WO2022151994A1 - 一种氨氯地平干混悬剂及其制备方法 - Google Patents

一种氨氯地平干混悬剂及其制备方法 Download PDF

Info

Publication number
WO2022151994A1
WO2022151994A1 PCT/CN2021/143500 CN2021143500W WO2022151994A1 WO 2022151994 A1 WO2022151994 A1 WO 2022151994A1 CN 2021143500 W CN2021143500 W CN 2021143500W WO 2022151994 A1 WO2022151994 A1 WO 2022151994A1
Authority
WO
WIPO (PCT)
Prior art keywords
amlodipine
dry suspension
mixture
preparation
hypromellose
Prior art date
Application number
PCT/CN2021/143500
Other languages
English (en)
French (fr)
Inventor
李捍雄
王显著
陈伟棠
陈元
郭萍
吴泳仪
覃永梅
黄洪雪
王丽
Original Assignee
广州一品红制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州一品红制药有限公司 filed Critical 广州一品红制药有限公司
Priority to US18/272,796 priority Critical patent/US20240082160A1/en
Publication of WO2022151994A1 publication Critical patent/WO2022151994A1/zh

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/44221,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Definitions

  • the invention belongs to the technical field of amlodipine preparation, and more particularly relates to a dry suspension of amlodipine and a preparation method thereof.
  • Amlodipine is a calcium channel blocker that is used in the treatment of hypertension and coronary heart disease.
  • amlodipine is oral tablet, such as Norvasc.
  • oral tablet such as Norvasc.
  • solid dosage forms are generally unfriendly to children or the elderly due to the increased risk of choking; additionally, the dose of amlodipine to a child is calculated based on the child's weight, when the calculated dose differs from one or more intact solids
  • the solid dosage form must be separated to provide the correct dosage, and when solid tablets are applied to children, it is difficult to ensure that the dosage is administered accurately.
  • Patents WO2018067959 A1 and WO2019200143A1 disclose an oral liquid preparation of amlodipine, and the corresponding patented product amlodipine suspension ( AZURITY PHARMACEUTICALS INC) has been launched in the United States, which solves the technical problems of amlodipine solid preparations for some patients with difficulty in ingesting and swallowing, and difficulty in dose splitting, and provides patients with higher dose accuracy, compliance and availability of preparations, It can meet the needs of all kinds of patients (especially children and the elderly).
  • amlodipine suspension ( AZURITY PHARMACEUTICALS INC)
  • AZURITY PHARMACEUTICALS INC with poor stability, stable storage conditions of 5 ⁇ 5 °C, high requirements for storage temperature, and oral liquid preparations have disadvantages such as bulky and inconvenient to carry.
  • the technical problem to be solved by the present invention is to provide an oral preparation of amlodipine with no difficulty in ingestion and swallowing, easy to divide doses, convenient to take, good taste, easy to carry and good stability.
  • amlodipine provided by the present invention is prepared by commercially available amlodipine besylate into a salt-forming form with low solubility, which solves the problem that because amlodipine besylate is slightly soluble in water, it is not suitable for preparing Problems with dry suspensions.
  • the present invention discloses a preparation method of amlodipine dry suspension, comprising the following steps:
  • step c) include: pharmaceutically acceptable diluents, suspending agents, defoaming agents, adhesives, glidants, flavoring agents, fillers, lubricants agent and other ingredients, granulated with amlodipine besylate.
  • the oral liquid of amlodipine in the prior art is prepared as a dry suspension, which is easy to divide doses and is convenient to carry. Because amlodipine besylate is slightly soluble in water, it is not suitable to be prepared into a dry suspension, but amlodipine benzoate suitable for preparation into a dry suspension has no commercially available raw materials for sale.
  • the suspension is prepared by preparing the commercially available amlodipine besylate into a salt-formed form with lower solubility without changing the active ingredient of amlodipine, which is more suitable for a dry suspension dosage form.
  • Prior art WO2019200143A1 discloses: a method for preparing amlodipine benzoate, the method comprising: (i) providing an aqueous mixture comprising amlodipine salt, which is more soluble in an aqueous medium than benzyl amlodipine; ( ii) adding sodium benzoate to the aqueous mixture to form a first mixture; (iii) subjecting the first mixture to ultrasonic agitation to form a second mixture comprising amlodipine benzoate.
  • surfactants such as polysorbate 80 in each step: such as adding polysorbate 80 to the aqueous mixture of step (i), and adding more benzene than benzene Methyl amlodipine is more soluble in aqueous media prior to mixing of amlodipine salts (such as amlodipine besylate), minimizing amlodipine adhesion to manufacturing equipment commonly used in metal containers such as those made of stainless steel on the possibility.
  • amlodipine salts such as amlodipine besylate
  • the benzoate of amlodipine was prepared in a stainless steel vessel in the absence of polysorbate 80, amlodipine besylate will adsorb/adher to stainless steel surfaces by adding purified water to the stainless steel vessel , and start mixing with a stirrer with stainless steel paddle, add amlodipine besylate, prepare a batch without polysorbate 80, mix the suspension for about 5 minutes, then add sodium benzoate, it will be observed that in the suspension Large crystals formed rapidly in the medium, and solid material could be observed adhering to and coating the shaft and impeller of the stainless steel stirring paddle and the inner surface of the stainless steel vessel.
  • step (ii) or mixing an aqueous mixture comprising amlodipine besylate and polysorbate 80 before adding sodium benzoate in step (ii); or mixing a first mixture comprising amlodipine besylate, polysorbate 80 and sodium benzoate Mix, and then perform ultrasonic stirring; to ensure uniform dispersion of amlodipine besylate, which is beneficial to the formation of amlodipine benzoate.
  • the method further adding the total amount water, which facilitates the formation of amlodipine benzoate suspensions.
  • the preparation process of the amlodipine dry suspension disclosed in the present invention does not add surfactants such as polysorbate 80, and the amlodipine is fully wetted by the high-speed homogenization process, which solves the problem that the surfactant needs to be added in the prior art
  • polysorbate 80 avoids the adhesion of amlodipine and the difficulty of dispersion of amlodipine besylate, which is not conducive to the formation of amlodipine benzoate.
  • Stirring, high-speed homogenization process is easier to achieve scale-up and industrial production.
  • the technical personnel of the present invention unexpectedly found that the stability of the finished preparation was significantly improved by not adding common surfactants such as polysorbate 80 and sodium lauryl sulfate.
  • the particle size of the API is closely related to the preparation of the dry suspension. Too large particle size or too wide particle size distribution will lead to poor sedimentation volume ratio and dose uniformity of the suspension, which are not conducive to the quality of the dry suspension. It has been verified by experiments. , the high-speed homogenization process can not only fully wet amlodipine, solve the technical problem of reduced stability caused by the incompatibility of surfactants such as polysorbate 80 with amlodipine, and the prepared amlodipine particle size Smaller and narrower in particle size distribution, the prepared dry suspension has the best effect and is suitable for large-scale industrial production; the sodium benzoate added is used for amlodipine salt formation, and has the effect of preservatives, and diluents, auxiliary agents are added. Suspending agent, suspending and dispersing.
  • the weight percentage of amlodipine besylate in the dry suspension in the preparation step a) is 0.5% to 2%, and the weight percentage in the aqueous mixture 1 is 1% to 5%;
  • the weight ratio of sodium formate and amlodipine besylate in step a) is 1 to 5:1;
