acesulfame potassium, sucrose, sucralose, saccharin sodium or neotame;

[0018] The antibacterial agent is one or more of methyl parahydroxybenzoate and ethyl parahydroxybenzoate;

[0019] The flow aid is one or more of colloidal silicon dioxide, fumed silicon dioxide, mesoporous silicon dioxide, magnesium aluminum silicate, bentonite or kaolin.

[0020] In one embodiment, in the mirabegron taste-masking preparation, the weight percentage of the functional excipient is 1.0%-4.0%.

[0021] In one embodiment, in the mirabegron taste-masking preparation, the weight percentage of the active pharmaceutical ingredient is 5%-20%.

[0022] In one embodiment, the dosage form of the mirabegron taste-masking preparation is a dry suspension.

[0023] In one embodiment, in the mirabegron taste-masking preparation, the mass ratio of the active pharmaceutical ingredient to the ion exchange resin is 1:(2-3); and / or

[0024] The weight percentage of the suspending agent is 1%-8%; and / or

[0025] The weight percentage of the adhesive is 1%-10%; and / or

[0026] The weight percentage of the filler is 25%-90%; and / or

[0027] The weight percentage of the flavoring agent is 0.5%-2.5%; and / or

[0028] The weight percentage of the antibacterial agent is 1.5%-3.0%; and / or

[0029] The weight percentage of the glidant is 0.01%-5%.

[0030] The second aspect of the present invention provides a method for preparing the mirabegron taste-masking preparation as described above, comprising the following steps:

[0031] The active pharmaceutical ingredient and the pharmaceutical solvent are mixed, the ion exchange resin is added, heated and stirred, and dried to prepare a composite powder;

[0032] Mixing the flavoring agent, the binder and water to prepare a binder solution;

[0033] The composite powder, suspending agent, filler and antibacterial agent are mixed, the adhesive solution, functional auxiliary materials and glidant are added, and the mixture is dried and granulated to prepare the mirabegron taste-masking preparation.

[0034] In one embodiment, the drug solvent is a dilute hydrochloric acid aqueous solution; in the dilute hydrochloric acid aqueous solution, the volume percentage of hydrochloric acid is 5%-20%.

[0035] In one embodiment, the step of preparing the composite powder satisfies at least one of the following conditions:

[0036] (1) The heating and stirring temperature is 30℃-70℃;

[0037] (2) The heating and stirring time is 0.5h-2h;

[0038] (3) The drying temperature is 40℃-60℃.

[0039] The third aspect of the present invention provides the use of the taste-masked preparation of mirabegron as described above in the preparation of a medicament for treating neurogenic detrusor overactivity in pediatric patients aged 3 years and above.

[0040] Compared with the prior art, this application has the following beneficial effects:

[0041] The present application uses mirabegron or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient, and achieves multiple effects of taste masking, lubrication, flow-aiding and defoaming by adding the functional excipient behenic acid glyceryl in the prescription. After performance testing, the mirabegron taste-masking preparation is found to have sufficient taste masking, better lubrication performance, better defoaming performance, more stable chemical properties, and fewer types of preparation excipients, so the product quality is more stable and easier to implement in commercial production.

[0042] In addition, the preparation method of the mirabegron taste-masking preparation is simple and economical. The production method is a simple three-in-one equipment one-pot method for preparing the composite, fluidized bed granulation and physical mixing. Compared with the complex melt spraying, centrifugal drying or filtration, fluidized bed granulation and total mixing process in the traditional method, it is simpler to operate and easier to industrialize, and has significant economic and social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0044] Figure 1 This is a graph showing the properties and foam generation of the reference preparation and suspension sample of Example 3 in this application.

[0045] Figure 2 The dissolution curves of the reference preparation and the sample of Example 3 in this application in a pH 6.8 medium.

[0046] Figure 3 The dissolution curves of the reference preparation and the sample of Example 4 in this application in a pH 6.8 medium.

[0047] Figure 4 The dissolution curves of the reference preparation and the sample of Example 5 in this application in a pH 6.8 medium.

[0048] Figure 5 The dissolution curves of the reference preparation and the sample of Example 1 in this application in a pH 6.8 medium.

