WO2021238232A1 - 盐酸普拉克索口服溶液 - Google Patents

盐酸普拉克索口服溶液 Download PDF

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WO2021238232A1
WO2021238232A1 PCT/CN2021/070732 CN2021070732W WO2021238232A1 WO 2021238232 A1 WO2021238232 A1 WO 2021238232A1 CN 2021070732 W CN2021070732 W CN 2021070732W WO 2021238232 A1 WO2021238232 A1 WO 2021238232A1
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Prior art keywords
pramipexole
pramipexole hydrochloride
paraben
flavor
oral liquid
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PCT/CN2021/070732
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English (en)
French (fr)
Inventor
范新华
张严源
贺赟
李鹏飞
张翔
吴龙昊
彭鹏
庄苏静
肖立
屠永锐
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常州市第四制药厂有限公司
北京兴源联合医药科技有限公司
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Application filed by 常州市第四制药厂有限公司, 北京兴源联合医药科技有限公司 filed Critical 常州市第四制药厂有限公司
Priority to CN202180022049.5A priority Critical patent/CN115297843A/zh
Priority to US17/799,950 priority patent/US11801236B2/en
Publication of WO2021238232A1 publication Critical patent/WO2021238232A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/08—Solutions
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

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  • the present invention relates to pramipexole or a pharmaceutical salt preparation thereof, and preferably provides a pramipexole hydrochloride oral solution. It belongs to the field of pharmaceutical preparations.
  • Parkinson’s disease (Parkinson’s disease) is a common, slowly progressing neurodegenerative disease that occurs in middle-aged and elderly people, and most patients develop the disease after 60 years of age. The main manifestations are slow movements of the patient, tremors of hands, feet or other parts of the body, and the body loses its original flexibility and coordination. At present, there is no complete cure for the disease, and long-term, continuous drug treatment is needed to inhibit the progression of the disease. Therefore, for such patients, there is a need for a medicine that is easy to take, has low side effects, stable curative effect, and good tolerability and compliance. Pramipexole can be used alone in the treatment of Parkinson's disease to reduce the incidence of dyskinesia caused by levodopa treatment. Combined with levodopa, it can reduce the dose and adverse effects of levodopa. Early use of pramipexole and earlier use of levodopa can delay the onset of these symptoms and improve the patient's quality of life.
  • Pramipexole (Pramipexole), chemical name (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole, is an antihistamine, and is mainly used clinically to treat Parkinson's Disease and its syndromes.
  • Pramipexole hydrochloride refers to the monohydrate of pramipexole containing two hydrochloric acid molecules, the chemical formula is C 10 H 17 N 3 S ⁇ 2HCl ⁇ H 2 O, and the molecular weight is 211.32.
  • dosage forms include immediate-release tablets and sustained-release tablets, of which the market specifications of immediate-release tablets are: 0.125mg, 0.25mg, 0.5mg, 1.0mg and 1.5mg, and the tablets are packaged in aluminum.
  • immediate-release tablets 0.125mg, 0.25mg, 0.5mg, 1.0mg and 1.5mg
  • the pramipexole dihydrochloride monohydrate tablets marketed in the United States in 2005 have the problem of instability in storage. After 18 months of storage, there is only about 95% of the active ingredient in the average labelled amount, which affects the The curative effect of the medicine also increases the cost and safety of manufacturing and medication for patients.
  • pramipexole or its pharmaceutically acceptable salts such as pramipexole hydrochloride
  • the stability in solution restricts the development of its formulations, especially for elderly patients who have difficulty swallowing.
  • CN102846541A discloses a pramipexole oral liquid containing a buffer and a preparation method thereof. It is believed that controlling the pH range of the oral liquid has a great influence on the stability of the preparation. This document does not record the determination method of related substances in the stability influencing factor test.
  • the inventors conducted a stability influencing factor test on the pramipexole oral solution in CN102846541A, which claimed to use citrate-sodium citrate buffer solution as the buffer, and the results showed the stability of the oral solution. It is still not ideal and needs to be improved.
  • the inventors unexpectedly found a method to improve or improve the stability of pramipexole or its pharmaceutical salt formulations in the research. , And further provide a preparation of pramipexole or its salt with stable storage, especially a new pramipexole hydrochloride oral solution.
  • the present invention provides a method for improving or improving the stability of pramipexole or its pharmaceutical salt formulation, which is characterized in that the formulation does not contain a buffer and/or a buffer system.
  • the method described above, wherein the pramipexole or its pharmaceutically acceptable salt is pramipexole hydrochloride.