  • the diluent is preferably one or a mixture of mannitol, erythritol and maltitol, which is in the dry suspension
  • the weight percentage of hypromellose is 80% to 95%;
  • the suspending agent is preferably hypromellose K4M [hypromellose is divided into four types of substitution according to the content of methoxy and hydroxypropoxy, this product is 2208 Type, K series, viscosity (2%) 2700-5040mPa.s, molecular weight 400000, ("Chinese Pharmacopoeia" 2020 Edition 4, the same below)], hypromellose K750 [2208 type, K series, visco
  • defoaming agent such as simethicone
  • glidant such as colloidal silicon dioxide, silicon dioxide or talcum powder
  • flavoring agents such as with sucralose, sodium saccharin or aspartame, to adjust the taste.
  • Binders such as hypromellose E5 [Type 2910, E series, viscosity (2%) 4-6mPa.s] are convenient for granulation.
  • the granulation method of the preparation step c) is preferably high shear wet granulation or fluidized bed granulation.
  • the diluent is mannitol
  • the suspending agent is hypromellose K4M
  • the binder is hypromellose E5, wherein the mannitol has a good taste, and the reducing sugar content is relatively low, which is similar to amlodipine.
  • Good capacity does not affect product stability, hypromellose K4M has good suspending effect, and is easy to disperse, which is conducive to the preparation of products before taking.
  • the present invention specifically provides a kind of preferred prescription as follows:
  • the present invention specifically provides a kind of concrete prescription and preparation method as follows:
  • mixture 1 adds the sodium benzoate of recipe quantity, and high-speed homogenization is prepared into mixture 2, for subsequent use;
  • step b c) adding mannitol, hypromellose K4M and simethicone into the wet mixing granulator, adding 5% hypromellose E5 aqueous solution for granulation, drying and granulating to obtain blank granules; spraying into step b to prepare The mixture 2 is subjected to one-step granulation, the whole granulation is mixed, colloidal silicon dioxide and sucralose are added, and the mixture is mixed and packaged separately.
  • the particle size range is preferably as follows: D90 ⁇ 70um, 10um ⁇ D50 ⁇ 50um.
  • amlodipine dry suspension disclosed by the invention has the advantages of simple and safe ingredients, good preparation stability, simple and easy process, convenient portability, and good market prospect.
  • the preparation process is as follows:
  • mixture 1 adds the sodium benzoate of recipe quantity, prepares by high-speed homogenization process, speed 10000RPM, prepares 10 minutes, prepares into mixture 2, standby;
  • step b Add mannitol and hypromellose K4M into the wet mixing granulator, add purified water b for granulation, dry and granulate to obtain blank granules; add the blank granules into the fluidized bed granulation dryer, spray into The mixture 2 prepared in step b is granulated in one step;
  • each bottle contains 100 mg of amlodipine besylate in terms of amlodipine.
  • the preparation process is as follows:
  • mixture 1 adds the sodium benzoate of recipe quantity, prepares by high-speed homogenization process, speed 8000RPM, prepares for 10 minutes, prepares into mixture 2, standby;
  • each bottle contains 100 mg of amlodipine besylate in terms of amlodipine.
  • the preparation process is as follows:
  • mixture 1 adds the sodium benzoate of recipe quantity, prepares by high-speed homogenization process, speed 8000RPM, prepares for 10 minutes, prepares into mixture 2, standby;
  • step b adding maltitol, erythritol, hypromellose K750 and simethicone into the fluidized bed granulating dryer, spraying the mixture 2 prepared in step b, and carrying out one-step granulation;
  • each bottle contains 100 mg of amlodipine besylate in terms of amlodipine.
  • the preparation process is as follows:
  • mixture 1 adds the sodium benzoate of recipe quantity, prepares by high-speed homogenization process, speed 8000RPM, prepares for 10 minutes, prepares into mixture 2, standby;
  • each bottle contains 100 mg of amlodipine besylate in terms of amlodipine.
  • the preparation process is as follows:
  • mixture 1 adds the sodium benzoate of recipe quantity, prepares by high-speed homogenization process, speed 15000RPM, prepares for 10 minutes, prepares into mixture 2, standby;
  • each bottle contains 100 mg of amlodipine besylate in terms of amlodipine.
  • mixture 1 adds the sodium benzoate of recipe quantity, prepares by high-speed homogenization process, speed 5000RPM, prepares 20 minutes, prepares into mixture 2, standby;
  • each bottle contains 100 mg of amlodipine besylate in terms of amlodipine.
  • mixture 1 adds the sodium benzoate of recipe quantity, prepares by high-speed homogenization process, speed 15000RPM, prepares for 15 minutes, prepares into mixture 2, standby;
  • each bottle contains 100 mg of amlodipine besylate in terms of amlodipine.
  • Comparative example 1 commercially available amlodipine suspension ( AZURITY PHARMACEUTICALS INC)
  • the preparation method is the same as in Example 7.
  • the preparation method is the same as in Example 7.
  • mixture 1 adds the sodium benzoate of recipe quantity, stirs for 30 minutes, prepares into mixture 2, standby;
  • step d) adding the blank particles prepared in step c to the fluidized bed granulation dryer, spraying into the mixture 2 prepared in step b, and performing one-step granulation;
  • mixture 1 was added with the sodium benzoate of the recipe amount, and ultrasonically stirred for 30 minutes to prepare mixture 2 for subsequent use;
  • step d) adding the blank particles prepared in step c to the fluidized bed granulation dryer, spraying into the mixture 2 prepared in step b, and performing one-step granulation;
  • test results of the samples prepared by the above examples and comparative examples of the present invention are as follows
  • Stability investigation The stability is evaluated by the related substances, and the related substances are detected by HPLC.
  • the chromatographic conditions are as follows:
  • octadecylsilane-bonded silica gel as filler (Phenomenex Luna C18 4.6mm ⁇ 250mm, 5 ⁇ m or equivalent chromatographic column); use 1% triethylamine solution (adjust pH to 2.8 with phosphoric acid) as mobile phase A , use methanol-acetonitrile (70:30) as mobile phase B, and perform gradient elution according to the following table; the flow rate is 1.0 ml per minute; the column temperature is 30 °C; the injector temperature is 10 °C. The detection wavelength was 237 nm; the injection volume was 15 ⁇ l.
  • Re-dispersion effect Add an appropriate amount of water to the bottle, shake slightly for 1 minute, and observe whether the particles are completely dispersed.
  • Particle size distribution take an appropriate amount of this product, use a laser diffraction particle size analyzer, according to the particle size and particle size distribution determination method (Chinese Pharmacopoeia 2015 edition of the fourth part of the general rule 0982 third method wet method), take the saturated solution of amlodipine besylate as the dispersion medium , measure.
  • Sedimentation volume ratio Take an appropriate amount of this product, add water to make a suspension containing about 1mg of amlodipine per 1ml, take 50ml of the solution, put it in a stoppered measuring cylinder, seal it tightly, shake vigorously for 1 minute, and let it stand for 45 minutes. Comply with the regulations (General Rule 0123). The specific results are shown in Table 4.
  • the amlodipine dry suspension prepared by the stirring process and the ultrasonic stirring process has larger particle size, wider particle size distribution, faster sedimentation, and higher sedimentation volume. The ratio does not meet the requirements; the amlodipine dry suspension prepared by the high-speed homogenization process has smaller particle size, narrow particle size distribution, slower sedimentation, and the sedimentation volume ratio meets the requirements.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种氨氯地平干混悬剂,其含有稀释剂、助悬剂等,不含表面活性剂,制备方法包括如下步骤:a)以高速均质法制备包含苯磺酸氨氯地平的水性混合物1;b)在混合物1中加入苯甲酸钠,高速均质,得混合物2;c)混合物2与其他组分制粒,干燥。采用高速均质混合原料,制备过程不加入表面活性剂,通过高速均质工艺使氨氯地平充分润湿,简化了处方成份,更适合儿童应用;并且相较于超声搅拌,高速均质工艺更易实现放大和工业化生产,同时制剂稳定性良好,方便携带。

