WO2023193745A1 - 一种右美沙芬奎尼丁口崩片及其应用 - Google Patents

一种右美沙芬奎尼丁口崩片及其应用 Download PDF

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WO2023193745A1
WO2023193745A1 PCT/CN2023/086493 CN2023086493W WO2023193745A1 WO 2023193745 A1 WO2023193745 A1 WO 2023193745A1 CN 2023086493 W CN2023086493 W CN 2023086493W WO 2023193745 A1 WO2023193745 A1 WO 2023193745A1
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Prior art keywords
dextromethorphan
quinidine
orally disintegrating
sodium
taste
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PCT/CN2023/086493
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English (en)
French (fr)
Inventor
戴莉香
裘少君
殷乐
陈强欣
李海燕
陈红敏
赖才达
王文首
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北京剂泰医药科技有限公司
杭州剂泰医药科技有限责任公司
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Publication of WO2023193745A1 publication Critical patent/WO2023193745A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and specifically relates to an orally disintegrating tablet containing dextromethorphan and quinidine and its preparation method and application.
  • Dextromethorphan hydrobromide and quinidine sulfate are a compound drug developed by Avanir Pharmaceuticals Inc to treat pseudobulbar affect (PBA). It was first approved by the FDA in October 2010. The drug is the first and only drug used to treat PBA, also known as emotional incontinence, which is mainly secondary to neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and stroke. Sudden involuntary crying or laughing.
  • Patients with neurological diseases often have symptoms such as difficulty swallowing and salivation.
  • PBA patients basically have difficulty swallowing, so capsules are not suitable for PBA patients. Swallowing capsules increases the pain of these patients.
  • CN113209042, CN107072990 and Journal of Affective Disorders (2014), 167, 333-335 disclose dextromethorphan quinidine capsules and ordinary tablets, which cannot meet the medication needs of patients with dysphagia.
  • the purpose of the present invention is to solve the problems in the prior art and provide a dextromethorphan quinidine orally disintegrating tablet with good taste and disintegration speed and high dissolution rate, its preparation method and application.
  • the invention provides an orally disintegrating tablet of dextromethorphan and quinidine, which contains dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof, quinidine, a pharmaceutically acceptable salt thereof or a hydrate thereof. substances, flavoring agents and disintegrating agents.
  • the “dextromethorphan” in the dextromethorphan and quinidine orally disintegrating tablets described in the present invention refers to dextromethorphan, its pharmaceutically acceptable salts or its hydrates, including but not limited to hydrobromide, salts Acid salt, phosphate, hydroiodide, nitrate, formate, sulfate, acetate, propionate, butyrate, trifluoroacetate, p-toluenesulfonate, lysine salt, N,N'dibenylethylenediamine salt, procaine salt, chloroprocaine salt, diethylene glycolamine salt, ethylenediamine salt, meglumine salt, lithium salt, sodium salt, potassium salt, calcium salt Salt, magnesium salt or hydrate of the above salt, preferably hydrobromide, hydrochloride, phosphate, hydroiodide or hydrate of the above salt, more preferably hydrobromide or hydrobromide hydrate ; "Quinidine” refer
  • dextromethorphan and quinidine have poor taste, and both dextromethorphan and quinidine taste bitter and numbing.
  • flavoring agents in addition to disintegrating agents.
  • the flavoring agent of the dextromethorphan and quinidine orally disintegrating tablets provided by the present invention is one or more of sweeteners, flavors and sour agents, preferably containing at least one sweet taste. agent.
  • the inventor of the present application discovered during the early development process that the fragrance of the essence is difficult to blend with the taste of the raw material medicine, which has a taste-masking effect.
  • the bitterness, numbing taste and the smell of the essence are all relatively obvious in the prepared preparation, and the sour taste is
  • the agent can improve the taste of orally disintegrating tablets, but it is not enough to meet the taste-masking requirements. Only sweeteners can achieve a good taste-masking effect.
  • the sweetener of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is sucrose or its derivatives, aspartame, fructose, steviol glycosides, mannitol or sorbitol.
  • the flavor of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is one or more of sweet orange flavor, mint flavor, milk flavor and strawberry flavor, preferably sweet orange flavor. , one or more of mint flavor or milk flavor, more preferably one or more of sweet orange flavor or mint flavor.
  • sweeteners On the basis of adding sweeteners, adding flavors can improve the medication experience of medicines. Furthermore, with the addition of sweeteners, sweet orange flavor, mint flavor and milk flavor all have a positive impact on the taste masking of dextromethorphan and quinidine, while strawberry flavor has a negative impact.
  • the inventor of the present application conducted raw material and auxiliary material compatibility testing on various flavoring agents before high-throughput screening of flavoring agents.
  • the results showed that cherry flavor, pineapple flavor and vitamin C would lead to an increase in impurities under the test conditions and had poor compatibility with dextromethorphan and quinidine, so they were not selected.
  • the sweetener steviol glycoside itself will have new impurities and cannot meet the compatibility requirements of raw materials and excipients, so it is not selected.