[0049] Figure 6 The dissolution curves of the reference preparation, comparative example 5, and samples of Examples 1, 3, 4, and 5 in this application in a medium of pH 6.8 are shown. DETAILED DESCRIPTION

[0050] The present application will be further described in detail below in conjunction with specific embodiments. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0052] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0053] As used herein, "pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0054] Herein, "pharmaceutically acceptable salt" refers to a salt suitable for use as a drug formed by any compound in the structure shown and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. Among them, one type of salt is a salt formed by the compound of the present application and an acid. Acids suitable for forming salts include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another type of salt is a salt formed by the compound of the present application and a base. Suitable bases for forming salts include but are not limited to alkali metal salts (such as sodium salts or potassium salts), alkaline earth metal salts (such as magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0055] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0056] Herein, the optional scope of "and / or", "or / and", and "and / or" includes any one of two or more relevant listed items, and also includes any and all combinations of the relevant listed items, wherein said any and all combinations include any two relevant listed items, any more relevant listed items, or a combination of all relevant listed items.

[0057] Herein, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0058] Herein, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. In addition, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0059] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0060] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0061] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0062] The temperature parameters in this application, unless otherwise specified, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed.

[0063] Since the active ingredient mirabegron in mirabegron preparations tastes extremely bitter and is difficult to accept when taken directly, a study has disclosed a pharmaceutical composition containing mirabegron, the prescription of which contains mirabegron or its pharmaceutically acceptable salt, mannitol, sodium polystyrene sulfonate, xanthan gum, hydroxypropyl methylcellulose, magnesium stearate, dilute hydrochloric acid, acesulfame potassium, methyl paraben, ethyl paraben, silicon dioxide, dimethicone, etc. The study involves a pharmaceutical composition containing mirabegron or its pharmaceutically acceptable salt and sodium polystyrene sulfonate to form a complex. The drug-resin complex prepared by the API (active pharmaceutical ingredient) mirabegron and sodium polystyrene sulfonate through ion exchange reaction in dilute hydrochloric acid aqueous solution relies on ions in body fluids for ion exchange and drug release after entering the human body.

[0064] In addition, a study disclosed a method for preparing a mirabegron resin complex, in which a series of equipment such as a spray dryer, a fluidized bed, and a centrifugal filter were used in the preparation process. The production process of the complex is cumbersome, and uses a spray dryer, a fluidized bed, a centrifuge, a filter, etc. There are many types of equipment, the production cost is huge, and it is not friendly to the environment and operators. In modern industrial production practice, the spray dryer has obvious defects such as large equipment volume, high power consumption, low volume heat transfer coefficient and thermal efficiency, and the one-time investment of the spray drying production line is large. The centrifuge has obvious problems such as high speed, high risk of shaft breakage, and great safety hazards in production, and it is classified as a non-closed equipment. The mirabegron dry suspension preparation uses dilute hydrochloric acid solution in production. After centrifugal dumping, a large amount of tail gas is generated to form acid mist, which poses a great risk to the health of front-line workshop operators and is not environmentally friendly. Therefore, this production link urgently needs to optimize equipment and processes to meet the requirements of EHS (environmental and occupational health and safety management system) in the production of pharmaceutical GMP (Good Manufacturing Practice for Pharmaceuticals). There are also studies that disclose "a mirabegron composition", which involves ion exchange between mirabegron and ion exchange resin to form a mirabegron-ion exchange resin complex, and coating the surface with sustained-release materials to prepare a mirabegron-ion exchange resin complex with a sustained-release coating; and using this as a material for mixed tableting. This invention solves the problem of insufficient taste masking through the dual means of ion exchange resin + sustained-release material (non-ionic polymer ethyl cellulose, plasticizer, etc.) coating, but its target dosage form is tablets. For pediatric patients, tablets have inherent disadvantages such as poor compliance and inconvenient administration, and its preparation process is cumbersome, the process is complex, and commercial production is difficult.

[0065] In summary, at present, there is no public technical method to solve the problems of insufficient taste masking of mirabegron dry suspension, risk of lubricant in prescription design, insufficient defoaming ability, and cumbersome and environmentally inadequate production process. Based on the many defects in the current prescription and preparation process of mirabegron dry suspension, the technical personnel of this application, after extensive research, provide a mirabegron taste masking preparation and a preparation method thereof: by introducing the functional excipient behenic acid glyceryl, magnesium stearate and dimethyl silicone oil in the original prescription are replaced, achieving the multiple effects of taste masking, lubrication and flow aid and foam elimination. In production, it is a simple three-in-one equipment one-pot method for preparing composites, fluidized bed granulation and physical mixing methods, which is simpler and easier to industrialize than the complex melt spraying, centrifugal drying or filtration, fluidized bed granulation and total mixing process disclosed in the traditional method.