Description

一种氨氯地平干混悬剂及其制备方法
本申请要求申请日为2021年1月18的中国专利申请202110063061.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于氨氯地平制备技术领域,更具体地,涉及一种氨氯地平干混悬剂及其制备方法。
背景技术
氨氯地平是一种钙通道阻滞剂,应用于治疗高血压、冠心病等,氨氯地平临床上已广泛应用多年,疗效确切,是最经常使用的降压药物之一。
氨氯地平临床上应用最广的剂型为口服片剂,如Norvasc。但多达四分之一的人口存在摄取和吞咽固体制剂困难,这部分人群对固体剂型药物疗法顺应性差,从而导致疗法无效。此外,由于窒息的风险增加,固体剂型对于儿童或老年人通常是不友好的;另外,根据儿童的体重计算给儿童的氨氯地平的剂量,当计算的剂量不同于一种或多种完整固体剂型中存在的剂量时,必须将固体剂型分开以提供正确的剂量,当固体片剂应用于儿童时,难以确保给药剂量准确。
专利WO2018067959 A1和WO2019200143A1公开了一种氨氯地平口服液体制剂,相应的专利产品氨氯地平混悬液(
Figure PCTCN2021143500-appb-000001
AZURITY PHARMACEUTICALS INC)已在美上市,解决了氨氯地平固体制剂对于部分患者存在摄取和吞咽困难,及剂量拆分困难的技术问题,为患者提供更高的剂量准确性、顺应性和可用性制剂,可满足各类患者(特别是儿童和老年人)的需求。但市售的专利产品氨氯地平混悬液(
Figure PCTCN2021143500-appb-000002
AZURITY PHARMACEUTICALS INC),稳定性较差,稳定保存的条件为5±5℃,对保存温度要求高,且口服液体制剂存在体积大,携带不便等缺点。
发明内容
本发明要解决的技术问题是提供一种无摄取吞咽困难,易于分剂量,服用方便,口感较好,且携带方便,稳定性好的氨氯地平口服制剂。
此外,本发明提供的氨氯地平口服制剂是以市售的苯磺酸氨氯地平制备成溶解度较低的成盐形式,解决了因苯磺酸氨氯地平在水中微溶,不适宜制备成干混悬剂的问题。
为解决上述技术问题,本发明公开了一种氨氯地平干混悬剂的制备方法,包括如下步骤:
a)采用高速均质法制备含苯磺酸氨氯地平的水性混合物1;
b)在混合物1中加入苯甲酸钠,高速均质后得混合物2;
c)混合物2与其他组分制粒,干燥;
以上各步骤中均不含表面活性剂。本发明提及的制备方法中,步骤c)中其他组分包括:药学上可接受的稀释剂、助悬剂、消泡剂、粘合剂、助流剂、矫味剂、填充剂、润滑剂等成分,与苯磺酸氨氯地平制粒。
本发明通过将现有技术中的氨氯地平口服液制备为干混悬剂,易于分剂量及携带方便。因苯磺酸氨氯地平在水中微溶,不适宜制备成干混悬剂,而适合制备成干混悬剂的苯甲酸氨氯地平无市售原料出售,本发明所公开的氨氯地平干混悬剂,通过在不改变氨氯地平活性成分的前提下,将可市售的苯磺酸氨氯地平制备成溶解度较低的成盐形式,更适合干混悬剂剂型。
现有技术WO2019200143A1公开了:一种制备苯甲酸氨氯地平的方法,该方法包括:(i)提供包含氨氯地平盐的水性混合物,其比苯甲基氨氯地平更易溶于水性介质;(ii)将苯甲酸钠加入到水性混合物中以形成第一混合物;(iii)将第一混合物进行超声搅拌,从而形成包含苯甲酸氨氯地平的第二混合物。但为取得较好的技术效果及适应工业化生产,其需要在各步骤加入表面活性剂如聚山梨酯80:如将聚山梨酯80添加到步骤(i)的水性混合物中,并在添加比苯甲基氨氯地平更易溶于水性介质的氨氯地平盐(如苯磺酸氨氯地平)之前进行混合,最小化了氨氯地平粘附到生产常用设备金属容器例如由不锈钢制成的那些容器上的可能性。在不存在聚山梨酯80的情况下,在不锈钢容器中制备氨氯地平的苯甲酸盐,苯磺酸氨氯地平将吸附/粘附在不锈钢表面上,通过将纯净水添加到不锈钢容器中,并用含不锈钢搅拌桨的搅拌器开始混合,加入苯磺酸氨氯地平,制备不具有聚山梨酯80的批料,将悬浮液混合约5分钟,然后加入苯甲酸钠,将观察到在悬浮液中迅速形成的大晶体,并且能观察到固体材料粘附并涂覆在不锈钢搅拌桨的轴和叶轮以及不锈钢容器的内表面上。或在步骤(ii)中添加苯甲酸钠之前,混合包含苯磺酸氨氯地平和聚山梨酯80的水性混合物;或将包含苯磺酸氨氯地平,聚山梨酯80和苯甲酸钠的第一混合物混合,然后进行超声搅拌;以确保苯磺酸氨氯地平均匀分散,有利于苯甲酸氨氯地平的形成。在制备氨氯地平苯甲酸氨氯地平悬浮液时,还包括在步骤(iii)之后,将第二部分聚山梨酯80添加到包含苯甲酸氨氯地平的第二混合物,该方法进一步添加总量的水,从而有利于形成苯甲酸氨氯地平悬浮液。
本发明所公开的氨氯地平干混悬剂制备过程不加入聚山梨酯80等表面活性剂,而通过高速均质工艺使氨氯地平充分润湿,解决了现有技术中需添加表面活性剂如聚山梨酯80以避免氨氯地平粘附及苯磺酸氨氯地平不易分散,不利于苯甲酸氨氯地平的形成的技术问题,简化了处方成份,更适合儿童应用;并且相较于超声搅拌,高速均质工艺更易实现放大和工业化生产。且本发明技术人员意外发现,不加入聚山梨酯80、十二烷基硫酸钠等常用的表面活性剂,显著提高了制剂成品稳定性。