  • the preparation is preferably a solution dosage form, for example, an oral solution or an injection solution; more preferably, the preparation is an oral liquid.
  • a pramipexole hydrochloride oral liquid which contains pramipexole hydrochloride, a preservative and water, characterized in that the oral liquid does not contain a buffer or a buffer system.
  • the pramipexole hydrochloride oral liquid described above wherein the preservative may be paraben or its salt, benzoic acid or its salt, sorbic acid or its salt.
  • the aforementioned pramipexole hydrochloride oral liquid wherein the preservative is selected from the group consisting of methyl paraben, propyl paraben, ethyl paraben, butyl paraben, and paraben One or more of sodium methyl ester, sodium ethyl paraben, sodium propyl paraben, sodium butyl paraben, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate; more preferably, The preservative mentioned is methyl paraben and/or propyl paraben.
  • the aforementioned pramipexole hydrochloride oral liquid is characterized in that it further contains a chelating agent; preferably, the chelating agent is selected from the group consisting of aminotriacetic acid, hydroxyethylethylenediaminetriacetic acid, and diethylenetriacetic acid.
  • the chelating agent is selected from the group consisting of aminotriacetic acid, hydroxyethylethylenediaminetriacetic acid, and diethylenetriacetic acid.
  • the chelating agent is selected from the group consisting of aminotriacetic acid, hydroxyethylethylenediaminetriacetic acid, and diethylenetriacetic acid.
  • EDTA-2Na disodium ethylenediaminetetraacetic acid
  • EDTA-CaNa 2 calcium sodium ethylenediaminetetraacetate
  • the pramipexole hydrochloride oral solution described above in the present invention may also contain a flavoring agent, and the flavoring agent usually refers to a sweetening agent or a flavoring agent.
  • the sweetener may be selected from one or more of sucrose, xylitol, sorbitol, fructose, glucose, aspartame, sucralose, acesulfame K, and sodium saccharin, for example, sucralose is preferred.
  • Flavors usually refer to fruit flavors, which can be selected from one or two of strawberry flavor, orange flavor, lychee flavor, mixed berry flavor, banana flavor, orange flavor, grape flavor, lime flavor, etc., for example, preferably Blended with berry flavor.
  • the content of pramipexole hydrochloride per unit preparation is 0.01 mg/ml-10 mg/ml; preferably, the content of pramipexole hydrochloride per unit preparation is 0.02 mg /ml ⁇ 1.0mg/ml; preferably, the content of pramipexole hydrochloride per unit preparation is 0.05mg/ml ⁇ 0.3mg/ml; as a specific embodiment of the present invention, the pramipexole hydrochloride described above is taken orally Liquid, more preferably, the content of pramipexole hydrochloride per unit preparation or per unit dose is 0.125-0.25 mg/ml.
  • the pramipexole or its salt formulations of the present invention do not contain buffers and/or buffer systems, and the formulations show excellent stability and bioavailability.
  • Buffers also known as acid-base stabilizers, are generally salts, such as strong acid and weak base or weak acid and strong base salts, which gradually release the acid or base in the salt during reaction or storage to maintain a stable pH;
  • the buffer system is generally a mixture of weak acids or weak bases and their salts.
  • the buffer or buffer system in the present invention refers to a commonly used or conventional buffer or buffer system in the pharmaceutical field, and is not particularly limited, for example, including but not limited to citric acid-disodium hydrogen phosphate buffer solution, Citrate-sodium citrate buffer solution, sodium dihydrogen phosphate-sodium hydroxide buffer solution, tartaric acid-sodium hydroxide, phosphate buffer solution, etc.
  • the content or amount of preservatives, chelating agents, and correctives can be used according to requirements in accordance with conventional amounts in the art, and there is no particular limitation.
  • the preservative content is usually 0.02% to 0.5% (w/v); the chelating agent usually contains 0.01-0.25% (w/v) ), the content of flavoring agent is 0.01-60% (w/v).
  • the preservative content can be 0.02% to 0.2% (w/v)
  • the chelating agent content can be 0.01 to 0.05% (w/v)
  • the flavoring agent content can be 0.1-10% (w/v).
  • the present invention surprisingly found that pramipexole or its pharmaceutically acceptable salt formulations, especially pramipexole hydrochloride oral solution, without a buffer and/or buffer system, the stability of the formulation has been significantly improved or improved .