[0066] The first aspect of the present invention provides a mirabegron taste-masking preparation, comprising a pharmaceutically active ingredient and a pharmaceutically acceptable excipient;

[0067] The active pharmaceutical ingredient comprises mirabegron or a pharmaceutically acceptable salt thereof;

[0068] The pharmaceutically acceptable excipients include functional excipients, ion exchange resins, suspending agents, adhesives, fillers, flavoring agents, antibacterial agents and glidants;

[0069] The functional auxiliary material is glyceryl behenate.

[0070] In some examples, the ion exchange resin is one or more of sodium polystyrene sulfonate or calcium polystyrene sulfonate;

[0071] The suspending agent is one or more of xanthan gum, gum arabic, guar gum, tragacanth gum, sodium carboxymethyl cellulose or povidone;

[0072] The binder is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or polyethylene oxide;

[0073] The filler is one or more of mannitol, sorbitol, lactose, erythritol or glycerol fructose;

[0074] The flavoring agent is one or more of acesulfame potassium, sucrose, sucralose, saccharin sodium or neotame;

[0075] The antibacterial agent is one or more of methyl parahydroxybenzoate and ethyl parahydroxybenzoate;

[0076] The flow aid is one or more of colloidal silicon dioxide, fumed silicon dioxide, mesoporous silicon dioxide, magnesium aluminum silicate, bentonite or kaolin.

[0077] In some of the examples, the weight percentage of the functional excipients in the mirabegron taste-masking preparation is 1.0%-4.0%. It is understandable that the weight percentage of the functional excipients in the mirabegron taste-masking preparation includes but is not limited to 1.0%, 2.0%, 3.0%, and 4.0%. Specifically, through a large number of screening studies, the present application adopts glyceryl behenate to replace magnesium stearate, avoids the use of defoaming agent dimethicone, and controls the amount of glyceryl behenate. While reducing and replacing the excipients of the original preparation, a product with better taste-masking effect, better lubrication and defoaming performance, more stable chemical properties, and similar in vitro dissolution as the original preparation is obtained.

[0078] In some examples, the weight percentage of the active pharmaceutical ingredient in the mirabegron taste-masking preparation is 5%-20%. It is understandable that the weight percentage of the active pharmaceutical ingredient in the mirabegron taste-masking preparation includes but is not limited to 5%, 7%, 9%, 11%, 13%, 15%, 17%, 18%, and 20%.

[0079] In one embodiment, the dosage form of the mirabegron taste-masking preparation is a dry suspension.

[0080] In some examples, in the mirabegron taste-masking preparation, the mass ratio of the active pharmaceutical ingredient to the ion exchange resin is 1:(2-3). It is understood that the mass ratio of the active pharmaceutical ingredient to the ion exchange resin includes but is not limited to 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.

[0081] In some examples, the weight percentage of the suspending agent in the mirabegron taste-masking preparation is 1%-8%. Further, the weight percentage of the suspending agent in the mirabegron taste-masking preparation is 2%-4%. It is understandable that the weight percentage of the suspending agent in the mirabegron taste-masking preparation includes but is not limited to 2%, 2.5%, 3.0%, 3.5%, and 4%.

[0082] In some examples, the weight percentage of the binder in the mirabegron taste-masking preparation is 1%-10%. Further, the weight percentage of the binder in the mirabegron taste-masking preparation is 2%-4%. It is understandable that the weight percentage of the binder in the mirabegron taste-masking preparation includes but is not limited to 2%, 2.5%, 3.0%, 3.5%, and 4%.

[0083] In some examples, in the mirabegron taste-masking preparation, the weight percentage of the filler is 25%-90%. Further, in the mirabegron taste-masking preparation, the weight percentage of the filler is 25%-65%. It is understandable that in the mirabegron taste-masking preparation, the weight percentage of the filler includes but is not limited to 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%.

[0084] In some examples, the weight percentage of the flavoring agent in the mirabegron taste-masking preparation is 0.5%-2.5%. It can be understood that the weight percentage of the flavoring agent in the mirabegron taste-masking preparation includes but is not limited to 0.5%, 1.0%, 1.5%, 2.0%, and 2.5%.

[0085] In some examples, the weight percentage of the antibacterial agent in the mirabegron taste-masking preparation is 1.5%-3.0%. It can be understood that the weight percentage of the antibacterial agent in the mirabegron taste-masking preparation includes but is not limited to 1.5%, 2.0%, 2.5%, and 3.0%.