  • the sour agent of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is sodium carbonate, potassium carbonate, sodium chloride, potassium chloride, sodium hydroxide, vitamin C, citric acid,
  • One or more lactic acids are preferably one or more sodium carbonate, potassium carbonate, sodium chloride, potassium chloride, and sodium hydroxide, and more preferably sodium chloride or sodium carbonate.
  • the sour agent can increase the decomposition of saliva in the oral cavity, supplement the saliva consumed when the orally disintegrating tablets of dextromethorphan and quinidine disintegrate in the oral cavity, and improve the taste of the orally disintegrating tablets.
  • the flavor screening method for dextromethorphan quinidine orally disintegrating tablets includes the following steps:
  • the present invention adopts a method that combines high-throughput experiments and computer artificial intelligence. Compared with traditional experimental methods, the taste-masking effect of each taste-masking excipient on dextromethorphan-quinidine can be obtained efficiently and intuitively.
  • the inventor of the present application used an electronic tongue to test the taste-masking effect of the taste-masking prescription. It was found that unlike the taste-masking effect of a single prescription of quinil in the prior art, for the dextromethorphan-quinidine composition, after adding different concentrations of commonly used flavoring agents, the evaluation results of the electronic tongue all showed that the composition had a bitter taste. There is basically no improvement in the taste such as sourness and dextromethorphan. It may be that the taste-masking mechanism of the dextromethorphan-quinidine combination is inconsistent with the taste-masking mechanism of quinid or the bitter taste of dextromethorphan-quinidine is too great. Therefore, this application uses the oral taste of volunteers. way to obtain more accurate taste masking results.
  • the disintegrating agent of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is crospovidone, sodium carboxymethyl starch, low-substituted cellulose, and low-substituted hydroxypropylcellulose. , one or more of crospovidone, croscarmellose sodium, preferably at least crospovidone, more preferably crospovidone or crospovidone and croscarmellose Sodium methylcellulose combination.
  • the disintegration properties of dextromethorphan and quinidine are greatly affected.
  • the inventor of the present application found that when the disintegrant contains crospovidone, especially when the disintegrant is crospovidone or crospovidone and croscarmellose sodium, the orally disintegrating tablets It can disintegrate within 40s and has good disintegration performance.
  • the weight of the disintegrant of the dextromethorphan and quinidine orally disintegrating tablets provided by the present invention accounts for 10-35% of the total weight of the dextromethorphan and quinidine orally disintegrating tablets, preferably 20 -30%.
  • the added flavoring agent is highly hygroscopic and the dosage is large, which leads to the need to add more disintegrants to ensure the disintegration of the orally disintegrating tablets.
  • the dosage of disintegrant is more than 10%, the requirement of disintegration of orally disintegrating tablets within 60 seconds can be met.
  • the mass content of the disintegrant is more than 20%, the disintegration time can be within 40 seconds.
  • the dextromethorphan quinidine orally disintegrating tablets provided by the present invention also contain one or more of lubricants and fillers.
  • the lubricant is colloidal silica, sodium stearyl fumarate, magnesium stearate, polymer One or more of ethylene glycol, magnesium lauryl sulfate, hydrogenated vegetable oil, talc, and micronized silica gel, preferably one or more of colloidal silica and sodium stearyl fumarate.
  • the filler is one of microcrystalline cellulose, mannitol, xylitol, starch, powdered sugar, saccharin, lactose, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, and calcium carbonate.
  • the filler is one of microcrystalline cellulose, mannitol, xylitol, starch, powdered sugar, saccharin, lactose, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, and calcium carbonate.
  • the invention also provides a preparation method of dextromethorphan quinidine orally disintegrating tablets, which includes the following steps:
  • step (2) Granulate the mixture obtained in step (1) using a dry granulator to obtain mixture granules;
  • step (3) Mix the granules prepared in step (2) with a lubricant and a disintegrating agent;
  • step (3) Compress the mixture obtained in step (3) into tablets to obtain dextromethorphan-quinidine orally disintegrating tablets.
  • Another object of the present invention is to provide a dextromethorphan and quinidine orally disintegrating tablet prepared for the treatment and/or prevention of pseudobulbar mood, dysphagia, salivation or language disorders, and cognitive defects in patients with neurological diseases. uses in.
  • the present invention provides a dextromethorphan-quinidine preparation that is easy to swallow and has good taste-masking effect.
  • the present invention combines high-throughput screening experiments with computer artificial intelligence to efficiently and accurately obtain the impact of each flavoring agent on the taste-masking effect of dextromethorphan-quinidine.
  • Figure 1 is an important factor analysis diagram of the high-throughput experimental results of the screening of flavoring agents of the present invention.
  • dextromethorphan quinine Nidin is an orally disintegrating tablet.
  • Volunteers should not eat, drink, or chew gum for at least 1 hour before the test, and rinse their mouths with deionized water. Use a dropper to draw 1 mL of sample into your mouth, hold the sample solution in your mouth for 5 seconds and rinse your mouth so that the taste sensing areas at the base and sides of the tongue can fully feel the taste of the drug, spit it out, and rinse your mouth with deionized water until there is no odor in your mouth before proceeding to the next time. experiment.
