WO2023207815A1 - 含盐酸去氧肾上腺素片剂、制备方法及应用 - Google Patents

含盐酸去氧肾上腺素片剂、制备方法及应用 Download PDF

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WO2023207815A1
WO2023207815A1 PCT/CN2023/089967 CN2023089967W WO2023207815A1 WO 2023207815 A1 WO2023207815 A1 WO 2023207815A1 CN 2023089967 W CN2023089967 W CN 2023089967W WO 2023207815 A1 WO2023207815 A1 WO 2023207815A1
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preparation
phenylephrine hydrochloride
tablets
mass ratio
auxiliary materials
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English (en)
French (fr)
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贺敦伟
秦杰子
胡愈璋
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则正(上海)生物科技有限公司
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention belongs to the field of pharmaceutical technology, and specifically relates to phenylephrine hydrochloride-containing tablets, preparation methods and applications.
  • Phenylephrine Hydrochloride (C 9 H 13 NO 2 ⁇ HCl, 203.67) is an adrenergic receptor agonist, commonly used to prevent and treat hypotension caused by spinal anesthesia, general anesthesia, chlorpromazine application, etc. Also used for supraventricular tachycardia and dilated pupil examination.
  • phenylephrine hydrochloride can react with chlorpheniramine maleate to form an adduct, which limits the use of phenylephrine hydrochloride in the development of multi-API drugs, and there is an urgent need to provide A feasible multi-API composition containing phenylephrine hydrochloride, and a solution for improving the stability of phenylephrine hydrochloride in multi-API drugs.
  • the object of the present invention is to provide a method for preparing tablets with multiple active pharmaceutical components.
  • the active pharmaceutical components include phenylephrine hydrochloride, in order to improve the removal of phenylephrine hydrochloride through reasonable compounding of different active pharmaceutical components. Stability of oxyepinephrine.
  • Another object of the present invention is to provide drugs with multi-active pharmaceutical components prepared by the above preparation method and their applications, so as to solve the instability of phenylephrine hydrochloride that exists during the use of existing phenylephrine hydrochloride-containing drugs. technical issues.
  • the present invention provides the following technical solutions:
  • the present invention provides a preparation method for tablets containing phenylephrine hydrochloride.
  • the preparation method includes granules a obtained by dry granulation with phenylephrine hydrochloride as a single active pharmaceutical component, mixed with other granules and then pressed piece;
  • the other particles include at least one of particles b and particles c;
  • the granule b contains the active pharmaceutical component acetaminophen
  • the granule c contains the active pharmaceutical components dextromethorphan hydrobromide and chlorpheniramine maleate.
  • the mass ratio of the pharmaceutically active component of particle b and phenylephrine hydrochloride is 20 to 80:1, and the mass ratio of the pharmaceutically active component of particle c and phenylephrine hydrochloride is The ratio is 1.2 ⁇ 4.8:1.
  • the mass ratio of the pharmaceutically active component of particle b and phenylephrine hydrochloride is 40-60:1, preferably 50:1; the pharmaceutically active component of particle c and hydrochloric acid
  • the mass ratio of phenylephrine is 2 to 2.8:1, preferably 2.4:1.
  • auxiliary materials are added during the preparation process, and the auxiliary materials include calcium silicate and other commonly used auxiliary materials.
  • the other commonly used auxiliary materials include at least one of the following:
  • Stabilizer preferably calcium silicate
  • filler preferably mannitol or maltodextrin
  • Lubricant preferably magnesium stearate
  • Defoaming agent preferably dimethicone
  • Flavoring agent preferably strawberry powder flavor
  • Pigment preferably Allura Red
  • the acid source is preferably anhydrous citric acid
  • Sweetener preferably sucralose
  • Binder preferably povidone K30;
  • the alkali source is preferably potassium bicarbonate or sodium bicarbonate.
  • the mass ratio of the excipients used to phenylephrine hydrochloride is 5-200:1, and the mass ratio of calcium silicate to phenylephrine hydrochloride is 1 ⁇ 10:1.
  • the particles b and c are granulated separately;
  • the particles b and c are wet-granulated separately.
  • the present invention provides the application of the preparation method according to any one of the preceding embodiments in preparing a drug for the symptomatic treatment of colds.
  • the present invention provides tablets prepared by using the preparation method described in any one of the preceding embodiments.
  • the tablet dosage form includes oral tablets, buccal tablets, sublingual tablets, external tablets, microcapsule tablets, effervescent tablets or multi-layer tablets.