[0086] In some examples, the weight percentage of the glidant in the mirabegron taste-masking preparation is 0.01%-5%. Further, the weight percentage of the glidant in the mirabegron taste-masking preparation is 0.01%-1%. It can be understood that the weight percentage of the glidant in the mirabegron taste-masking preparation includes but is not limited to 0.01%, 0.04%, 0.06%, 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, and 1%.

[0087] The second aspect of the present invention provides a method for preparing the mirabegron taste-masking preparation as described above, comprising the following steps:

[0088] The active pharmaceutical ingredient and the pharmaceutical solvent are mixed, the ion exchange resin is added, heated and stirred, and dried to prepare a composite powder;

[0089] Mixing the flavoring agent, the binder and water to prepare a binder solution;

[0090] The composite powder, suspending agent, filler and antibacterial agent are mixed, the adhesive solution, functional auxiliary materials and glidant are added, and the mixture is dried and granulated to prepare the mirabegron taste-masking preparation.

[0091] In some of these examples, the drug solvent is a dilute aqueous hydrochloric acid solution.

[0092] In some of the examples, the volume percentage of hydrochloric acid in the dilute hydrochloric acid aqueous solution is 5%-20%. It is understandable that the volume percentage of hydrochloric acid in the dilute hydrochloric acid aqueous solution includes but is not limited to 5%, 7%, 9%, 11%, 13%, 15%, 17%, 19%, and 20%.

[0093] In some examples, the step of preparing the composite powder satisfies at least one of the following conditions:

[0094] (1) The heating and stirring temperature is 30℃-70℃;

[0095] (2) The heating and stirring time is 0.5h-2h;

[0096] (3) The drying temperature is 40℃-60℃.

[0097] In some of the examples, the steps of preparing the taste-masked preparation of mirabegron include: mixing the composite powder, suspending agent, filler and antibacterial agent, spraying the binder solution, drying, granulating, and preparing dry granules;

[0098] The dry granules, functional excipients and glidants are mixed and filled to prepare the mirabegron taste-masking preparation.

[0099] In some of the examples, the steps for preparing the mirabegron taste-masking preparation include: mixing the complex powder, suspending agent, filler and antibacterial agent, spraying the binder solution, adding the functional excipients, melt spray granulation, drying, mixing with a flow aid after granulation, and filling to prepare the mirabegron taste-masking preparation.

[0100] In summary, the present application replaces magnesium stearate and dimethicone in the original prescription by adding the functional excipient glyceryl behenate, thereby achieving multiple effects of masking taste, lubricating and aiding flow, and eliminating foam:

[0101] (1) Taste masking: This application introduces behenic acid glyceryl into the preparation in the form of solid powder mixing and melt spray granulation, forming a dual taste masking mechanism of ion exchange resin combined with functional encapsulation taste masking, which effectively solves the problem of insufficient taste masking in the disclosed method. In the oral cavity, if a small amount of mirabegron is released by ion exchange, this small amount of mirabegron is still wrapped by the good-tasting behenic acid glyceryl, which will not cause adverse taste perception, and significantly improve the compliance of children with medication.

[0102] (2) Lubrication: This application uses glyceryl behenate as a lubricant instead of magnesium stearate or sodium stearyl fumarate used in existing public materials. Glyceryl behenate does not contain ions in its chemical structure and has good drug compatibility. It has a suitable melting point, a high specific surface area, as well as amphiphilicity and film-forming tendency, and is an excellent lubricant in solid preparations. This application applies it to mirabegron preparations, and the research results show that after adding glyceryl behenate, an unexpected lubricating effect is produced.

[0103] (3) Defoaming: This application uses behenic acid glyceryl ester to replace dimethicone or simethicone used in existing public materials. Compared with dimethicone or simethicone in liquid form, behenic acid glyceryl ester is in the form of white powder and is easier to add in production. The experimental research results show that behenic acid glyceryl ester has a better defoaming effect.

[0104] (4) Simplified production process: This application uses a filter-washing-drying machine (three-in-one) to replace the spray dryer, fluidized bed, centrifuge, filter and other equipment in the traditional method. The finished product is then granulated and mixed in the fluidized bed. The overall production cost is lower, more environmentally friendly, and easier to commercialize.

[0105] In summary, the present application achieves better technical effects of taste masking, lubrication and defoaming after adding behenic acid glyceryl to the mirabegron dry suspension prescription.