  • the taste results of 251 prescriptions were modeled using computer artificial intelligence (sour value ⁇ 5, -5 ⁇ bitter value ⁇ 0, -5 ⁇ numbing value ⁇ 0, and the comprehensive score>0 is a positive sample, otherwise it is a negative sample sample), and analyze the characteristic importance of each excipient, the results are shown in Figure 1.
  • the SHAP value > 0 indicates that the point may be a positive sample. The larger the value, the greater the possibility of becoming a positive sample.
  • the dark dots in the figure indicate that the prescription contains this excipient, and the light dots indicate that the prescription does not contain this excipient.
  • sucralose, aspartame, fructose, sucrose, steviol glycosides, sorbitol or mannitol have a positive impact on the taste-masking effect.
  • sucralose and aspartame Batame has a similar effect on the flavoring effect, about 2-3 times that of fructose, sucrose or stevia glycosides, and 3-4 times that of mannitol or sorbitol.
  • sweeteners With the addition of sweeteners, the strawberry essence in the flavor and the citric acid and lactic acid in the sour agent still have a negative impact on the taste-masking effect.
  • the orally disintegrating tablets prepared by the present invention can meet the disintegration time requirements of orally disintegrating tablets.
  • the content of crospovidone in the prescription increases, the disintegration rate of the orally disintegrating tablets increases.
  • the content range of the disintegrant is selected to be 20-30% (w%).
  • the orally disintegrating tablets prepared according to the present invention are tested in enzyme-free simulated gastric juice (pH 1.2) (temperature 37.0°C ⁇ 0.5°C) using the first method (basket method) of the four dissolution and release determination methods in the 2020 version of the Chinese Pharmacopoeia
  • the dissolution rate (%) was determined by high performance liquid chromatography.
  • the dissolution data are shown in Table 6.
  • Example 1 The sweetener in Example 1 was removed, and the remaining components remained unchanged to prepare dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets.
  • Example 2 or 3 The sweetener in Example 2 or 3 was replaced with mannitol to prepare dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets.
  • dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets were prepared.
  • Dextromethorphan hydrobromide orally disintegrating tablets containing 20 mg of dextromethorphan hydrobromide were prepared according to the prescription in Example 3 of patent document CN1720917A.
  • the prescription table is as follows:
  • Example 2 or 3 The sweetener in Example 2 or 3 was replaced with saccharin sodium to prepare dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets.
  • Each prepared orally disintegrating tablet was tasted manually to evaluate the taste-masking effect. Ten volunteers were selected for each batch of drugs to conduct the experiment.
  • the taste method is as follows: volunteers moisten their mouths before taking the medicine. Place the tablet on the upper part of the tongue, move the tongue until the tablet lumps disappear, and then spit the medicine out. Record the numbness and bitterness of the slices you taste. Rinse your mouth until no bitter taste remains in your mouth before tasting the next batch of tablets.
  • Example 3 of the patent document CN1720917A which only masks the taste of dextromethorphan hydrobromide orally disintegrating tablets, is unsatisfactory. It can be seen that the patent document CN1720917A does not pay attention to the orally disintegrating tablets. The taste masking effect.
  • quinidine sulfate is added according to the formula of patent document CN1720917A, although the numbness of the tongue is basically covered, only 2-3 people think it is not bitter, that is, the bitter taste is not well covered.
  • the inventor also selected saccharin sodium with relatively high sweetness (300-600 sweetness relative to sucrose) to prepare a formula and conducted a taste experiment.
  • the experimental results showed that although the numbness of the tongue was basically covered, there was as much as 8 people thought that the medicinal taste was bitter; correspondingly, only 3 people thought that aspartame, which has a relative sweetness lower than saccharin (the sweetness relative to sucrose is 200), was bitter or extremely bitter.
  • This experiment further proves that for dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets, the selection of sweeteners needs to rely on specific experimental evaluations and cannot be selected solely based on conventional indicators such as relative sweetness.
  • the technical solution of the present application has obvious advantages in the taste-masking effect of dextromethorphan hydrobromide and quinidine sulfate compared with the technical solution without adding sweetener and the patent document CN1720917A.