  • the solution formulation formed by mixing pramipexole hydrochloride with preservatives and water shows excellent stability and bioavailability, and achieves unexpected effects, thereby providing a simple and stable pramipexole hydrochloride Oral liquid, and because it can perfectly realize the problem of multi-dose administration, it provides a new type of pramipexole hydrochloride dosing regimen for the clinic, which can effectively treat Parkinson’s disease to improve the compliance and accessibility of patients’ medication sex.
  • Figure 1 Comparison of the bioavailability results of the oral preparation of Example 2 of the present invention and the comparative preparation pramipexole hydrochloride tablets (specification: 0.25 mg)
  • R drug- refers to the comparative preparation
  • a drug- refers to the preparation of Example 2.
  • the total volume of each batch is 10000ml, but when the formula and the configuration process are listed, the formula and preparation method are explained by the composition of each 100ml of the drug solution. At the time, the amount of liquid medicine per bottle is initially set at 100ml.
  • the detection method involved in the present invention the detection method of related substances is determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Fourth General Rule 0512).
  • the stability test was conducted in accordance with the fourth part of the stability test of the Chinese Pharmacopoeia 2015 edition.
  • pramipexole hydrochloride reference substance and impurity A (6S)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine), accurately weigh, add solvent to dissolve and dilute to each 1ml solution containing 7.5 ⁇ g pramipexole hydrochloride and 3.0 ⁇ g impurity A is used as the system suitability solution. Precisely measure 5 ⁇ L of the system suitability solution and inject it into the liquid chromatograph, and record the chromatogram.
  • the resolution of impurity A and pramipexole hydrochloride shall not be less than 6.0, and the pramipexole hydrochloride tailing factor shall not be greater than 2.0.