原料药的粒度和干混悬剂的制备密切相关,粒度过大或粒度分布过宽将导致混悬液沉降体积比和剂量均匀性较差,均不利于干混悬剂的质量,经试验验证,高速均质工艺不仅可使氨氯地平充分润湿,解决因加入聚山梨酯80等表面活性剂与氨氯地平不相容所导致的稳定性降低的技术问题,且制备的氨氯地平粒度较小,粒度分布较窄,制备的干混悬剂效果最佳,且适合工业化大生产;其中加入的苯甲酸钠用于氨氯地平成盐,且具有防腐剂的作用,另加入稀释剂、助悬剂,助悬及助分散。
其中优选制备步骤a)中的苯磺酸氨氯地平在干混悬剂的重量百分比为0.5%~2%,在水性混合物1的重量百分比为1%~5%;制备步骤b)中的苯甲酸钠与步骤a)中苯磺酸氨氯地平的重量比为1~5:1;稀释剂优选为甘露醇、赤藓糖醇、麦芽糖醇中的一种或混合,其在干混悬剂中的重量百分比为80%~95%;助悬剂优选羟丙甲纤维素K4M【根据甲氧基与羟丙氧基含量的不同将羟丙甲纤维素分为四种取代型,本品为2208型,K系列,粘度(2%)2700-5040mPa.s,分子量400000,(《中国药典》2020版4部,下同)】、羟丙甲纤维素K750【2208型,K系列,粘度(2%)560-1050mPa.s,分子量250000】、羟丙甲纤维素K1500【2208型,K系列,粘度(2%)1125-2100mPa.s,分子量300000】中的一种或混合,其在干混悬剂中的重量百分比为1-5%。
本发明还可以加入消泡剂,如西甲硅油,用于消泡,避免服用前配制过程中产生过多气泡;及加入助流剂,如胶态二氧化硅、二氧化硅或滑石粉,调节流动性,同时避免颗粒结块;及加入矫味剂,如与三氯蔗糖、糖精钠或阿司帕坦,调节口感。粘合剂如羟丙甲纤维素E5【2910型,E系列,粘度(2%)4-6mPa.s】,便于制粒。
制备步骤c)制粒方式优选为高剪切湿法制粒或流化床制粒。
最优选地,稀释剂为甘露醇,助悬剂为羟丙甲纤维素K4M,粘合剂为羟丙甲纤维素E5,其中甘露醇口感良好,且还原糖含量较低,与氨氯地平相容性较好,不影响产品稳定性,羟丙甲纤维素K4M助悬效果良好,且容易分散,有利于产品服用前的配制。
本发明具体提供了一种优选处方如下:
物料名称 每瓶处方量(g)
苯磺酸氨氯地平 0.1~0.5
苯甲酸钠 0.1~0.5
纯化水 a 2.5~5
甘露醇 10~20
羟丙甲纤维素K4M 0.3~0.5
羟丙甲纤维素E5 0.05~0.15
西甲硅油 0.01~0.02
纯化水 b 2~5
三氯蔗糖 0.05~0.15
胶态二氧化硅 0.03~0.07
本发明具体提供了一种具体处方及制备方法如下:
物料名称 每瓶处方量(g)
苯磺酸氨氯地平 0.139
苯甲酸钠 0.5
纯化水 a 3.34
甘露醇 13.721
羟丙甲纤维素K4M 0.375
羟丙甲纤维素E5 0.1
西甲硅油 0.015
纯化水 b 2
三氯蔗糖 0.1
胶态二氧化硅 0.05
a)在纯化水a中加入处方量的苯磺酸氨氯地平,高速均质,使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质,制备成混合物2,备用;
c)将甘露醇、羟丙甲纤维素K4M及西甲硅油加入湿法混合制粒机中,加入5%羟丙甲纤维素E5水溶液制粒,干燥整粒得空白颗粒;喷入步骤b中制备的混合物2,进行一步制粒,整粒总混,加入胶态二氧化硅和三氯蔗糖,总混,分装,即得。
用水分散后,粒度范围优选如下:D90≤70um,10um≤D50≤50um。
本发明所公开的氨氯地平干混悬剂,成份简单安全,制剂稳定性良好,且工艺简单易实施,方便携带,具有较好的市场前景。
具体实施方式
以下通过具体实施例再对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅局限于以下的实施例。在不脱离本发明上述技术思想的情况下,根据本领域普通技术知识和惯用手段做出的各种替换或变更,均应包括在本发明的范围内。
实施例1
处方:
物料名称 处方量
苯磺酸氨氯地平 13.9g
苯甲酸钠 13.9g
纯化水 a 1155.0g
甘露醇 621.1g
羟丙甲纤维素K4M 13.0g
纯化水 b 200.0g
制备工艺如下:
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,高速均质工艺制备,速度5000RPM,制备2分钟使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质工艺制备,速度10000RPM,制备10分钟,制备成混合物2,备用;
c)将甘露醇、羟丙甲纤维素K4M加入湿法混合制粒机中,加入纯化水 b制粒,干燥整粒得空白颗粒;将空白颗粒加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
d)整粒总混;
e)颗粒分装,每瓶含苯磺酸氨氯地平以氨氯地平计100mg。
实施例2
处方:
物料名称 处方量
苯磺酸氨氯地平 13.9g
苯甲酸钠 28g
纯化水 a 250.2g
乙醇 27.8g
赤藓糖醇 677.1g
羟丙甲纤维素K1500 31.9g
西甲硅油 1.0g
制备工艺如下:
a)在纯化水 a和乙醇混合溶剂中加入处方量的苯磺酸氨氯地平,高速均质工艺制备,速度8000RPM,制备2分钟使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质工艺制备,速度8000RPM,制备10分钟,制备成混合物2,备用;
c)将赤藓糖醇、羟丙甲纤维素K1500及西甲硅油加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