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Abstract

一种右美沙芬奎尼丁口崩片、其制备方法及其在制备用于治疗和/或预防神经***疾病患者中假性延髓情绪、吞咽困难、流涎或语言障碍、认知缺陷药物中的用途，该右美沙芬奎尼丁口崩片包含右美沙芬、其药学上可接受的盐或其水合物、奎尼丁、其药学上可接受的盐或其水合物、矫味剂和崩解剂，其中加入矫味剂改善了右美沙芬和奎尼丁味道极苦极麻的问题，且制得的口崩片易于崩解，解决了神经***疾病患者吞咽困难问题，同时改善了患者的用药体验。

Description

一种右美沙芬奎尼丁口崩片及其应用
相关申请的交叉引用
本发明要求2022年04月06日向中国国家知识产权局提交的专利申请号为202210353658.5，发明名称为“一种右美沙芬奎尼丁口崩片及其应用”的在先申请的优先权。该件在先申请的全文通过引用的方式结合于本发明中。
技术领域
本发明涉及药物制剂领域，具体涉及一种包含右美沙芬和奎尼丁的口崩片及其制备方法和应用。
背景技术
氢溴酸右美沙芬和硫酸奎尼丁是由Avanir pharmaceuticals Inc公司开发的一种治疗假性延髓情绪(PBA)的复方药物，于2010年10月首次获得FDA批准上市。该药物是第一个且唯一一个用于治疗PBA的药物，PBA又名情绪失禁，主要继发于帕金森病、多发性硬化、肌萎缩性脊髓侧索硬化和中风等神经***疾病，表现特征为突然出现无意识的哭或笑。
右美沙芬和奎尼丁的味道很差，又苦又麻，目前上市的剂型为胶囊。神经***疾病患者常伴有吞咽困难、流涎等症状。有研究表明，帕金森病患者吞咽困难的发生率是11-87％。超过50％的急性脑梗死患者伴有不同程度的吞咽障碍。脑卒中患者中吞咽困难的发病率约为51-73％。PBA患者基本都存在吞咽困难的问题，所以胶囊剂并不适合PBA患者，吞咽胶囊增加了这些患者的痛苦。
CN113209042、CN107072990和Journal of Affective Disorders(2014),167,333-335公开了右美沙芬奎尼丁胶囊和普通片剂，无法满足吞咽困难患者的用药需求。
Pharm Dev Technol.24(6)，711-719，2019，公开了氢溴酸右美沙芬口崩片中的润滑剂硬脂富马酸钠可起到增强的掩味作用。Chem.Pharm.Bull.50(12)，1589-1593，2002，公开了三氯蔗糖、阿斯巴甜、氯化钠、磷脂酸和单宁酸对奎尼丁光学异构体奎尼的掩味效果和可能的掩味机理，表明使用电子传感器(电子舌)与人尝味可获得一致的苦味评估结果。但上述两篇掩味相关文献均未公开对右美沙芬奎尼丁组合物的掩味。本申请发明 人在前期研究中发现，对于右美沙芬奎尼丁组合物，加入不同浓度的常用矫味剂后，电子舌的评估结果均表明组合物的苦味、酸味等口感基本无改善，故需要对右美沙芬奎尼丁组合物的掩味进行深入的研究。
综上所述，为减轻病人痛苦，亟需开发一种能够同时满足掩味及易于吞咽的新剂型。
发明内容
本发明的目的在于解决现有技术中的问题，提供一种口感和崩解速度良好、溶出度高的右美沙芬奎尼丁口崩片、其制备方法和应用。
本发明的目的可通过以下技术方案实现：
本发明提供一种右美沙芬奎尼丁口崩片，该口崩片包含右美沙芬、其药学上可接受的盐或其水合物、奎尼丁、其药学上可接受的盐或其水合物、矫味剂和崩解剂。
本发明中所述的右美沙芬奎尼丁口崩片中的“右美沙芬”是指右美沙芬、其药学上可接受的盐或其水合物，包括但不限于氢溴酸盐、盐酸盐、磷酸盐、氢碘酸盐、硝酸盐、甲酸盐、硫酸盐、乙酸盐、丙酸盐、丁酸盐、三氟乙酸盐、对甲苯磺酸盐、赖氨酸盐、N,N’二卞基乙二胺盐、普鲁卡因盐、氯普鲁卡因盐、二乙二醇胺盐、乙二胺盐、葡甲胺盐、锂盐、钠盐、钾盐、钙盐、镁盐或上述盐的水合物，优选为氢溴酸盐、盐酸盐、磷酸盐、氢碘酸盐或上述盐的水合物，更优选为氢溴酸盐或氢溴酸盐水合物；“奎尼丁”是指奎尼丁、其药学上可接受的盐或其水合物，包括但不限于硫酸盐、聚半乳糖醛酸盐、盐酸盐、氢碘酸盐、氢溴酸盐、磷酸盐、硝酸盐、乙二酸盐、对甲苯磺酸盐、葡萄糖酸盐、赖氨酸盐、N,N’二卞基乙二胺盐、普鲁卡因盐、氯普鲁卡因盐、二乙二醇胺盐、乙二胺盐、葡甲胺盐、锂盐、钠盐、钾盐、钙盐、镁盐或上述盐的水合物，优选为硫酸盐、聚半乳糖醛酸盐、盐酸盐或上述盐的水合物，更优选为硫酸盐或硫酸盐水合物。