  • Determination method Take an appropriate amount of this product and dilute it with a solvent to a solution containing 1.5mg of pramipexole hydrochloride per 1ml, as the test solution; accurately measure an appropriate amount of the test solution, add a solvent to dissolve and dilute to a solution containing pramipexole hydrochloride per 1ml A 1.5 ⁇ g solution was used as a self-control solution. Precisely measure 5 ⁇ L each of the test solution and the self-control solution, respectively inject them into the liquid chromatograph, and record the chromatogram. Calculate according to the following formula. If there are chromatographic peaks in the test solution chromatogram, the sum of the peak areas of each impurity must not be greater than 5 times (0.5%) of the main peak area of the control solution.
  • Impurity content% ( ru /r s )*(C s /C u )*100%
  • composition of the prescription is as follows:
  • Pramipexole hydrochloride 0.0125 Active ingredient Methyl paraben 0.18 preservative Propylparaben 0.02 preservative water 99.7875 Solvent
  • composition of the prescription is as follows:
  • composition of the prescription is as follows:
  • composition of the prescription is as follows:
  • composition of the prescription is as follows:

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Abstract

提供了一种提高或改善普拉克索及其药用盐制剂稳定性的方法，并进而提供一种盐酸普拉克索水溶液形式的口服给药的药物组合物，口服溶液制备工艺简单，化学稳定性好，可解决多剂量给药问题，进一步避免老年患者的吞咽问题，口服溶液与含有盐酸普拉克索的片剂显示出生物等效性，同时具有更好稳定性和优良的口服吸收效果。

Description

盐酸普拉克索口服溶液 技术领域
本发明涉及普拉克索或其药用盐制剂，优选地，提供一种盐酸普拉克索口服溶液。属于药物制剂领域。
发明背景
帕金森病(Parkinson’S disease)是一种常见的发生于中老年人的缓慢进展的神经系统变性疾病，患者多在60岁以后发病。主要表现为患者动作缓慢，手脚或身体其它部分的震颤，身体失去了原有的柔软性和协调性。目前该病尚无彻底治愈的方法，需要长期、持续的药物治疗，抑制病情进展。因此，对于该类患者，需要一种易于服用、副作用小、疗效稳定、耐受性和顺应性好的药品。普拉克索可单独应用于帕金森病的治疗，减少左旋多巴治疗所致运动障碍的发生率，与左旋多巴联用，可减少左旋多巴的剂量和不良反应。早期使用普拉克索较早期使用左旋多巴能够延缓这些症状的出现，并能够改善患者的生存质量。
普拉克索(Pramipexole)，化学名称(S)-2-氨基-4，5，6，7-四氢-6-丙胺-苯并噻唑，为抗组胺药，临床上主要用于治疗帕金森病及其综合征。盐酸普拉克索是指普拉克索含有两个盐酸分子的一水合物，化学式为C 10H 17N 3S·2HCl·H 2O，分子量为211.32。目前上市剂型有速释片和缓释片，其中速释片上市规格有：0.125mg、0.25mg、0.5mg、1.0mg和1.5mg，片子采用铝包装。2005年在美国上市的普拉克索二盐酸盐单水合物片剂存在存放不稳定的问题，在储存18个月后片剂中大约只有95％的平均标示量的活性成份，以致影响了该药的疗效并增加了制造及病人用药的成本及安全性。
目前市售盐酸普拉克索药物多以固体制剂为主，这些剂型对于治疗目的是可接受的。然而，固体剂型的使用在该类患者中增加了严重的依从性(compliant)问题，因该药物针对老年患者，该固体剂型对于老年患者吞咽是困难的。
普拉克索或其药用盐，例如盐酸普拉克索，其制剂的稳定性问题，特别是在溶液中的稳定性问题，限制了其制剂的开发，特别是针对吞咽困难的老年患者的制剂。
CN102846541A公开了一种含有缓冲剂的普拉克索口服液及其制备方法，认为控制口服液pH值的范围对制剂的稳定性影响很大。该文献没有记载稳定性影响因素试验中有关物质测定方法。并且，发明人在研究中，对CN102846541A中声称最优选以枸橼酸-枸橼酸钠缓冲溶液为缓冲剂的普拉克索口服液进行了稳定性影响因素试验，结果都显示口服溶液的稳定性仍不理想，有待提高。