[0106] The third aspect of the present invention provides the use of the taste-masked preparation of mirabegron as described above in the preparation of a medicament for treating neurogenic detrusor overactivity in pediatric patients aged 3 years and above.

[0107] The following is further described in conjunction with specific embodiments. The raw materials involved in the following specific embodiments, unless otherwise specified, can all be commercially available; the instruments used, unless otherwise specified, can all be commercially available; the processes involved, unless otherwise specified, are all routinely selected by those skilled in the art.

[0108] The following are specific embodiments.

[0109] Example 1

[0110]

[0111] Preparation method:

[0112] (1) Preparation of composites: Add the prescribed amount of mirabegron to a glass-lined reactor, add an appropriate amount of 10% dilute hydrochloric acid aqueous solution, stir, and heat until dissolved; then add sodium polystyrene sulfonate, heat to 70°C and stir for 1 h; after the reaction is completed, transfer the composite liquid through a pipeline to a filter washing and drying machine, set the drying temperature to 50°C, and collect the material to obtain a composite powder.

[0113] (2) Preparation of adhesive solution: Weigh a certain amount of purified water and add it to a stirring tank. Start stirring, add the prescribed amount of acesulfame potassium and stir until dissolved and clear. Then gradually add hypromellose to the purified water and stir until completely dissolved to prepare a 5% concentration of hypromellose aqueous solution.

[0114] (3) Granule preparation: The composite powder obtained in step (1) is added to a fluidized bed, and then mannitol, xanthan gum, methyl parahydroxybenzoate, and ethyl parahydroxybenzoate are added. After the equipment is turned on, fluidization mixing is carried out for 10 minutes; then, heating is turned on, the inlet air temperature is set to <50°C, the material temperature is controlled to <40°C, the binder solution is sprayed, dried, and then granulated using a pulverizer, and a 1.0 mm round hole screen is selected to obtain dry granules.

[0115] (4) Total mixing and filling: Add dry granules, glyceryl behenate and colloidal silicon dioxide into the mixer in sequence, mix at 15 rpm for 10 min to obtain total mixed granules. Use a filling machine to fill the bottle at 8.3 g / bottle, screw the cap, and obtain the dry suspension of this product.

[0116] Example 2

[0117]

[0118] The preparation method is the same as that of Example 1, and 2.0% behenic acid glyceryl is added in the total mixing step, and finally the mirabegron dry suspension is obtained by filling.

[0119] Example 3

[0120]

[0121] The preparation method is the same as that of Example 1, and 3.0% behenic acid glyceryl is added in the total mixing step, and finally the mirabegron dry suspension is obtained by filling.

[0122] Example 4

[0123]

[0124] The preparation method is the same as that of Example 1, and 4.0% behenic acid glyceryl is added in the total mixing step, and finally the mirabegron dry suspension is obtained by filling.

[0125] Example 5

[0126]

[0127] The preparation method is basically the same as that of Example 1, except for step (3), which is as follows:

[0128] Steps (1) and (2) are the same as in Example 1.

[0129] (3) Granule preparation: Add the composite powder, mannitol, xanthan gum, methyl parahydroxybenzoate and ethyl parahydroxybenzoate into a fluidized bed, start the equipment for fluidized mixing for 10 minutes; then start the heating, set the inlet air temperature to <50°C, control the material temperature to <40°C, spray the binder solution, and after the spraying is completed, spray the molten behenic acid glyceryl ester onto the fluidized particles, and fluidize and dry. After the drying is completed, collect the material, use a crushing and granulating machine for granulation, select a 1.0 mm round hole screen, and obtain dry particles.

[0130] Step (4) is the same as in Example 1, and finally a dry suspension is obtained.

[0131] Example 6

[0132]

[0133] The preparation method is the same as that of Example 1, except that some auxiliary materials are replaced, and in addition, 3% behenic acid glyceryl is added in the total mixing step, and finally the mirabegron dry suspension is obtained by filling.

[0134] Example 7

[0135]

[0136] The preparation method is the same as that of Example 1, except that some auxiliary materials are replaced, and in addition, 3% behenic acid glyceryl is added in the total mixing step, and finally the mirabegron dry suspension is obtained by filling.

[0137] Comparative Example 1

[0138] The commercially available mirabegron dry suspension from Astellas was purchased as a reference preparation with batch number 21J0202.