右美沙芬和奎尼丁的味道均较差，右美沙芬和奎尼丁味道均又苦又麻。为制得易于接受的口崩片，提高患者的顺应性，在加入崩解剂的基础上还需要加入矫味剂。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片的矫味剂为甜味剂、香精和酸味剂的一种或多种，优选为至少含有一种甜味剂。
本申请发明人在前期开发过程中发现，香精的香味很难与原料药的味道相融合，起到掩味的效果，做成的制剂中苦味、麻味以及香精的气味感受均较为明显，酸味剂可改善口崩片的口感，但不足以满足掩味的要求，仅甜味剂能够较好地起到掩味的效果。
在加入甜味剂的基础上，为获得最优的掩味处方，我们将高通量实验和计算机人工智能相结合，选用易得的甜味剂、香精、酸味剂及其组合，从可能的过千种掩味组合样本数据中，得出了各辅料对右美沙芬奎尼丁掩味效果的影响力情况。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片的甜味剂为蔗糖或其衍生物、阿斯巴甜、果糖、甜菊糖苷、甘露醇或山梨醇中的一种或多种，优选为蔗糖或其衍生物、阿斯巴甜、果糖或甜菊糖苷中的一种或多种，更优选为三氯蔗糖或阿斯巴甜中的一种或多种。
以高通量筛选实验结果为数据，计算机人工智能分析表明，甜味剂的掩味效果与其甜度没有必然关系。进一步地，三氯蔗糖、阿斯巴甜、果糖、蔗糖、甜菊糖苷、山梨醇或甘露醇均对掩味效果有正向的影响。其中，三氯蔗糖和阿斯巴甜对掩味效果的影响相当，约为果糖、蔗糖或甜菊糖苷影响力的2-3倍、山梨醇或甘露醇的3-4倍，是右美沙芬奎尼丁掩味的优选甜味剂。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片的香精为甜橙香精、薄荷香精、牛奶香精和草莓香精中的一种或多种，优选为甜橙香精、薄荷香精或牛奶香精中的一种或多种，更优选为甜橙香精或薄荷香精中的一种或多种。
在添加甜味剂的基础上，加入香精可以提高药品的用药体验。更进一步地，在加入甜味剂的情况下，甜橙香精、薄荷香精和牛奶香精均对右美沙芬奎尼丁的掩味具有正向影响，草莓香精则具有负向影响。
另外，本申请发明人在高通量筛选矫味剂之前，对多种矫味剂进行了原辅料相容性检测。结果表明，樱桃香精、菠萝香精和维生素C在测试条件下会导致杂质增多，与右美沙芬奎尼丁的相容性差，故不选用。甜味剂甜菊糖苷本身会有新增杂质，无法满足原辅料相容性要求，故也不选用。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片的酸味剂为碳酸钠、碳酸钾、氯化钠、氯化钾、氢氧化钠、维生素C、柠檬酸、乳酸中的一种或多种，优选为碳酸钠、碳酸钾、氯化钠、氯化钾、氢氧化钠中的一种或多种，更优选为氯化钠或碳酸钠。
酸味剂可以增加口腔中唾液的分解，补充右美沙芬奎尼丁口崩片在口腔内崩解时消耗的唾液，改善口崩片的口感。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片的矫味剂筛选方法包括如下步骤：
(1)、配制右美沙芬、其药学上可接受的盐或其水合物和奎尼丁、其药学上可接受的盐或其水合物的水溶液；
(2)、配制矫味剂的水溶液；
(3)、通过Halton采样法选取部分样本进行高通量实验，分别在孔板中加入步骤(1)和步骤(2)配制好的水溶液，混合均匀后，测试掩味效果，获得掩味结果；其中，测试掩味效果优选人工尝味；
(4)、根据掩味结果用计算机人工智能建立模型，得到矫味效果好的矫味剂。
本发明采用高通量实验和计算机人工智能相结合的方法，较传统实验方法，可高效直观地得到各掩味辅料对右美沙芬奎尼丁的掩味效果。
在研发前期，本申请发明人使用电子舌测试掩味处方的掩味效果。发现与现有技术中对奎尼单个处方的掩味效果不同，对于右美沙芬奎尼丁组合物而言，加入不同浓度的常用矫味剂后，电子舌的评估结果均表明组合物的苦味、酸味等口感基本无改善，可能是右美沙芬奎尼丁组合的掩味与奎尼的掩味机制不一致或右美沙芬奎尼丁的苦味太大导致，故本申请采用志愿者口尝的方式以更准确地获得掩味结果。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片的崩解剂为交联聚维酮、羧甲基淀粉钠、低取代纤维素、低取代羟丙纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维钠中的一种或多种，优选为至少含有交联聚维酮，更优选为交联聚维酮或交联聚维酮与交联羧甲基纤维素钠的组合。