发明内容
为解决普拉克索或其药用盐制剂，特别是溶液剂型存在的存放不稳定问题，发明人在研究中令人意外地发现了提高或改善普拉克索或其药用盐制剂稳定性的方法，并进而提供一种存放稳定的普拉克索或其盐的制剂，尤其是提供了一种新的盐酸普拉克索口服溶液。
本发明技术方案如下：
本发明提供一种提高或改善普拉克索或其药用盐制剂稳定性的方法，其特征在于所述制剂中不含缓冲剂和/或缓冲剂系统。
优选地，上述所述的方法，其中所述普拉克索或其药用盐为盐酸普拉克索。
本发明上述所述的方法，其中所述的制剂，优选为溶液剂型，例如为口服溶液或注射溶液；更优选地，所述的制剂为口服液。
作为本发明另一目的，还提供了一种盐酸普拉克索口服液，其包含盐酸普拉克索、防腐剂和水，其特征在于所述口服液不含缓冲剂或缓冲剂系统。
优选地，上述所述的盐酸普拉克索口服液，其中所述的防腐剂可以为尼泊金酯或其盐、苯甲酸或其盐类、山梨酸或其盐类。
更优选地，上述所述的盐酸普拉克索口服液，其中所述的防腐剂选自尼泊金甲酯、尼泊金丙酯、尼泊金乙酯、尼泊金丁酯、尼泊金甲酯钠、尼泊金乙酯钠、尼泊金丙酯钠、尼泊金丁酯钠、苯甲酸、苯甲酸钠、山梨酸、山梨酸钾中的一种或多种；更优选地，所述的防腐剂为尼泊金甲酯和/或尼泊金丙酯。
优选地，上述所述的盐酸普拉克索口服液，其特征在于还含有螯合剂；优选地，所述的螯合剂选自氨基三乙酸、羟乙基乙二胺三乙酸、二亚乙基三胺五乙酸、乙二胺四乙酸、乙二胺四乙酸二钠(EDTA-2Na)、乙二胺四乙酸钙钠(EDTA-CaNa 2)中的一种或多种。
如果需要，本发明上述所述的盐酸普拉克索口服溶液，还可以含有矫味剂， 该矫味剂通常指甜味剂或香味剂。
甜味剂可选自蔗糖、木糖醇、山梨醇、果糖、葡萄糖、阿司帕坦、三氯蔗糖、安赛蜜、糖精钠中的一种或多种，例如优选为三氯蔗糖。
香味剂通常指水果味香精，可选自草莓香精、橙味香精、荔枝香精、混合莓味香精、香蕉香精、桔味香精、葡萄香精、青柠香精等的一种或两种，例如优选为混合莓味香精。
本发明上述所述的盐酸普拉克索口服液，其中，每单位制剂中，盐酸普拉克索含量为0.01mg/ml～10mg/ml；优选地，每单位制剂中盐酸普拉克索含量为0.02mg/ml～1.0mg/ml；优选地，每单位制剂中盐酸普拉克索含量为0.05mg/ml～0.3mg/ml；作为本发明的具体实施方式，本发明上述所述的盐酸普拉克索口服液，更优选地，每单位制剂或每单位剂量中，盐酸普拉克索含量为0.125～0.25mg/ml。
本发明的普拉克索或其盐制剂，特别是盐酸普拉克索口服溶液剂，不含缓冲剂和/或缓冲剂系统，制剂显示出优良的稳定性和生物利用度。缓冲剂，也被称为酸碱稳定剂，一般是盐类，如强酸弱碱或弱酸强碱盐类，在反应或保存中逐渐释出盐中的酸或碱以保持稳定的酸碱值；缓冲剂系统一般是弱酸或弱碱与其盐的混合物。本发明所述的缓冲剂或缓冲剂系统，是指制药领域中常用的或常规的缓冲剂或缓冲剂系统，没有特别限制，例如，包括但不限于枸橼酸-磷酸氢二钠缓冲溶液、枸橼酸-枸橼酸钠缓冲溶液、磷酸二氢钠-氢氧化钠缓冲溶液、酒石酸-氢氧化钠、磷酸盐缓冲液等。
本发明上述所述的盐酸普拉克索口服液，其中防腐剂、螯合剂、矫味剂的含量或用量，可以根据需要，按本领域中常规的用量，没有特别的限制。例如，所述的盐酸普拉克索口服液，每单位制剂或每单位剂量中，防腐剂含量通常为0.02％～0.5％(w/v)；螯合剂通常含量为0.01-0.25％(w/v)，矫味剂含量为0.01-60％(w/v)。优选的，防腐剂含量可以为0.02％～0.2％(w/v)，螯合剂含量可以为0.01～0.05％(w/v)，矫味剂含量可以为0.1-10％(w/v)。
本发明令人惊讶地发现，普拉克索或其药用盐制剂，特别是盐酸普拉克索口服溶液剂，在不含缓冲剂和/或缓冲剂系统时，制剂的稳定性具有显著提高或改善，将盐酸普拉克索与防腐剂和水混合在一起形成的溶液制剂显示出优良的稳定 性和生物利用度，取得令人预料不到的效果，从而提供一种简单、稳定的盐酸普拉克索口服液，且因其可完美的实现多剂量给药问题，为临床提供了一种新型的盐酸普拉克索的给药方案，可有效地治疗帕金森症以改善患者用药的顺应性及可及性。
附图说明
图1：本发明实施例2的口服制剂与比较制剂盐酸普拉克索片(规格：0.25mg)的生物利用度对比结果图
其中：R药-指比较制剂；A药-指实施例2的制剂。
具体实施方式
通过下面的实施例可以对本发明进行进一步描述，但本发明的范围并不限于下述实施例。
在下面配置各种组合物中，如未另外说明，每批的总配液量为10000ml，但是列明配方和配置过程时，以每100ml药液中的组成阐明配方和制法，在分装时，每瓶的药液量初定为100ml。
本发明涉及的检测方法：有关物质检测方法照高效液相色谱法(中国药典2015版第四部通则0512)测定。稳定性试验按照中国药典2015年版第四部稳定性试验进行。
色谱条件和系统适用性试验：用十八烷基硅烷键合硅胶为填充剂(150mm×4.6mm，5μm)；以9.1g磷酸二氢钾-5.0g辛烷磺酸酸钠溶液(用磷酸调节pH值至3.0)为流动相A相，乙腈-流动相A相(1：1)为流动相B相，乙腈-流动相A相(1：4)为溶剂，检测波长为264nm，流速为1.5ml/min，进样量为5μl，柱温40±5℃，梯度洗脱程序见下面表1：
表1梯度洗脱程序
时间(min) 0 15 15.1 20