[0139] Comparative Example 2

[0140] The prescription composition refers to the reference preparation, and the amount of lubricant magnesium stearate is adjusted to 3.0%. The prescription is as follows:

[0141]

[0142] Preparation method:

[0143] (1) Preparation of composite: same as step (1) in Example 1.

[0144] (2) Preparation of adhesive solution: Weigh a certain amount of purified water and add it to a stirring tank. Start stirring. Add the prescribed amount of acesulfame potassium and stir until dissolved and clear. Then gradually add hydroxypropyl methylcellulose to the purified water and stir until completely dissolved to obtain a 5% hydroxypropyl methylcellulose aqueous solution. Finally, add the prescribed amount of dimethyl silicone oil dropwise to the above solution and stir to disperse evenly to obtain an adhesive solution.

[0145] (3) Particle preparation: same as step (3) in Example 1.

[0146] (4) Total mixing and filling: Add dry granules, magnesium stearate and colloidal silicon dioxide into the mixer in sequence and mix at 15 rpm for 10 min to obtain total mixed granules. Use a filling machine to fill the bottle at 8.3 g / bottle and screw the cap to obtain the dry mixed suspension of this product.

[0147] Comparative Example 3

[0148]

[0149] Preparation method:

[0150] (1) Preparation of composite: same as step (1) in Example 1.

[0151] (2) Preparation of adhesive solution: same as step (2) in Comparative Example 2.

[0152] (3) Particle preparation: same as step (3) in Example 1.

[0153] (4) Total mixing and filling: Add dry granules, sodium stearyl fumarate and colloidal silicon dioxide into the mixer in sequence and mix at 15 rpm for 10 min to obtain total mixed granules. Use a filling machine to fill the bottle at 8.3 g / bottle and screw the cap to obtain the dry mixed suspension of this product.

[0154] Comparative Example 4

[0155]

[0156] The preparation method is the same as that of Example 1, and 0.5% behenic acid glyceryl is added in the total mixing step, and finally the mirabegron dry suspension is obtained by filling.

[0157] Comparative Example 5

[0158]

[0159] The preparation method is the same as that of Example 1, and 5% behenic acid glyceryl is added in the total mixing step, and finally the mirabegron dry suspension is obtained by filling.

[0160] The dry suspensions prepared in Examples 1-7 and Comparative Examples 1-5 were subjected to tests on palatability, fluidity, defoaming performance, stability,

[0161] The performance tests such as release and dissolution performance are as follows.

[0162] 1. The dry suspensions obtained in Examples 1-7 and Comparative Examples 1-5 were tested on adults to evaluate the palatability of the preparations. The relevant test designs and results are as follows:

[0163] (1) Experimental design:

[0164] The selection criteria for volunteers are as follows:

[0165] Aged 22-35 years old, no severe allergies, no history of genetic diseases, no cholecystitis, no bad habits, no recent medical history, no drinking alcohol one day before the test, and no inhalation of irritating odor gases. A total of 12 qualified volunteers were selected, and each of them tasted the suspension samples prepared from the above dry suspension. After tasting each sample, rinse the mouth with water and wait for 1 hour before evaluating the next sample.

[0166] The evaluation scheme is detailed in Table 1.

[0167] Table 1

[0168]

[0169] (2) The research results are summarized in Table 2.

[0170] Table 2 (n=3; average value)

[0171]

[0172] Based on the above research results, we can know that:

[0173] The samples of the prescription group without adding behenic acid glyceryl, that is, comparative examples 2, 3 and the reference preparation group, were found to have a weak bitter taste, indicating that the bitterness masking effect of the prescription was defective.

[0174] After adding glyceryl behenate, an unexpected bitterness masking effect was produced. Moreover, the bitterness masking effect was related to the amount of glyceryl behenate added. When the amount of glyceryl behenate added was 0.5%, it still had a weak bitter taste like the reference preparation; when its addition amount increased from 1% to 3%, the bitterness at the entrance was reduced from weak to slight, and the aftertaste bitterness was significantly weakened, which was generally more acceptable to the volunteers. When the amount of glyceryl behenate increased to 4% and 5%, the bitterness masking effect was not significantly different from 3.0%.

[0175] For the same 3.0% behenic acid glyceryl formulation (Example 3 and Example 5), the bitterness masking effect of adding the total blend and adding the sample by hot melt spraying is equivalent, indicating that the addition method of behenic acid glyceryl has no significant effect on the taste masking effect of this product.