由于吸湿性矫味剂的加入，右美沙芬奎尼丁的崩解性能受到了极大的影响。本申请发明人发现，当崩解剂中含有交联聚维酮时，特别是崩解剂为交联聚维酮或交联聚维酮与交联羧甲基纤维素钠时，口崩片可在40s内崩解，崩解性能较好。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片的崩解剂的重量占右美沙芬奎尼丁口崩片总片重的10-35％，优选为20-30％。
如上所述，由于右美沙芬奎尼丁的味道太差，加入的矫味剂吸湿性大且用量多，导致需要加入较多的崩解剂来保证口崩片的崩解。当崩解剂的用量在10％以上时，可满足口崩片60s以内崩解的要求。当崩解剂的质量含量为20％以上时，可使得崩解时间在40s以内。
在一种优选的实施方式中，本发明提供的右美沙芬奎尼丁口崩片还包含润滑剂、填充剂中的一种或多种。
在一种优选的实施方式中，润滑剂为胶态二氧化硅、硬脂富马酸钠、硬脂酸镁、聚 乙二醇、月桂醇硫酸镁、氢化植物油、滑石粉、微粉硅胶中的一种或多种，优选为胶态二氧化硅、硬脂富马酸钠中的一种或多种。
在一种优选的实施方式中，填充剂为微晶纤维素、甘露醇、木糖醇、淀粉、糖粉、糖精、乳糖、预胶化淀粉、硫酸钙、磷酸氢钙、碳酸钙中的一种或多种，优选为微晶纤维素、木糖醇、甘露醇中的一种或多种。
本发明同时提供一种右美沙芬奎尼丁口崩片的制备方法，包括如下步骤：
(1)、将右美沙芬、其药学上可接受的盐或其水合物、奎尼丁、其药学上可接受的盐或其水合物与润滑剂混合后过筛，加入填充剂、矫味剂和崩解剂混合后过筛，再加入润滑剂混合；
(2)、将步骤(1)所得的混合物使用干法制粒机制粒，得混合物颗粒；
(3)、将步骤(2)制得的颗粒与润滑剂和崩解剂混合；
(4)、将步骤(3)得到的混合物压片，得到右美沙芬奎尼丁口崩片。
本发明的另一个目的是提供一种右美沙芬奎尼丁口崩片在制备用于治疗和/或预防神经***疾病患者中假性延髓情绪、吞咽困难、流涎或语言障碍、认知缺陷药物中的用途。
与现有技术相比，本发明取得了以下预料不到的技术效果：
1、本发明提供了一种易于吞咽且掩味效果好的右美沙芬奎尼丁制剂。
2、本发明将高通量筛选实验和计算机人工智能相结合，高效准确地获得了各矫味剂对右美沙芬奎尼丁掩味效果的影响。
3、本发明提供的口崩片在加入吸湿性矫味剂的条件下，崩解时间较短，味道易于接受，大大提高了神经***疾病患者的用药体验。
附图说明
图1为本发明矫味剂筛选的高通量实验结果的重要因子分析图。
具体实施方式
下面将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1
称取20mg氢溴酸右美沙芬、10mg硫酸奎尼丁和2mg胶态二氧化硅，混合后过筛，加入32mg甘露醇、16mg木糖醇、40mg微晶纤维素、10mg交联聚维酮、10mg交联羧甲基纤维素钠、4mg三氯蔗糖和4mg薄荷香精，混合后过筛，再次混合均匀，加入2mg过筛后的硬脂富马酸钠，混合均匀后使用干法制粒机制粒。再加入10mg过筛后的交联聚维酮、10mg过筛后的交联羧甲基纤维素钠和2mg过筛后的硬脂富马酸钠，混合均匀后压片，得到右美沙芬奎尼丁口崩片。
实施例2
称取20mg氢溴酸右美沙芬、10mg硫酸奎尼丁和2mg胶态二氧化硅，混合后过筛，加入32mg甘露醇、16mg木糖醇、40mg微晶纤维素、20mg交联聚维酮、4mg三氯蔗糖和4mg薄荷香精，混合后过筛，再次混合均匀，加入2mg过筛后的硬脂富马酸钠，混合均匀后使用干法制粒机制粒。再加入20mg过筛后的交联聚维酮和2mg过筛后的硬脂富马酸钠，混合均匀后压片，得到右美沙芬奎尼丁口崩片。
实施例3
称取20mg氢溴酸右美沙芬、10mg硫酸奎尼丁和2mg胶态二氧化硅，混合后过筛，加入32mg甘露醇、16mg木糖醇、40mg微晶纤维素、20mg交联聚维酮、4mg阿斯巴甜和4mg薄荷香精，混合后过筛，再次混合均匀，加入2mg过筛后的硬脂富马酸钠，混合均匀后使用干法制粒机制粒。再加入20mg过筛后的交联聚维酮和2mg过筛后的硬脂富马酸钠，混合均匀后压片，得到右美沙芬奎尼丁口崩片。
实施例4
称取20mg氢溴酸右美沙芬、10mg硫酸奎尼丁和2mg胶态二氧化硅，混合后过筛，加入32mg甘露醇、16mg木糖醇、24mg微晶纤维素、20mg交联聚维酮、20mg蔗糖和4mg薄荷香精，混合后过筛，再次混合均匀，加入2mg过筛后的硬脂富马酸钠，混合均匀后使用干法制粒机制粒。再加入20mg过筛后的交联聚维酮和2mg过筛后的硬脂富马酸钠，混合均匀后压片，得到右美沙芬奎尼丁口崩片。
实施例5
选用表1所示的常用甜味剂、香精及酸味剂，均配制成浓度为10.4mg/mL的水溶液。从中选取任意三种且保证至少含有一种甜味剂，一共有1372种矫味处方，采用Halton采样法选取251组样本进行高通量实验，选取的样本如表2所示。