A相％ 60 20 60 60
B相％ 40 80 40 40
取盐酸普拉克索对照品、杂质A((6S)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine)适量，精密称定，加溶剂溶解并稀释成每1ml含盐酸普拉克索7.5μg、含杂质A 3.0μg的溶液，作为系 统适用性溶液。精密量取系统适用性溶液5μL注入液相色谱仪，记录色谱图。杂质A和盐酸普拉克索的分离度不得小于6.0，盐酸普拉克索拖尾因子不得大于2.0。
测定法 取本品适量，加溶剂稀释成每1ml含盐酸普拉克索1.5mg的溶液，作为供试品溶液；精密量取供试品溶液适量，加溶剂溶解并稀释成每1ml含盐酸普拉克索1.5μg的溶液，作为自身对照溶液。精密量取供试品溶液与自身对照溶液各5μL，分别注入液相色谱仪，记录色谱图。按以下公式计算，供试品溶液色谱图中如有色谱峰，各杂质峰面积的和不得大于自身对照溶液主峰面积的5倍(0.5％)。
杂质含量％＝(r u/r s)*(C s/C u)*100％
r u：供试品溶液中每个杂质的峰面积
r s：自身对照溶液中盐酸普拉克索的峰面积
C s：自身对照溶液中盐酸普拉克索对照品的浓度(mg/ml)
C u：供试品溶液中盐酸普拉克索的浓度(mg/ml)
参考例：盐酸普拉克索片在光照和不同温度下的总杂质含量
样品：取有效期内的盐酸普拉克索片(商品名：森福罗，规格0.25mg)进行实验。采用上述方法对其有关物质进行检测，其结果如下表2所示：
表2盐酸普拉克索片各条件下总杂质含量(％)
Figure PCTCN2021070732-appb-000001
结果表明，盐酸普拉克索片在光照、40℃、60℃条件下放置，均有很大程度降解，在稳定性方面存在较大问题，这对患者用药安全性上存在很大隐患，这也印证有关盐酸普拉克索片稳定性方面的现有技术报道。
实施例1：盐酸普拉克索口服溶液剂
处方组成如下：
表3实施例1中盐酸普拉克索口服液的配方表
组分 用量(g) 功能
盐酸普拉克索 0.0125 活性成分
尼泊金甲酯 0.18 防腐剂
尼泊金丙酯 0.02 防腐剂
水 99.7875 溶剂
制备方法：
将处方量水于配制罐中，开启加热，温度80℃，开启搅拌，转速400转/分钟，15分钟后，将处方量尼泊金甲酯、尼泊金丙酯加入其中，搅拌至溶解后，加入处方量盐酸普拉克索至溶解，过滤、罐装，即得盐酸普拉克索口服溶液。
用上述方法对有关物质进行检测，结果分别见表4-5所示。
表4实施例1盐酸普拉克索口服溶液各条件下pH值变化表
Figure PCTCN2021070732-appb-000002
表5实施例1盐酸普拉克索口服溶液各条件下总杂质含量(％)
Figure PCTCN2021070732-appb-000003
实施例2：盐酸普拉克索口服溶液剂
处方组成如下：
表6实施例2中盐酸普拉克索口服液剂的配方表
组分 用量(g) 功能
盐酸普拉克索 0.0125 活性成分
尼泊金甲酯 0.18 防腐剂
尼泊金丙酯 0.02 防腐剂
EDTA-2Na 0.025 螯合剂
水 99.7625 溶剂
制备方法：
将处方量水于配制罐中，开启加热，温度80℃，开启搅拌，转速400转/分钟， 15分钟后，将处方量尼泊金甲酯、尼泊金丙酯加入其中，搅拌至溶解后，加入处方量EDTA-2Na、盐酸普拉克索至溶解，过滤、罐装，即得盐酸普拉克索口服溶液。
用上述方法对有关物质进行检测，结果分别见表7-8所示。
表7实施例2盐酸普拉克索口服溶液各条件下pH值变化表
Figure PCTCN2021070732-appb-000004
表8实施例2盐酸普拉克索口服溶液加速条件下总杂质含量(％)
Figure PCTCN2021070732-appb-000005
实施例3：盐酸普拉克索口服溶液剂
处方组成如下：
表9实施例3中盐酸普拉克索口服液剂的配方表
Figure PCTCN2021070732-appb-000006
制备方法：
分别将处方量水于配制罐中，开启加热，温度80℃，开启搅拌，转速400转/分钟，15分钟后，将处方量尼泊金甲酯、尼泊金丙酯加入其中，搅拌至溶解后，分别加入处方量氨基三乙酸/羟乙基乙二胺三乙酸/二亚乙基三胺五乙酸/EDTA-GaNa、盐酸普拉克索至溶解后，过滤、罐装，即得盐酸普拉克索口服溶液。
用上述方法对有关物质进行检测，结果分别见表10-12所示：
表10实施例3处方1盐酸普拉克索口服溶液总杂质含量(％)
Figure PCTCN2021070732-appb-000007
表11实施3处方2盐酸普拉克索口服溶液总杂质含量(％)
Figure PCTCN2021070732-appb-000008
表12实施例3处方3盐酸普拉克索口服溶液总杂质含量(％)
Figure PCTCN2021070732-appb-000009
表13实施例3处方4盐酸普拉克索口服溶液总杂质含量(％)
Figure PCTCN2021070732-appb-000010
Figure PCTCN2021070732-appb-000011
对比例1：盐酸普拉克索口服溶液剂
处方组成如下：
表14对比例1盐酸普拉克索口服液剂的配方表
Figure PCTCN2021070732-appb-000012
制备方法：