  • the multi-active component pharmaceutical composition provided by the present invention can ensure the stability of phenylephrine hydrochloride through the reasonable compounding of different API components and phenylephrine hydrochloride.
  • the present invention provides the use of the above pharmaceutical composition to prepare multi-API effervescent tablets and a preparation method thereof.
  • the preparation method separately dry-granulates phenylephrine hydrochloride to obtain Phenylephrine hydrochloride has good stability during the preparation and use of multi-API drugs.
  • the present invention provides a preparation method of tablets containing phenylephrine hydrochloride, which preparation method includes granules a obtained by dry granulation with phenylephrine hydrochloride as the single active pharmaceutical component. Mix with other granules and press into tablets;
  • the other particles include at least one of particles b and particles c;
  • the granule b contains the active pharmaceutical component acetaminophen
  • the granule c contains the active pharmaceutical components dextromethorphan hydrobromide and chlorpheniramine maleate.
  • the mass ratio of the pharmaceutically active component of particle b and phenylephrine hydrochloride is 20 to 80:1, and the mass ratio of the pharmaceutically active component of particle c and phenylephrine hydrochloride is It is 1.2 ⁇ 4.8:1.
  • the mass ratio of the pharmaceutically active component of particle b and phenylephrine hydrochloride is 40-60:1, preferably 50:1; the pharmaceutically active component of particle c and phenylephrine hydrochloride have a mass ratio of The mass ratio of oxyadrenaline is 2 to 2.8:1, preferably 2.4:1.
  • auxiliary materials are added during the preparation process, and the auxiliary materials include calcium silicate and other Commonly used excipients.
  • the calcium silicate is a porous material, and phenylephrine hydrochloride is coated in micropores to avoid the impact of light and oxygen on phenylephrine hydrochloride, and at the same time, it can also reduce the contact between other active ingredients and phenylephrine hydrochloride. , thereby improving the stability of phenylephrine hydrochloride.
  • the other commonly used excipients refer to excipient components that can be obtained by those skilled in the art through routine selection among existing excipients without affecting the stability of phenylephrine hydrochloride. At the same time, this excipient component The addition of points will not change the functional relationship between the above multiple APIs.
  • the other commonly used auxiliary materials include at least one of the following:
  • Stabilizer preferably calcium silicate
  • filler preferably mannitol or maltodextrin
  • Lubricant preferably magnesium stearate
  • Defoaming agent preferably dimethicone
  • Flavoring agent preferably strawberry powder flavor
  • Pigment preferably Allura Red
  • the acid source is preferably anhydrous citric acid
  • Sweetener preferably sucralose
  • Binder preferably povidone K30;
  • the alkali source is preferably potassium bicarbonate or sodium bicarbonate.
  • the mass ratio of the excipients used to phenylephrine hydrochloride is 5 to 200:1, and the mass ratio of calcium silicate to phenylephrine hydrochloride is 1 to 10. :1.
  • the particles b and c are granulated separately.
  • the particles b and c are wet-granulated separately.
  • the present invention provides the application of the preparation method according to any one of the preceding embodiments in preparing symptomatic medicine for treating colds.
  • the present invention provides tablets prepared by using the preparation method described in any one of the preceding embodiments.
  • the tablet dosage form includes oral tablets, buccal tablets, sublingual tablets, external tablets, microcapsule tablets, effervescent tablets or multi-layer tablets.
  • the preparation method includes the following steps:
  • Preparation of granule b Weigh the raw and auxiliary materials, dissolve allura red in water, mix the remaining raw and auxiliary materials in a wet granulator, add allura red aqueous solution to make soft materials, granulate with a rocking granulation mechanism, dry in a fluidized bed, and use a rocking granulator Whole grain.
  • Preparation of granules c Weigh the raw and auxiliary materials, mix them with the raw materials in equal amounts, mix in the wet granulator, add water to make soft materials, granulate with a rocking granulation mechanism, dry in a fluidized bed, and complete with a rocking granulator. grain.
  • the preparation method is the same as Example 1.
  • the preparation method is the same as Example 1.
  • the preparation method is the same as Example 1.
  • Preparation of granules Weigh the raw and auxiliary materials, dissolve allura red in water, add phenylephrine hydrochloride and maltodextrin in equal amounts and mix gradually, then mix with mannitol, then mix with the other raw and auxiliary materials, and place in a wet granulator Mix, add allura red aqueous solution to make soft materials, granulate with rocking granulator, dry in fluidized bed, and granulate with rocking granulator.