[0176] 2. The angle of repose and compression (Carr's index) of the mixed granules of the dry suspension intermediate products obtained in Examples 1-7 and Comparative Examples 2-5 were measured to evaluate the fluidity of the granule samples and further evaluate the lubricating effects of different lubricants.

[0177] (1) Experimental design:

[0178] The evaluation scheme is detailed in Table 3.

[0179] Table 3

[0180]

[0181] (2) The research results are summarized in Table 4.

[0182] Table 4

[0183]

[0184] Based on the above research results, we can know that:

[0185] After adding glyceryl behenate, an unexpected lubricating effect was produced. Moreover, the lubricating effect is related to the amount of glyceryl behenate added. When the amount of glyceryl behenate added increases from 1% to 4%, the lubricating effect on the particles tends to increase. When the amount of glyceryl behenate added increases to 5%, the product has the best lubricating effect.

[0186] In summary, for the dry suspension of this product, glyceryl behenate has the best lubrication effect, and the particle flow characteristics are "good"; sodium stearyl fumarate has the second best lubrication effect, and the particle flow characteristics are "acceptable"; magnesium stearate has the worst lubrication effect, and the particle flow characteristics are "acceptable", which is barely acceptable.

[0187] 3. Add water to Example 3 and the reference preparation samples to prepare a suspension, observe the properties of the suspension, focus on the foam generation, and evaluate the defoaming performance of the samples.

[0188] (1) Experimental design:

[0189] Tap the sealed bottle several times to loosen the particles inside. Then measure 100 mL of water, add it to the bottle, and immediately shake it vigorously for 1 minute, then let it stand for 20 minutes. Shake it vigorously again for 1 minute. Observe the properties of the suspension and the generation of foam.

[0190] (2) The research results are summarized in Table 5. The suspension properties and foam generation are detailed in Figure 1 .

[0191] Table 5

[0192]

[0193] From Table 5 and Appendix Figure 1 It can be seen that after adding 3.0% behenic acid glyceryl ester in Example 3 of the present application, the defoaming effect of the suspension prepared was significantly enhanced compared with the reference preparation, and no obvious foam was generated.

[0194] 4. Light stability

[0195] The mirabegron dry suspensions of Examples 1 and 3 and Comparative Examples 1 and 2 were subjected to an investigation of the factors affecting light exposure. The investigation conditions were as follows: the suspensions were placed under an illumination of 4500Lx±500Lx, with a total illumination of not less than 1.2x10Lux-hr and a near-ultraviolet energy of not less than 200w·hr / m 2 , samples were taken for testing at 0, 5, and 12 days, and the impurity results of the samples under different light conditions were compared. The results are shown in Table 6.

[0196] Table 6

[0197]

[0198] As can be seen from Table 6, after the experiment on the influence of light, the impurities of the mirabegron dry suspension prepared in Examples 1 and 3 were significantly lower than those in Comparative Examples 1 and 2. In particular, as time increased, the impurity content in Comparative Examples 1 and 2 was much higher than that in Examples 1 and 3. This result further proves that the mirabegron dry suspension prepared in the present application has high light stability and stable product quality.

[0199] 5. Dissolution test

[0200] Dissolution curve determination method: paddle method, rotation speed of 100 rpm, pH 6.8 medium, medium volume of 900 mL, sampling points of 0.15 h, 0.25 h, 1 h, 2 h, 4 h, 6 h, and 8 h.

[0201] The dissolution curves of Examples 1, 3 to 5, the reference preparation and Comparative Example 5 were compared. The results are shown in Tables 7 and Figure 2-6 , F2 in the table is the similarity factor.

[0202] The similarity comparison of dissolution curves is usually carried out by using the similarity factor (f2) method in the non-model-dependent method. The similarity comparison of dissolution curves in this method is to compare the average dissolution amount of the test sample with the average dissolution amount of the reference sample. The average dissolution amount should be the average of 12 tablets (granules).

[0203] Calculation formula:

[0204] In the formula, R t T is the average dissolution amount of the reference sample at time t; t is the average dissolution amount of the test sample at time t; n is the number of sampling time points.