分别在高通量实验装置的孔板中加入表2所示组合的矫味剂溶液，每种矫味剂溶液 取0.1mL，向每个孔中分别加入0.5mL氢溴酸右美沙芬水溶液(10.4mg/mL)和0.5mL硫酸奎尼丁水溶液(5.2mg/mL)，混合均匀后，进行人工尝味。尝味步骤如下：
志愿者在测试前至少1小时内不吃、不喝、不嚼口香糖，并用去离子水漱口。使用滴管吸取1mL样品至口中，***样品溶液5s并做漱口动作，使舌根及舌侧的味道感受区充分感受药物味道，吐出，用去离子水漱口至口中没有异味再进行下一次实验。
志愿者对所尝处方的苦味、麻味、酸味及甜味四项进行按10分制评分，分值越高，表明感受到的相应味道越强烈。苦味和麻味按负值计分，酸味，甜味按正值计分，四项得分相加得到综合得分。
表1
表2


将251个处方的尝味结果用计算机人工智能进行建模(酸味值<5,-5<苦味值<0,-5<麻味值<0，且综合得分>0为正样本，否则为负样本)，并且对每种辅料的特征重要性进行分析，结果如图1。图1中，SHAP值>0，表明该点可能为正样本，该值越大，成为正样本的可能性越大。同时，图中深色的点表示该处方中含有此种辅料，浅色的点表示该处方中不含此种辅料。
对各种辅料特征重要性进行定量分析，得到各种辅料对右美沙芬奎尼丁矫味效果的贡献大小，即影响力大小，结果见表3。
表3

结合图1及表3可以得出，三氯蔗糖、阿斯巴甜、果糖、蔗糖、甜菊糖苷、山梨醇或甘露醇均对掩味效果有正向的影响，其中的三氯蔗糖和阿斯巴甜对矫味效果的影响相当，约为果糖、蔗糖或甜菊糖苷影响力的2-3倍、甘露醇或山梨醇的3-4倍。在加入甜味剂的条件下，香精中的草莓香精，酸味剂中的柠檬酸和乳酸，依然对掩味效果起到负向影响。
实施例6
使用相同的矫味剂，加入不同的崩解剂，制成不含活性成分的空白处方，考察其崩解时间，结果见表4。
表4
结果表明，崩解剂中含有交联聚维酮时，可取得较满意的崩解效果。
实施例7
按照实施例1相同的制备方法，制备不同崩解剂含量的处方并检测其崩解时间，结果见表5。
表5
结果表明，本发明制得的口崩片均可满足口崩片对崩解时间的要求。随着处方中交联聚维酮的含量增大，口崩片的崩解速度加快。为保证崩解时间在40s以内，且保证掩味效果，选取崩解剂的含量范围为20-30％(w％)。
实施例8
采用中国药典2020版四部溶出度与释放度测定法第一法(篮法)检测本发明制得的口崩片在不含酶的模拟胃液(pH1.2)(温度37.0℃±0.5℃)中氢溴酸右美沙芬和硫酸奎尼丁的溶出情况，分别在5min、10min和30min取样，以高效液相色谱法测定溶出度(％)，以实施例4制得的口崩片为例，其溶出数据见表6。
表6
结果表明，本发明得到的口崩片在不含酶的模拟胃液(pH1.2)中的溶出度均非常好，在5min时氢溴酸右美沙芬和硫酸奎尼丁的溶出度均已经达到90％以上，满足速释制剂的溶出度要求。
对比例
对比例1
将实施例1中的甜味剂去除，其余组分不变，制备氢溴酸右美沙芬硫酸奎尼丁口崩片。
对比例2
实施例2或3中的甜味剂等质量替换为甘露醇制备氢溴酸右美沙芬硫酸奎尼丁口崩片。
对比例3-4
参照专利文献CN1720917A实施例2-3的处方比例，制备氢溴酸右美沙芬20mg，硫酸奎尼丁10mg的氢溴酸右美沙芬硫酸奎尼丁口崩片。
对比例3处方表：

对比例4处方表
对比例5
按照专利文献CN1720917A实施例3的处方等比例，制备含氢溴酸右美沙芬20mg的氢溴酸右美沙芬口崩片，处方表如下：

对比例6
实施例2或3中的甜味剂等质量替换为糖精钠制备氢溴酸右美沙芬硫酸奎尼丁口崩片。
对比例7：掩味效果分析
对制备得到的各个口崩片进行人工尝味，进行掩味效果评估，每批次药品选择10名志愿者进行实验。
尝味方法为：志愿者服药前润湿口腔。将片剂放入舌头上部，可蠕动舌头至片子块状物消失，将药品吐出。记录所尝片子的麻舌轻重与苦味等级。漱口至口腔中无苦味残留后进行下一批次片剂的尝味。
由于有些片子麻味较重，且麻味具有一定的滞后效果，多批次片子的麻味累加后对后续麻味的评估有影响，故当志愿者感到明显麻味时，需等待至麻味消除再进行下一批次的尝味实验。
经尝味实验，获得各个实施例和对比例的掩味效果如下表7
表7

结果表明，采用本申请的实施例1-3制得的氢溴酸右美沙芬硫酸奎尼丁口崩片，麻舌基本被掩盖，且有7-10人认为不苦。与之相比，当去掉本申请实施例1中的甜味剂或将2-3其中的甜味剂替换为甘露醇之后，不苦人数为0，对于对比例2，甚至有一半的志愿者认为极苦，且麻味也重。可见，本申请中甜味剂三氯蔗糖或阿斯巴甜的加入，对于掩味效果而言，起到了非常大的作用。