  • Preparation of granules 2 Weigh the raw and auxiliary materials, mix the auxiliary materials with the raw materials in equal amounts, mix in the wet granulator, add water to make soft materials, granulate with a swing granulation mechanism, dry in a fluidized bed, and complete with a swing granulator. grain.
  • the prescription is as follows:
  • Preparation of granules Weigh the raw and auxiliary materials, dissolve allura red in water, mix the remaining raw and auxiliary materials in a wet granulator, add allura red aqueous solution to make soft materials, granulate with a rocking granulation mechanism, dry in a fluidized bed, and use a rocking granulator Whole grain.
  • Preparation of Granules 2 Weigh the raw and auxiliary materials, mix the raw materials and maltodextrin in equal amounts in increments, and then mix with the sweetener. Mix with alcohol, mix with other auxiliary materials, mix in wet granulator, add water to make soft material, granulate with rocking granulator, dry in fluidized bed, and granulate with rocking granulator.
  • the prescription is as follows:
  • Preparation of granules Weigh the raw and auxiliary materials, dissolve allura red in water, mix the remaining raw and auxiliary materials in a wet granulator, add allura red aqueous solution to make soft materials, granulate with a rocking granulation mechanism, dry in a fluidized bed, and use a rocking granulator Whole grain.
  • Preparation of granules 2 Weigh the raw and auxiliary materials, mix the auxiliary materials with the raw materials in equal amounts, mix in the wet granulator, add water to make soft materials, granulate with a swing granulation mechanism, dry in a fluidized bed, and complete with a swing granulator. grain.
  • Preparation of granule three Weigh the raw and auxiliary materials, add phenylephrine hydrochloride and maltodextrin in equal amounts and mix incrementally, then mix with mannitol, mix with magnesium stearate, and press into flakes with a dry granulator to make granules.
  • the prescription is as follows:
  • Preparation of granules Weigh the raw and auxiliary materials, dissolve allura red in water, mix the remaining raw and auxiliary materials in a wet granulator, add allura red aqueous solution to make soft materials, granulate with a rocking granulation mechanism, dry in a fluidized bed, and use a rocking granulator Whole grain.
  • Preparation of granules 2 Weigh the raw and auxiliary materials, mix the auxiliary materials with the raw materials in equal amounts, mix in the wet granulator, add water to make soft materials, granulate with a swing granulation mechanism, dry in a fluidized bed, and complete with a swing granulator. grain.
  • Preparation of granule three Weigh the raw and auxiliary materials, mix phenylephrine hydrochloride, dextromethorphan hydrobromide, and calcium silicate, then add and mix with maltodextrin in equal amounts, then mix with mannitol, and stearin Magnesium acid is mixed, and the dry granulator is pressed into flakes and granulated.
  • the prescription is as follows:
  • Preparation of granules Weigh the raw and auxiliary materials, dissolve allura red in water, mix the remaining raw and auxiliary materials in a wet granulator, add allura red aqueous solution to make soft materials, granulate with a rocking granulation mechanism, dry in a fluidized bed, and use a rocking granulator Whole grain.
  • Preparation of granules 2 Weigh the raw and auxiliary materials, mix the auxiliary materials with the raw materials in equal amounts, mix in the wet granulator, add water to make soft materials, granulate with a swing granulation mechanism, dry in a fluidized bed, and complete with a swing granulator. grain.
  • Preparation of granule three Weigh the raw and auxiliary materials, mix phenylephrine hydrochloride, chlorpheniramine maleate, and calcium silicate, then add and mix with maltodextrin in equal amounts, then mix with mannitol, and mix with hard The magnesium fatty acid is mixed, and the dry granulator is pressed into flakes and granulated.
  • Phenylephrine hydrochloride impurity C C 9 H 11 NO 2 ⁇ HCl, 201.65, 1-(3-Hydroxyphenyl)-2-(methylamino)ethan-1-one hydrochloride, molecular structure formula is:
  • Phenylephrine hydrochloride impurity I C 10 H 13 NO 2 , 179.22, 2-Methyl-1,2,3,4-tetrahydroisoquinoline-4,6-diol, the molecular structural formula is:
  • Phenylephrine hydrochloride impurity II, C 7 H 6 O 2 , 122.12, 3-Hydroxybenzaldehyde, molecular structure formula is:
  • Comparative Example 3 is dry granulated, but there is no stabilizer calcium silicate in the granules. It can be seen that after long-term storage, the impurity C also exceeds 0.1%.
  • Comparative Example 4 dextromethorphan hydrobromide and phenylephrine hydrochloride were dry-granulated together.
  • Comparative Example 5 chlorpheniramine maleate and phenylephrine hydrochloride were dry-granulated together. After 3 months and 6 months, After months of storage, impurity C increased significantly, proving the importance of separate granulation.