d)整粒总混;
e)颗粒分装,每瓶含苯磺酸氨氯地平以氨氯地平计100mg。
实施例3
处方:
物料名称 处方7
苯磺酸氨氯地平 13.9g
苯甲酸钠 66.8g
纯化水 a 334g
麦芽糖醇 1488.0g
赤藓糖醇 600.1
羟丙甲纤维素K750 33.2g
西甲硅油 1.3g
阿司帕坦 15g
滑石粉 4.2g
制备工艺如下:
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,高速均质工艺制备,速度8000RPM,制备2分钟使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质工艺制备,速度8000RPM,制备10分钟,制备成混合物2,备用;
c)将麦芽糖醇、赤藓糖醇、羟丙甲纤维素K750及西甲硅油加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
d)整粒总混:加入阿司帕坦和滑石粉,整粒总混;
e)颗粒分装,每瓶含苯磺酸氨氯地平以氨氯地平计100mg。
实施例4
处方:
物料名称 处方7
苯磺酸氨氯地平 13.9g
苯甲酸钠 31.9g
纯化水 a 310g
麦芽糖醇 501.1g
甘露醇 211.7
羟丙甲纤维素K4M 14.2g
羟丙甲纤维素K750 15.1g
羟丙纤维素EXF 10gg
西甲硅油 1.3g
纯化水 b 200g
胶态二氧化硅 3.6g
制备工艺如下:
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,高速均质工艺制备,速度8000RPM,制备2分钟使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质工艺制备,速度8000RPM,制备10分钟,制备成混合物2,备用;
C)将麦芽糖醇、甘露醇、羟丙甲纤维素K4M、羟丙甲纤维素K750及西甲硅油流化床制粒干燥机中,将羟丙纤维素EXF加入纯化水 b中溶解成粘合剂溶解,喷入流化床制粒干燥机中后,再喷入步骤b中制备的混合物2,进行一步制粒;
d)整粒总混:加入胶态二氧化硅,整粒总混;
e)颗粒分装,每瓶含苯磺酸氨氯地平以氨氯地平计100mg。
实施例5
处方:
物料名称 处方7
苯磺酸氨氯地平 13.9g
苯甲酸钠 66.8g
纯化水 a 334g
甘露醇 1377.8g
羟丙甲纤维素K750 36.8g
羟丙甲纤维素E5 10g
西甲硅油 1.5g
纯化水b 200g
阿司帕坦 15g
滑石粉 4.2g
制备工艺如下:
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,高速均质工艺制备,速度8000RPM,制备2分钟使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质工艺制备,速度15000RPM,制备10分钟,制备成混合物2,备用;
c)将甘露醇、羟丙甲纤维素K750及西甲硅油加入湿法混合制粒机中,将羟丙甲纤维素E5加入纯化水b中溶解成粘合剂溶液,加入制粒机中制粒,干燥整粒得空白颗粒;将空白颗粒加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
d)整粒总混:加入阿司帕坦和滑石粉,整粒总混;
e)颗粒分装,每瓶含苯磺酸氨氯地平以氨氯地平计100mg。
实施例6
处方:
物料名称 处方量
苯磺酸氨氯地平 13.9g
苯甲酸钠 50g
纯化水 a 413g
甘露醇 1371.6g
羟丙甲纤维素K4M 37.5g
羟丙甲纤维素E5 10g
西甲硅油 2.0g
纯化水 b 200g
糖精钠 10g
二氧化硅 4g
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,高速均质工艺制备,速度5000RPM,制备2分钟使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质工艺制备,速度5000RPM,制备20分钟,制备成混合物2,备用;
c)将甘露醇、羟丙甲纤维素K4M加入湿法混合制粒机中,将羟丙甲纤维素E5加入纯化水b中溶解成粘合剂溶液,加入制粒机中制粒,干燥整粒得空白颗粒;将空白颗粒加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
d)整粒总混:加入糖精钠和二氧化硅,整粒总混;
e)颗粒分装,每瓶含苯磺酸氨氯地平以氨氯地平计100mg。
实施例7
处方:
物料名称 处方量
苯磺酸氨氯地平 13.9g
苯甲酸钠 50g
纯化水 a 334g
甘露醇 1372.1g
羟丙甲纤维素K4M 37.5g
羟丙甲纤维素E5 10g
西甲硅油 1.5g
纯化水 b 200g
三氯蔗糖 10g
胶态二氧化硅 5g
制备方法:
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,高速均质工艺制备,速度5000RPM,制备2分钟使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,高速均质工艺制备,速度15000RPM,制备15分钟,制备成混合物2,备用;