分别将处方量水于配制罐中，开启加热，温度80℃，开启搅拌，转速为400/每分钟，15分钟后，将处方量尼泊金甲酯、尼泊金丙酯加入其中，搅拌至溶解后，分别加入处方量枸橼酸、枸橼酸钠、盐酸普拉克索至溶解后，过滤、罐装，即得盐酸普拉克索口服溶液。
用上述方法对有关物质进行检测，结果分别见表15-16所示。
表15对比例1盐酸普拉克索口服溶液各条件下pH值变化表
Figure PCTCN2021070732-appb-000013
Figure PCTCN2021070732-appb-000014
表16对比例1盐酸普拉克索口服溶液各条件下总杂质含量(％)
Figure PCTCN2021070732-appb-000015
对比例2：盐酸普拉克索口服溶液剂
处方组成如下：
表17对比例2盐酸普拉克索口服液剂的配方表
Figure PCTCN2021070732-appb-000016
Figure PCTCN2021070732-appb-000017
制备方法：
分别将处方量水于配制罐中，开启加热，温度80℃，开启搅拌，转速为400/每分钟，15分钟后，将处方量尼泊金甲酯、尼泊金丙酯加入其中，搅拌至溶解后，分别加入处方量无水磷酸氢二钠、磷酸、盐酸普拉克索至溶解后，过滤、罐装，即得盐酸普拉克索口服溶液。
用上述方法对有关物质进行检测，结果分别见表18-19所示。
表18对比例2盐酸普拉克索口服溶液各条件下pH值变化表
Figure PCTCN2021070732-appb-000018
表19对比例2盐酸普拉克索口服溶液各条件下总杂质含量(％)
Figure PCTCN2021070732-appb-000019
参考例、实施例1-3以及对比例1-2数据可以看出，本发明的口服制剂稳定性均优于盐酸普拉克索片剂和含有缓冲剂或缓冲剂体系的普拉克索口服制剂。
实施例4：生物等效性试验
使用在实施例2中制备的盐酸普拉克索口服溶液剂(0.125mg/ml)以及作为参比制剂的0.25mg的盐酸普拉克索片，进行了生物等效性试验。给药于空腹状态的Beagles犬(n＝6)的口腔中，让其进行吞咽。在给药前和给药后0.08h、0.17h、0.25h、0.5h、1h、1.5h、2h、3h、4h、6h、8h、12h、24h、36h和48h时采取血液样品，并通过HPLC-MS分析了血中药浓度。血中浓度的发展趋势如图1所示。药代动力学参数的比例，结果如下表20所示。
表20药代动力学参数的比例表(实施例2的制剂/比较制剂)
Figure PCTCN2021070732-appb-000020
Figure PCTCN2021070732-appb-000021
从图1和表20的结果可知，本发明的口服溶液剂与比较制剂0.25mg盐酸普拉克索片显示出生物等效性。

Claims (10)

  1. 一种提高或改善普拉克索或其药用盐制剂稳定性的方法，其特征在于所述制剂中不含缓冲剂和/或缓冲剂系统。
  2. 根据权利要求1所述的方法，其中所述普拉克索或其药用盐为盐酸普拉克索。
  3. 根据权利要求1-2所述的方法，其中所述的制剂为口服溶液或注射溶液。
  4. 一种盐酸普拉克索口服液，包含盐酸普拉克索、防腐剂和水，其特征在于所述口服液不含缓冲剂和/或缓冲剂系统。
  5. 根据权利要求4所述的盐酸普拉克索口服液，其中所述的防腐剂为尼泊金酯或其盐、苯甲酸或其盐类、山梨酸或其盐类。
  6. 根据权利要求4-5所述的盐酸普拉克索口服液，其中所述的防腐剂选自尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯、尼泊金甲酯钠、尼泊金乙酯钠、尼泊金丙酯钠、尼泊金丁酯钠、苯甲酸、苯甲酸钠、山梨酸、山梨酸钾中的一种或多种；优选地，所述的防腐剂为尼泊金甲酯和/或尼泊金丙酯。
  7. 根据权利要求4-6所述的盐酸普拉克索口服液，其特征在于还含有螯合剂；优选地，所述的螯合剂选自氨基三乙酸、羟乙基乙二胺三乙酸、二亚乙基三胺五乙酸、乙二胺四乙酸、乙二胺四乙酸二钠、乙二胺四乙酸钙钠中的一种或多种。
  8. 根据权利要求4-7所述的盐酸普拉克索口服液，其特征在于还含有矫味剂；优选地，所述矫味剂为甜味剂或香味剂；优选地，所述甜味剂例如可选自蔗糖、木糖醇、果糖、葡萄糖、山梨醇、阿司帕坦、三氯蔗糖、安赛蜜、糖精钠中的一种或多种；优选地，所述香味剂为水果味香精，例如可选自草莓香精、橙味香精、荔枝香精、混合莓味香精、香蕉香精、桔味香精、葡萄香精、青柠香精等的一种或多种。
  9. 根据权利要求4-8所述的盐酸普拉克索口服液，其特征在于每单位制剂中盐酸普拉克索含量为0.01mg/ml～10mg/ml；优选地，每单位制剂中盐酸普拉克索含量为0.02mg/ml～1.0mg/ml；更优选地，每单位制剂中盐酸普拉克索含量为0.05mg/ml～0.3mg/ml。
  10. 根据权利要求9所述的盐酸普拉克索口服液，其特征在于每单位制剂中盐酸普拉克索含量为0.125～0.25mg/ml。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080014259A1 (en) * 2006-05-16 2008-01-17 Knopp Neurosciences, Inc. Compositions of R(+) and S(-) Pramipexole and Methods of Using the Same