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Abstract

本发明提供盐酸去氧肾上腺素片剂、制备方法及应用。本发明提供的多活性组分的药物组合物通过不同API组分与盐酸去氧肾上腺素的合理复配，能够保证盐酸去氧肾上腺素的稳定性。同时本发明提供的应用上述药物组合物制备多API片剂药物及其制备方法，该制备方法在上述组合物提供各组分的基础上，将盐酸去氧肾上腺素单独干法制粒，使得到的多API药物在制备和使用过程中，盐酸去氧肾上腺素都具有良好的稳定性。

Description

含盐酸去氧肾上腺素片剂、制备方法及应用
本申请要求于2022年04月27日提交中国专利局、申请号为CN202210454188.1、发明名称为“含盐酸去氧肾上腺素片剂、制备方法及应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于制药技术领域，具体涉及含盐酸去氧肾上腺素片剂、制备方法及应用。
背景技术
盐酸去氧肾上腺素(Phenylephrine Hydrochloride，C9H13NO2·HCl，203.67)是一种肾上腺素受体激动药，常用于防治脊椎麻醉、全身麻醉、应用氯丙嗪等原因引起的低血压，也用于室上性心动过速和散瞳检查等。
由于施药实践中通常需要多种药物活性组分(API)共同发挥作用，因此，多API药物的研发是目前药物开发中的重要方向之一，而盐酸去氧肾上腺素自身性质不稳定，并且易与其他活性组分反应，在多API药物研发中具有明显的应用困难。例如龚亚等人报道了在固体制剂中，盐酸去氧肾上腺素能够与马来酸氯苯那敏反应生成加合物，使得盐酸去氧肾上腺素在多API药物开发中受到限制，亟需提供一种可行的含有盐酸去氧肾上腺素的多API组合物，以及提高盐酸去氧肾上腺素在多API药物中稳定性的解决方案。
发明内容
本发明的目的在于，提供一种多活性药物组分片剂的制备方法，所述活性药物组分包括盐酸去氧肾上腺素，以期通过不同活性药物组分之间的合理复配，提高盐酸去氧肾上腺素的稳定性。
本发明的另一个目的在于，提供应用上述制备方法制备的多活性药物组分的药物及其应用，以解决现有含盐酸去氧肾上腺素药物在使用过程中存在的盐酸去氧肾上腺素不稳定的技术问题。
为了解决上述技术问题，实现上述目的，本发明提供了以下技术方案：
第一方面，本发明提供含盐酸去氧肾上腺素片剂的制备方法，所述制备方法包括以盐酸去氧肾上腺素为单一药物活性组分干法制粒得到的颗粒a与其他颗粒混匀后压片；
所述其他颗粒包括颗粒b和颗粒c中至少一种；
所述颗粒b含有活性药物组分对乙酰氨基酚，所述颗粒c含有活性药物组分氢溴酸右美沙芬和马来酸氯苯那敏。
在可选的实施方式中，所述颗粒b的药物活性组分和盐酸去氧肾上腺素的质量比为20～80：1，所述颗粒c的药物活性组分和盐酸去氧肾上腺素的质量比为1.2～4.8：1。
在可选的实施方式中，所述颗粒b的药物活性组分和盐酸去氧肾上腺素的质量比为40～60：1，优选为50:1；所述颗粒c的药物活性组分和盐酸去氧肾上腺素的质量比为2～2.8：1，优选为2.4:1。
在可选的实施方式中，制备过程中添加辅料，所述辅料包括硅酸钙和其他常用辅料。
在可选的实施方式中，所述其他常用辅料包括以下至少一种：
稳定剂，优选为硅酸钙；
填充剂，优选为甘露醇或麦芽糊精；
润滑剂，优选为硬脂酸镁；
消泡剂，优选为二甲硅油；
调味剂，优选为草莓粉末香精；
色素，优选为诱惑红；
酸源，优选为无水枸橼酸；
甜味剂，优选为三氯蔗糖；
粘合剂，优选为聚维酮K30；
碱源优选为碳酸氢钾或碳酸氢钠。
在可选的实施方式中，颗粒a制备过程中，所使用的辅料与盐酸去氧肾上腺素的质量比为5～200：1，所使用的硅酸钙与盐酸去氧肾上腺素的质量比为1～10:1。
在可选的实施方式中，所述颗粒b和颗粒c分别单独制粒；
优选地，所述颗粒b和颗粒c分别湿法制粒。