c)将甘露醇、羟丙甲纤维素K4M及西甲硅油加入湿法混合制粒机中,将羟丙甲纤维素E5加入纯化水b中溶解成粘合剂溶液,加入制粒机中制粒,干燥整粒得空白颗粒;将空白颗粒加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
d)整粒总混:加入三氯蔗糖和胶态二氧化硅,整粒总混;
e)颗粒分装,每瓶含苯磺酸氨氯地平以氨氯地平计100mg。
对比例1市售氨氯地平混悬液(
Figure PCTCN2021143500-appb-000003
AZURITY PHARMACEUTICALS INC)
对比例2
处方:
物料名称 处方量
苯磺酸氨氯地平 13.9g
苯甲酸钠 50g
聚山梨酯80 6.7g
纯化水 a 334g
甘露醇 1372.1g
羟丙甲纤维素K4M 37.5g
羟丙甲纤维素E5 10g
西甲硅油 1.5g
纯化水 b 200g
三氯蔗糖 10g
胶态二氧化硅 5g
制备方法同实施例7
对比例3
处方:
物料名称 处方量
苯磺酸氨氯地平 13.9g
苯甲酸钠 50g
聚山梨酯20 5g
纯化水 a 334g
甘露醇 1372.1g
羟丙甲纤维素K4M 37.5g
羟丙甲纤维素E5 10g
西甲硅油 1.5g
纯化水 b 200g
三氯蔗糖 10g
胶态二氧化硅 5g
制备方法同实施例7。
对比例4
处方:物料名称 处方量
苯磺酸氨氯地平 13.9g
苯甲酸钠 50g
十二烷基硫酸钠 5g
纯化水 a 334g
甘露醇 1372.1g
羟丙甲纤维素K4M 37.5g
羟丙甲纤维素E5 10g
西甲硅油 1.5g
纯化水 b 200g
三氯蔗糖 10g
胶态二氧化硅 5g
制备方法同实施例7。
对比例5
处方同实施例7
制备方法:
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,搅拌使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,搅拌30分钟,制备成混合物2,备用;
c)将甘露醇、羟丙甲纤维素K4M及西甲硅油加入湿法混合制粒机中,加入羟丙甲纤维素E5水溶液制粒,干燥整粒得空白颗粒;
d)将步骤c中制备的空白颗粒加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
e)整粒总混:加入胶态二氧化硅和三氯蔗糖,总混,分装,即得。
对比例6
处方同实施例7
制备方法:
a)在纯化水 a中加入处方量的苯磺酸氨氯地平,超声搅拌使分散均匀,得混合物1;
b)混合物1加入处方量的苯甲酸钠,超声搅拌30分钟,制备成混合物2,备用;
c)将甘露醇、羟丙甲纤维素K4M及西甲硅油加入湿法混合制粒机中,加入羟丙甲纤维素E5水溶液制粒,干燥整粒得空白颗粒;
d)将步骤c中制备的空白颗粒加入流化床制粒干燥机中,喷入步骤b中制备的混合物2,进行一步制粒;
e)整粒总混:加入胶态二氧化硅和三氯蔗糖,总混,分装,即得。
本发明以上实施例及对比例所制备的样品的试验测试结果如下
1、稳定性考察:通过有关物质评价稳定性,有关物质采用HPLC检测,色谱条件如下:
用十八烷基硅烷键合硅胶为填充剂(Phenomenex Luna C18 4.6mm×250mm,5μm或效能相当的色谱柱);以1%三乙胺溶液(用磷酸调节pH值至2.8)为流动相A,以甲醇-乙腈(70:30)为流动相B,按下表进行梯度洗脱;流速为每分钟1.0ml;柱温为30℃;进样器温度为10℃。检测波长为237nm;进样体积15μl。
表1
Figure PCTCN2021143500-appb-000004
Figure PCTCN2021143500-appb-000005
结果显示,聚山梨酯80等表面活性剂的存在严重影响制剂的稳定性,实施例样品的稳定性优于含有润湿剂的对比例,具体结果见表2及表3。
表2 60℃10天有关物质稳定性数据对比
Figure PCTCN2021143500-appb-000006
Figure PCTCN2021143500-appb-000007
表3 40℃3个月有关物质稳定性数据对比
Figure PCTCN2021143500-appb-000008
Figure PCTCN2021143500-appb-000009
Figure PCTCN2021143500-appb-000010
2、再分散效果、粒度分布、沉降体积比:
再分散效果:在药瓶中加入适量的水,轻微振摇1分钟,观察颗粒是否完全分散。
粒度分布:取本品适量,使用激光衍射粒度分析仪,照粒度和粒度分布测定法(中国药典2015版四部通则0982第三法湿法),以苯磺酸氨氯地平的饱和溶液为分散介质,测定。
沉降体积比:取本品适量,加水制成每1ml约含氨氯地平1mg的混悬液,取溶液50ml,置具塞量筒中,密塞,用力振摇1分钟,静置45分钟,应符合规定(通则0123)。具体结果见表4。
表4
Figure PCTCN2021143500-appb-000011
Figure PCTCN2021143500-appb-000012
结果显示:实施例制备样品再分散效果、粒度分布、沉降体积比均符合要求,搅拌工艺及超声搅拌工艺制备的氨氯地平干混悬剂粒度较大,粒度分布宽,沉降较快,沉降体积比不符合要求;高速均质工艺制备的氨氯地平干混悬剂粒度较小,粒度分布窄,沉降较慢,沉降体积比均符合要求。