[0205] Table 7

[0206]

[0207] From the dissolution test results, it can be seen that the samples of Examples 1, 3-5 are similar to the reference preparation (F2>50). Among them, the sample of Example 3 (3.0% behenic acid glyceryl added) has the best fit and the largest F2 value. Compared with the reference, the samples of Examples 1, 4, and 5 have a slightly slower dissolution before 2 hours. At the same time, after adding behenic acid glyceryl, the dissolution performance of the mirabegron taste-masking preparation can be significantly improved. The dissolution effect is related to the amount of behenic acid glyceryl added. When the amount added is increased to 5%, the dissolution similarity factor F2 is significantly reduced, which may lead to the result that the in vitro dissolution is not equivalent to the reference preparation.

[0208] In summary, the present application provides a mirabegron taste-masked preparation and a preparation method thereof, which has sufficient taste-masking, better lubrication performance, better defoaming performance, more stable chemical properties, uses fewer types of preparation excipients than the reference, and is easier to implement in commercial production.

[0209] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0210] The above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be construed as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. A taste-masking preparation of mirabegron, characterized in that: Includes active pharmaceutical ingredients and pharmaceutically acceptable excipients; The active pharmaceutical ingredient comprises mirabegron or a pharmaceutically acceptable salt thereof; The pharmaceutically acceptable excipients include functional excipients, ion exchange resins, suspending agents, adhesives, fillers, flavoring agents, antibacterial agents and glidants; The functional auxiliary material is glyceryl behenate.

2. The taste-masking preparation of mirabegron according to claim 1, characterized in that The ion exchange resin is one or more of sodium polystyrene sulfonate or calcium polystyrene sulfonate; The suspending agent is one or more of xanthan gum, gum arabic, guar gum, tragacanth gum, sodium carboxymethyl cellulose or povidone; The binder is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or polyethylene oxide; The filler is one or more of mannitol, sorbitol, lactose, erythritol or glycerol fructose; The flavoring agent is one or more of acesulfame potassium, sucrose, sucralose, saccharin sodium or neotame; The antibacterial agent is one or more of methyl parahydroxybenzoate and ethyl parahydroxybenzoate; The flow aid is one or more of colloidal silicon dioxide, fumed silicon dioxide, mesoporous silicon dioxide, magnesium aluminum silicate, bentonite or kaolin.

3. The taste-masking preparation of mirabegron according to claim 1, characterized in that In the mirabegron taste-masking preparation, the weight percentage of the functional excipient is 1.0%-4.0%.

4. The taste-masking preparation of mirabegron according to claim 1, characterized in that In the mirabegron taste-masking preparation, the weight percentage of the active pharmaceutical ingredient is 5%-20%.

5. The taste-masking preparation of mirabegron according to claim 1, characterized in that: The dosage form of the mirabegron taste-masking preparation is a dry suspension.

6. The mirabegron taste-masking preparation according to any one of claims 1 to 5, characterized in that: In the mirabegron taste-masking preparation, the mass ratio of the active pharmaceutical ingredient to the ion exchange resin is 1:(2-3); and / or The weight percentage of the suspending agent is 1%-8%; and / or The weight percentage of the adhesive is 1%-10%; and / or The weight percentage of the filler is 25%-90%; and / or The weight percentage of the flavoring agent is 0.5%-2.5%; and / or The weight percentage of the antibacterial agent is 1.5%-3.0%; and / or The weight percentage of the glidant is 0.01%-5%.

7. A method for preparing the taste-masking preparation of mirabegron according to any one of claims 1 to 6, characterized in that: The following steps are involved: The active pharmaceutical ingredient and the pharmaceutical solvent are mixed, the ion exchange resin is added, heated and stirred, and dried to prepare a composite powder; Mixing the flavoring agent, the binder and water to prepare a binder solution; The composite powder, suspending agent, filler and antibacterial agent are mixed, the adhesive solution, functional auxiliary material and glidant are added, and the mixture is dried and granulated to prepare the mirabegron taste-masking preparation.

8. The method for preparing the taste-masking preparation of mirabegron according to claim 7, characterized in that: The drug solvent is a dilute hydrochloric acid aqueous solution; in the dilute hydrochloric acid aqueous solution, the volume percentage of hydrochloric acid is 5%-20%.

9. The method for preparing the taste-masking preparation of mirabegron according to claim 8, characterized in that: The step of preparing the composite powder satisfies at least one of the following conditions: (1) The heating and stirring temperature is 30℃-70℃; (2) The heating and stirring time is 0.5h-2h; (3) The drying temperature is 40℃-60℃.

10. Use of the taste-masked mirabegron preparation according to any one of claims 1 to 6 in the preparation of a medicament for treating neurogenic detrusor overactivity in pediatric patients aged 3 years and above.

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