第二方面，本发明提供前述实施方式任一项所述制备方法在制备感冒对症治疗药物中的应用。
第三方面，本发明提供采用前述实施方式任一项所述制备方法制备得到的片剂。
在可选的实施方式中，所述片剂剂型包括内服片、口含片、舌下片、外用片、微囊片、泡腾片或多层片。
本发明提供的多活性组分的药物组合物通过不同API组分与盐酸去氧肾上腺素的合理复配，能够保证盐酸去氧肾上腺素的稳定性。同时本发明提供的应用上述药物组合物制备多API泡腾片药物及其制备方法，该制备方法在上述组合物提供各组分的基础上，将盐酸去氧肾上腺素单独干法制粒，使得到的多API药物在制备和使用过程中，盐酸去氧肾上腺素都具有良好的稳定性。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。因此，基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
在具体的实施方式中，第一方面，本发明提供含盐酸去氧肾上腺素片剂的制备方法，所述制备方法包括以盐酸去氧肾上腺素为单一药物活性组分干法制粒得到的颗粒a与其他颗粒混匀后压片；
所述其他颗粒包括颗粒b和颗粒c中至少一种；
所述颗粒b含有活性药物组分对乙酰氨基酚，所述颗粒c含有活性药物组分氢溴酸右美沙芬和马来酸氯苯那敏。
可选的实施方式中，所述颗粒b的药物活性组分和盐酸去氧肾上腺素的质量比为20～80：1，所述颗粒c的药物活性组分和盐酸去氧肾上腺素的质量比为1.2～4.8：1。
可选的实施方式中，所述颗粒b的药物活性组分和盐酸去氧肾上腺素的质量比为40～60：1，优选为50:1；所述颗粒c的药物活性组分和盐酸去氧肾上腺素的质量比为2～2.8：1，优选为2.4:1。
可选的实施方式中，制备过程中添加辅料，所述辅料包括硅酸钙和其他 常用辅料。
所述硅酸钙为多孔材料，将盐酸去氧肾上腺素包覆在微孔中，避免光照和氧气对盐酸去氧肾上腺素的影响，同时也能减少其他活性成分与盐酸去氧肾上腺素的接触，从而提高了盐酸去氧肾上腺素的稳定性。应当理解的是，所述的其他常用辅料是指在不影响盐酸去氧肾上腺素稳定性的情况下，本领域技术人员能够在现有辅料中进行常规选择获得的辅料组分，同时该辅料组分的加入，也不会改变上述多个API之间的作用关系。
可选的实施方式中，所述其他常用辅料包括以下至少一种：
稳定剂，优选为硅酸钙；
填充剂，优选为甘露醇或麦芽糊精；
润滑剂，优选为硬脂酸镁；
消泡剂，优选为二甲硅油；
调味剂，优选为草莓粉末香精；
色素，优选为诱惑红；
酸源，优选为无水枸橼酸；
甜味剂，优选为三氯蔗糖；
粘合剂，优选为聚维酮K30；
碱源优选为碳酸氢钾或碳酸氢钠。
可选的实施方式中，颗粒a制备过程中，所使用辅料与盐酸去氧肾上腺素的质量比为5～200：1，所使用硅酸钙与盐酸去氧肾上腺素的质量比为1～10:1。
可选的实施方式中，所述颗粒b和颗粒c分别单独制粒。
优选地，所述颗粒b和颗粒c分别湿法制粒。
第二方面，本发明提供前述实施方式任一项所述制备方法在制备治疗感冒对症治疗药物中的应用。
第三方面，本发明提供采用前述实施方式任一项所述制备方法制备得到的片剂。
在可选的实施方式中，所述片剂剂型包括内服片、口含片、舌下片、外用片、微囊片、泡腾片或多层片。
可以理解的是，对于前述实施方式中所述得到具体的片剂剂型，本领域技术人员能够参考常规的成型制备方法而通过常规手段调整得到，因此，在前述实施方式中已经限定了其他剂型的情况下，应当理解为，与上述各片剂剂型制备方法相比，未作出实质性改变的其他固体剂型的制备方法也应当属于本发明的保护范围。本发明实施例所述的泡腾片的制备方法只是作为固体剂型制备方法的示例之一。
下面对本发明的一些实施方式作详细说明。在不冲突的情况下，下述的实施例及实施例中的特征可以相互组合。
实施例1
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：