Claims (10)

  1. 一种氨氯地平干混悬剂的制备方法,其特征在于,包括如下步骤:
    a)采用高速均质法制备含苯磺酸氨氯地平的水性混合物1;
    b)在混合物1中加入苯甲酸钠,高速均质后得混合物2;
    c)混合物2与其他组分制粒,干燥;
    以上各步骤中均不含表面活性剂。
  2. 根据权利要求1所述氨氯地平干混悬剂的制备方法,其特征在于,所述表面活性剂是指聚山梨酯80或十二烷基硫酸钠。
  3. 根据权利要求1所述氨氯地平干混悬剂的制备方法,其特征在于,采用高速均质法混合各原料,所述均质的转速为4000~10000转/每分钟,均质时间为2~4分钟。
  4. 根据权利要求1所述氨氯地平干混悬剂的制备方法,其特征在于,所述步骤a)中的苯磺酸氨氯地平在水性混合物1的重量百分比为1%~5%。
  5. 根据权利要求1所述氨氯地平干混悬剂的制备方法,其特征在于,所述步骤c)制粒方式为高剪切湿法制粒或流化床制粒。
  6. 根据权利要求1或4所述氨氯地平干混悬剂的制备方法,其特征在于,所述苯磺酸氨氯地平在干混悬剂的重量百分比为0.5%~2%,苯甲酸钠与苯磺酸氨氯地平的重量比为1~5:1。
  7. 一种权利要求1所述制备方法得到的氨氯地平干混悬剂,其特征在于,所述氨氯地平干混悬剂包括苯磺酸氨氯地平、苯甲酸钠、稀释剂、助悬剂。
  8. 根据权利要求7所述氨氯地平干混悬剂,其特征在于,所述稀释剂为甘露醇、赤藓糖醇或麦芽糖醇中的一种或多种,在干混悬剂中的重量百分比为80%~95%。
  9. 根据权利要求7所述氨氯地平干混悬剂,其特征在于,所述助悬剂为羟丙甲纤维素K4M,所述助悬剂在干混悬剂中的重量百分比为1~5%。
  10. 根据权利要求7所述氨氯地平干混悬剂,其特征在于,所述氨氯地平干混悬剂还包括药学可接受的消泡剂、粘合剂、助流剂和矫味剂。
PCT/CN2021/143500 2021-01-18 2021-12-31 一种氨氯地平干混悬剂及其制备方法 WO2022151994A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/272,796 US20240082160A1 (en) 2021-01-18 2021-12-31 Amlodipine dry suspension and preparation method therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110063061.2 2021-01-18
CN202110063061.2A CN112716903B (zh) 2021-01-18 2021-01-18 一种氨氯地平干混悬剂及其制备方法