WO2011012723A1 (en) * 2009-07-31 2011-02-03 Ascendis Pharma As Injectable sustained release compositions comprising a pramipexole prodrug
EP2308464A1 (en) * 2009-10-06 2011-04-13 Sanovel Ilac Sanayi ve Ticaret A.S. Orally disintegrating compositions of pramipexole
EP2364694B1 (en) * 2010-03-11 2013-11-06 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Controlled-release formulations of pramipexole
CN105949159A (zh) * 2016-05-19 2016-09-21 江苏神龙药业有限公司 盐酸普拉克索的药物组合物及其治疗偏头痛的用途
CN108685858A (zh) * 2017-04-08 2018-10-23 沈阳药科大学 一种注射用普拉克索缓释制剂及其制备方法
WO2020068832A1 (en) * 2018-09-25 2020-04-02 Chase Therapeutics Corporation Composition and use for the treatment of parkinson's disease and related disorders

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040266794A1 (en) * 2003-03-21 2004-12-30 Boehringer Ingelheim International Gmbh Pramipexole for the reduction of excessive food intake for children
WO2008001204A2 (en) * 2006-06-29 2008-01-03 Antares Pharma Ipl Ag Transdermal compositions of pramipexole having enhanced permeation properties
KR101406265B1 (ko) * 2010-03-17 2014-06-12 영진약품공업주식회사 안정성이 개선된 프라미펙솔을 함유하는 약제학적 조성물 및 이의 제조방법
CN102846541A (zh) * 2012-09-05 2013-01-02 北京万全阳光医学技术有限公司 一种普拉克索口服液及其制备方法
EP2870965A1 (en) * 2013-11-06 2015-05-13 Sanovel Ilac Sanayi ve Ticaret A.S. Oral liquid pharmaceutical formulations of pramipexole

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080014259A1 (en) * 2006-05-16 2008-01-17 Knopp Neurosciences, Inc. Compositions of R(+) and S(-) Pramipexole and Methods of Using the Same
WO2011012723A1 (en) * 2009-07-31 2011-02-03 Ascendis Pharma As Injectable sustained release compositions comprising a pramipexole prodrug
EP2308464A1 (en) * 2009-10-06 2011-04-13 Sanovel Ilac Sanayi ve Ticaret A.S. Orally disintegrating compositions of pramipexole
EP2364694B1 (en) * 2010-03-11 2013-11-06 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Controlled-release formulations of pramipexole
CN105949159A (zh) * 2016-05-19 2016-09-21 江苏神龙药业有限公司 盐酸普拉克索的药物组合物及其治疗偏头痛的用途
CN108685858A (zh) * 2017-04-08 2018-10-23 沈阳药科大学 一种注射用普拉克索缓释制剂及其制备方法
WO2020068832A1 (en) * 2018-09-25 2020-04-02 Chase Therapeutics Corporation Composition and use for the treatment of parkinson's disease and related disorders

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