制备方法包括以下步骤：
1、颗粒a制备：称取原辅料，盐酸去氧肾上腺素与硅酸钙混合，与麦芽糊精等量递加混合，与甘露醇混合，与硬脂酸镁混合，干法制粒机压薄片、制颗粒。
2、颗粒b制备：称取原辅料，诱惑红溶于水，其余原辅料湿法制粒机内混合，加诱惑红水溶液制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
3、颗粒c制备：称取原辅料，辅料采用等量递加方式与原料混合，湿法制粒机内混合，加水制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
4、总混：称取颗粒、外加辅料，硅酸钙吸附二甲硅油后，与颗粒、草莓粉末香精混合，再加入硬脂酸镁润滑。
5、旋转压片机、24mm圆形冲压片，环境湿度控制在相对湿度40％以下。
实施例2
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：


制备方法与实施例1相同。
实施例4
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：

制备方法与实施例1相同。
实施例5
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：
制备方法与实施例1相同。
对比例1
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：
制备工艺：
1、颗粒一制备：称取原辅料，诱惑红溶于水，盐酸去氧肾上腺素与麦芽糊精等量递加混合，在与甘露醇混合，在与其余原辅料混合，湿法制粒机内混合，加诱惑红水溶液制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
2、颗粒二制备：称取原辅料，辅料采用等量递加方式与原料混合，湿法制粒机内混合，加水制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
3、总混：称取颗粒、外加辅料，硅酸钙吸附二甲硅油后，与颗粒、草 莓粉末香精混合，再加入硬脂酸镁润滑。
4、旋转压片机、24mm圆形冲压片，环境湿度控制在相对湿度40％以下。
对比例2
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：
处方如下：
制备方法：
1、颗粒一制备：称取原辅料，诱惑红溶于水，其余原辅料湿法制粒机内混合，加诱惑红水溶液制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
2、颗粒二制备：称取原辅料，原料与麦芽糊精等量递加混合，再与甘 露醇混合，与其余辅料混合，湿法制粒机内混合，加水制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
3、总混：称取颗粒、外加辅料，硅酸钙吸附二甲硅油后，与颗粒、草莓粉末香精混合，再加入硬脂酸镁润滑。
4、旋转压片机、24mm圆形冲压片，环境湿度控制在相对湿度40％以下。
对比例3
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：
处方如下：
制备方法：
1、颗粒一制备：称取原辅料，诱惑红溶于水，其余原辅料湿法制粒机内混合，加诱惑红水溶液制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
2、颗粒二制备：称取原辅料，辅料采用等量递加方式与原料混合，湿法制粒机内混合，加水制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
3、颗粒三制备：称取原辅料，盐酸去氧肾上腺素与麦芽糊精等量递加混合，再与甘露醇混合，与硬脂酸镁混合，干法制粒机压薄片、制颗粒。
4、总混：称取颗粒、外加辅料，硅酸钙吸附二甲硅油后，与颗粒、草莓粉末香精混合，再加入硬脂酸镁润滑。
5、旋转压片机、24mm圆形冲压片，环境湿度控制在相对湿度40％以下。
对比例4
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：
处方如下：