Publications (1)

Publication Number Publication Date
WO2022151994A1 true WO2022151994A1 (zh) 2022-07-21

Family

ID=75592030

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/143500 WO2022151994A1 (zh) 2021-01-18 2021-12-31 一种氨氯地平干混悬剂及其制备方法

Country Status (3)

Country Link
US (1) US20240082160A1 (zh)
CN (2) CN115837012A (zh)
WO (1) WO2022151994A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115837012A (zh) * 2021-01-18 2023-03-24 广州一品红制药有限公司 一种氨氯地平干混悬剂及其制备方法
CN113209093B (zh) * 2021-05-17 2024-03-08 瑞阳制药股份有限公司 硝唑尼特药物组合物及其制备方法
CN114191402A (zh) * 2022-01-17 2022-03-18 成都恒瑞制药有限公司 苯磺酸氨氯地平片制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101422437A (zh) * 2008-11-14 2009-05-06 李铁军 一种依托泊苷干混悬剂及其制备方法
CN102114017A (zh) * 2011-01-05 2011-07-06 王定豪 包含氨氯地平和培哚普利的药物组合物及其应用
CN102988181A (zh) * 2012-12-31 2013-03-27 广州白云山天心制药股份有限公司 一种口服固体制剂的制粒方法及其用途
US20190314279A1 (en) * 2018-04-11 2019-10-17 Silvergate Pharmaceuticals, Inc. Amlodipine formulations
CN110974787A (zh) * 2019-12-31 2020-04-10 浙江普利药业有限公司 泊沙康唑干混悬剂及其制备方法
CN112716903A (zh) * 2021-01-18 2021-04-30 广州一品红制药有限公司 一种氨氯地平干混悬剂及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060125824A (ko) * 2003-12-01 2006-12-06 라이프사이클 파마 에이/에스 레르카니디핀을 포함한 약학적 조성물
CN1686121A (zh) * 2005-04-19 2005-10-26 昆明金殿制药有限公司 苯磺酸氨氯地平分散片及其制备方法
CN101966181A (zh) * 2010-07-08 2011-02-09 王丽燕 包含坎地沙坦和氨氯地平的口服固体制剂及其新应用
US10350171B2 (en) * 2017-07-06 2019-07-16 Dexcel Ltd. Celecoxib and amlodipine formulation and method of making the same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101422437A (zh) * 2008-11-14 2009-05-06 李铁军 一种依托泊苷干混悬剂及其制备方法
CN102114017A (zh) * 2011-01-05 2011-07-06 王定豪 包含氨氯地平和培哚普利的药物组合物及其应用
CN102988181A (zh) * 2012-12-31 2013-03-27 广州白云山天心制药股份有限公司 一种口服固体制剂的制粒方法及其用途
US20190314279A1 (en) * 2018-04-11 2019-10-17 Silvergate Pharmaceuticals, Inc. Amlodipine formulations
CN110974787A (zh) * 2019-12-31 2020-04-10 浙江普利药业有限公司 泊沙康唑干混悬剂及其制备方法
CN112716903A (zh) * 2021-01-18 2021-04-30 广州一品红制药有限公司 一种氨氯地平干混悬剂及其制备方法

Also Published As

Publication number Publication date
US20240082160A1 (en) 2024-03-14
CN112716903A (zh) 2021-04-30
CN112716903B (zh) 2023-03-21
CN115837012A (zh) 2023-03-24

Similar Documents

Publication Publication Date Title
WO2022151994A1 (zh) 一种氨氯地平干混悬剂及其制备方法
US20200323776A1 (en) Diclofenac formulations and methods of use
TWI228414B (en) Pharmaceutical composition comprising carvedilol and hydrochlorothiazide, solid dosage form comprising it, and process for the production of the same
UA72922C2 (uk) ФАРМАЦЕВТИЧНА КОМПОЗИЦІЯ З <font face="Symbol">b</font>-КАРБОЛІНОМ (ВАРІАНТИ) ТА СПОСІБ ЛІКУВАННЯ СЕКСУАЛЬНОЇ ДИСФУНКЦІЇ
HUE035013T2 (en) Delayed oral dosage forms containing amorphous CDDO-Me
CA1324083C (en) Pharmaceutical preparations containing non-steroidal anti-inflammatory agents
JP3518601B2 (ja) エバスタイムまたはその類似体に基づく医薬組成物
US20090155359A1 (en) Granulated particles, tablets and method for producing granulated particles
JP2849047B2 (ja) ジクロフェナクナトリウム持続性製剤およびその製法
RU2616500C2 (ru) Композиция пазопаниба
TWI724534B (zh) 纖維素粉末、錠劑及錠劑之製造方法
JP2002114674A (ja) 分岐鎖アミノ酸を含有する医薬用懸濁剤
WO2019004953A1 (en) LEVOCLOPERASTIN FENDIZOATE SUSPENSION HAVING IMPROVED DISSOLUTION AND SUSPENSION CAPACITY
FR2730163A1 (fr) Nouvelle composition pharmaceutique contenant la trimebutine et son procede de preparation
WO2013182625A1 (en) Pharmaceutical formulation with propargylamine compound
JPS58401B2 (ja) ケイコウヨウイヤクヒンソセイブツノ セイホウ
JP2003221329A (ja) 分岐鎖アミノ酸を含有するドライシロップ剤
JPH07173065A (ja) 速溶性の医療用アルギン酸ナトリウム造粒物およびその製造法
JPH04288013A (ja) 懸濁シロップ剤
JP3341766B2 (ja) 分岐鎖アミノ酸を含有する医薬用懸濁剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21919181

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 18272796

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205 DATED 17/11/2023)