相比于专利文献CN1720917A而言，专利文献CN1720917A本身实施例3仅对氢溴酸右美沙芬单方掩味的口崩片的掩味效果就不尽人意，可见专利文献CN1720917A并未关注口崩片的掩味效果。当按照专利文献CN1720917A的配方，加入硫酸奎尼丁之后，虽然麻舌基本被掩盖，但仅有2-3人认为不苦，即苦味未得到较好的掩盖。
此外，发明人还选取相对甜度较高的糖精钠(相对于蔗糖的甜度为300-600)制备了配方，进行了尝味实验，实验结果表明虽然麻舌基本被掩盖，但有多达8人认为药味苦；与之对应，相对甜度低于糖精的阿斯巴甜(相对于蔗糖的甜度为200)仅有3人认为苦或极苦。该实验进一步证明，对于氢溴酸右美沙芬硫酸奎尼丁口崩片而言，甜味剂的选择需要依赖具体的实验评估，不能仅依据相对甜度等常规指标进行选取。
综上所述，本申请的技术方案较不加甜味剂及专利文献CN1720917A的技术方案，在对氢溴酸右美沙芬硫酸奎尼丁的掩味效果上具有明显的优势。
需要指出的是，上述几个较佳实施例是对本发明技术方案作的进一步非限制的详细说明，仅为说明本发明的技术构思和特点。其目的在于让熟悉此项技术的人士能够了解本发明的内容并予以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (9)

  1. 一种右美沙芬奎尼丁口崩片，其特征在于：包含右美沙芬、其药学上可接受的盐或其水合物、奎尼丁、其药学上可接受的盐或其水合物、矫味剂和崩解剂。
  2. 如权利要求1所述的口崩片，其特征在于：所述矫味剂为甜味剂、香精和酸味剂中的一种或多种，优选为至少含有一种甜味剂。
  3. 如权利要求2所述的口崩片，其特征在于：所述甜味剂为蔗糖或其衍生物、阿斯巴甜、果糖、甜菊糖苷、甘露醇或山梨醇中的一种或多种，优选为蔗糖或其衍生物、阿斯巴甜、果糖或甜菊糖苷中的一种或多种，更优选为三氯蔗糖或阿斯巴甜中的一种或多种，更优选右美沙芬、奎尼丁和三氯蔗糖或阿斯巴甜的质量比例为5：2.5：1，或三氯蔗糖或阿斯巴甜的处方比例为2.33％；所述香精为甜橙香精、薄荷香精、牛奶香精或草莓香精中的一种或多种，优选为甜橙香精、薄荷香精或牛奶香精中的一种或多种，更优选为甜橙香精或薄荷香精中的一种或多种；所述酸味剂为碳酸钠、碳酸钾、氯化钠、氯化钾、氢氧化钠、柠檬酸、乳酸中的一种或多种，优选为碳酸钠、碳酸钾、氯化钠、氯化钾、氢氧化钠中的一种或多种，更优选为氯化钠或碳酸钠。
  4. 如权利要求1所述的口崩片，其特征在于：所述崩解剂为交联聚维酮、羧甲基淀粉钠、低取代纤维素、低取代羟丙纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠中的一种或多种，优选为至少含有交联聚维酮，更优选为交联聚维酮或交联聚维酮与交联羧甲基纤维素钠的组合。
  5. 如权利要求1所述的口崩片，其特征在于：所述崩解剂的重量占口崩片总片重的10％-35％，优选为20-30％。
  6. 如权利要求1所述的口崩片，其特征在于：还包含润滑剂、填充剂中的一种或多种。
  7. 如权利要求6所述的口崩片，其特征在于：所述润滑剂为胶态二氧化硅、硬脂富马酸钠、硬脂酸镁、聚乙二醇、月桂醇硫酸镁、氢化植物油、滑石粉、微粉硅胶中的一种或多种，优选为胶态二氧化硅、硬脂富马酸钠中的一种或多种；所述填充剂为微晶纤维素、木糖醇、甘露醇、淀粉、糖粉、糖精、乳糖、预胶化淀粉、硫酸钙、磷酸氢钙、碳酸钙中的一种或多种，优选为微晶纤维素、木糖醇或甘露醇中的一种或多种。
  8. 一种如权利要求1所述的口崩片的制备方法，其特征在于：包括如下步骤：
    (1)、将右美沙芬、其药学上可接受的盐或其水合物、奎尼丁、其药学上可接受的盐或其水合物与润滑剂混合后过筛，加入填充剂、矫味剂和崩解剂混合后过筛，再加入润滑剂混合；
    (2)、将步骤(1)所得的混合物使用干法制粒机制粒，得混合物颗粒；
    (3)、将步骤(2)制得的颗粒与润滑剂和崩解剂混合；
    (4)、将步骤(3)得到的混合物压片，得到右美沙芬奎尼丁口崩片。
  9. 一种如权利要求1所述的右美沙芬奎尼丁口崩片在制备用于治疗和/或预防神经***疾病患者中假性延髓情绪、吞咽困难、流涎或语言障碍、认知缺陷药物中的用途。
PCT/CN2023/086493 2022-04-06 2023-04-06 一种右美沙芬奎尼丁口崩片及其应用 WO2023193745A1 (zh)

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