制备工艺：
1、颗粒一制备：称取原辅料，诱惑红溶于水，其余原辅料湿法制粒机内混合，加诱惑红水溶液制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
2、颗粒二制备：称取原辅料，辅料采用等量递加方式与原料混合，湿法制粒机内混合，加水制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
3、颗粒三制备：称取原辅料，盐酸去氧肾上腺素、氢溴酸右美沙芬、硅酸钙混合后，再与麦芽糊精等量递加混合，再与甘露醇混合，与硬脂酸镁混合，干法制粒机压薄片、制颗粒。
4、总混：称取颗粒、外加辅料，硅酸钙吸附二甲硅油后，与颗粒、草莓粉末香精混合，再加入硬脂酸镁润滑。
5、旋转压片机、24mm圆形冲压片，环境湿度控制在相对湿度40％以下。
对比例5
本实施例提供了以下药物组合物处方，及使用该处方制备得到泡腾片的方法：
处方如下：

制备方法：
1、颗粒一制备：称取原辅料，诱惑红溶于水，其余原辅料湿法制粒机内混合，加诱惑红水溶液制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
2、颗粒二制备：称取原辅料，辅料采用等量递加方式与原料混合，湿法制粒机内混合，加水制软材，摇摆制粒机制颗粒，流化床干燥，摇摆制粒机整粒。
3、颗粒三制备：称取原辅料，盐酸去氧肾上腺素、马来酸氯苯那敏、硅酸钙混合后，再与麦芽糊精等量递加混合，再与甘露醇混合，与硬脂酸镁混合，干法制粒机压薄片、制颗粒。
4、总混：称取颗粒、外加辅料，硅酸钙吸附二甲硅油后，与颗粒、草莓粉末香精混合，再加入硬脂酸镁润滑。
5、旋转压片机、24mm圆形冲压片，环境湿度控制在相对湿度40％以下。
实验例1
1、使用高效液相色谱，按照如下色谱条件对上述实施例1～6中提供的泡腾片的盐酸去氧肾上腺素进行检测：
2、使用高效液相色谱，按照如下色谱条件对上述实施例1、对比例1～5中提供的泡腾片的盐酸去氧肾上腺素有关物质进行检测，所述有关物质为：
盐酸去氧肾上腺素杂质C，C9H11NO2·HCl，201.65，1-(3-Hydroxyphenyl)-2-(methylamino)ethan-1-one hydrochloride，分子结构式为：
盐酸去氧肾上腺素杂质Ⅰ，C10H13NO2，179.22， 2-Methyl-1,2,3,4-tetrahydroisoquinoline-4,6-diol，分子结构式为：
盐酸去氧肾上腺素杂质Ⅱ，C7H6O2，122.12，3-Hydroxybenzaldehyde，分子结构式为：
色谱检测条件：

上述盐酸去氧肾上腺素及有关物质检测结果如下：
由上述检测结果可以看出，盐酸去氧肾上腺素与硅酸钙混合后，干法制粒，并且颗粒内不添加其他活性成分，稳定性最好。其中实施例1中盐酸去氧肾上腺素为干法制粒，对比例1和对比例2为与其他活性成分共同湿法制粒，可以看出盐酸去氧肾上腺素采用单独干法制粒得到的泡腾片保存3个月后，杂质均小于0.1％，保存6个月后，其杂质C仅为0.1％，其他两种杂质仍小于0.1％，显示出优异的稳定性。对比例3与实施例1相比，同为干法制粒，但是颗粒中没有稳定剂硅酸钙，可以看出，长期保存后，其杂质C也超过了0.1％。对比例4中氢溴酸右美沙芬和盐酸去氧肾上腺素一同干法制粒，对比例5中马来酸氯苯那敏和盐酸去氧肾上腺素一同干法制粒，在经过3个月和6个月的保藏后，杂质C均明显增加，证明了单独制粒的重要性。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修 改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。

Claims (14)

  1. 含盐酸去氧肾上腺素片剂的制备方法，其特征在于，所述制备方法包括以盐酸去氧肾上腺素为单一药物活性组分干法制粒得到的颗粒a与其他颗粒混匀后压片；
    所述其他颗粒包括颗粒b和颗粒c中至少一种；
    所述颗粒b含有活性药物组分对乙酰氨基酚，所述颗粒c含有活性药物组分氢溴酸右美沙芬和马来酸氯苯那敏。
  2. 根据权利要求1所述的制备方法，其特征在于，所述颗粒b的药物活性组分和所述盐酸去氧肾上腺素的质量比为20～80：1，所述颗粒c的药物活性组分和所述盐酸去氧肾上腺素的质量比为1.2～4.8：1。
  3. 根据权利要求2所述的制备方法，其特征在于，所述颗粒b的药物活性组分和所述盐酸去氧肾上腺素的质量比为40～60：1；所述颗粒c的药物活性组分和所述盐酸去氧肾上腺素的质量比为2～2.8：1。
  4. 根据权利要求3所述的制备方法，其特征在于，所述颗粒b的药物活性组分和所述盐酸去氧肾上腺素的质量比为50：1；所述颗粒c的药物活性组分和所述盐酸去氧肾上腺素的质量比为2.4：1。
  5. 根据权利要求1～4任一项所述的制备方法，其特征在于，制备过程中添加辅料，所述辅料包括硅酸钙和其他常用辅料。
  6. 根据权利要求5所述的制备方法，其特征在于，所述其他常用辅料包括以下至少一种：
    稳定剂；
    填充剂；
    润滑剂；
    消泡剂；
    调味剂；
    色素；
    酸源；
    甜味剂；
    粘合剂；
    碱源。
  7. 根据权利要求6所述的制备方法，其特征在于，所述稳定剂为硅酸钙；
    所述填充剂为甘露醇或麦芽糊精；
    所述润滑剂为硬脂酸镁；
    所述消泡剂为二甲硅油；
    所述调味剂为草莓粉末香精；
    所述色素为诱惑红；
    所述酸源为无水枸橼酸；
    所述甜味剂为三氯蔗糖；
    所述粘合剂为聚维酮K30；
    所述碱源为碳酸氢钾或碳酸氢钠。
  8. 根据权利要求5所述的制备方法，其特征在于，所述颗粒a制备过程中，所使用辅料与盐酸去氧肾上腺素的质量比为5～200：1，所使用硅酸钙与盐酸去氧肾上腺素的质量比为1～10:1。
  9. 根据权利要求5所述的制备方法，其特征在于，所述干法制粒的环境湿度控制在相对湿度40％以下。
  10. 根据权利要求5所述的制备方法，其特征在于，所述颗粒b和颗粒c分别单独制粒。
  11. 根据权利要求10所述的制备方法，其特征在于，所述颗粒b和颗粒c分别湿法制粒。
  12. 权利要求1～11任一项所述制备方法在制备感冒对症治疗药物中的应用。
  13. 采用权利要求1～11任一项所述制备方法制备得到的含盐酸去氧肾上腺素片剂。
  14. 根据权利要求13所述的片剂，其特征在于，所述片剂的剂型包括内服片、口含片、舌下片、外用片、微囊片、泡腾片或多层片。
PCT/CN2023/089967 2022-04-27 2023-04-23 含盐酸去氧肾上腺素片剂、制备方法及应用 WO2023207815A1 (zh)

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