WO2022083063A1 - 雷沙吉兰或其药用盐舌下膜剂及其制备方法、应用 - Google Patents

雷沙吉兰或其药用盐舌下膜剂及其制备方法、应用 Download PDF

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WO2022083063A1
WO2022083063A1 PCT/CN2021/083192 CN2021083192W WO2022083063A1 WO 2022083063 A1 WO2022083063 A1 WO 2022083063A1 CN 2021083192 W CN2021083192 W CN 2021083192W WO 2022083063 A1 WO2022083063 A1 WO 2022083063A1
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rasagiline
film
hydroxypropyl
cyclodextrin
sublingual
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PCT/CN2021/083192
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English (en)
French (fr)
Inventor
陈芳
丁祎馨
王兵
李德祥
杨柳榴
傅麟勇
周敏
丁云晖
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上海上药中西制药有限公司
上海现代药物制剂工程研究中心有限公司
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Priority to JP2023548986A priority Critical patent/JP2023547273A/ja
Priority to EP21881489.5A priority patent/EP4233852A4/en
Priority to US18/248,867 priority patent/US20230414499A1/en
Publication of WO2022083063A1 publication Critical patent/WO2022083063A1/zh

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    • 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
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the invention relates to a sublingual film of rasagiline or a medicinal salt thereof, and a preparation method and application thereof.
  • Parkinson's disease as the second largest neurodegenerative disease, mostly occurs in people over 40 years old, and 2-3% of people over 65 years old are afflicted by this disease. Symptoms are different for each Parkinson's patient, but the most common symptoms are dyskinesia and skeletal muscle stiffness, tremors, bradykinesia, poor balance, and gait disturbance. Depression, sleep disturbances, dizziness, dementia, speech disturbances, respiratory problems, and dysphagia are often accompanied, and the symptoms worsen year by year, even leading to death.
  • the drugs for the treatment of Parkinson's disease mainly include levodopa, DA receptor agonists, MAO-B inhibitors, COMT inhibitors and anticholinergic preparations.
  • levodopa The most common one is levodopa.
  • levodopa can rapidly improve Parkinson's symptoms and has irreplaceable advantages, its superiority is only in the early years of treatment, and the clinical effect will be significantly weakened after long-term use. And there are serious side effects, including movement disorders, fluctuations in the drug's effect (commonly known as the "switch effect"), and mental confusion.
  • Rasagiline mesylate is a potent, selective and irreversible MAO-B inhibitor that is used to treat Parkinson's disease, Alzheimer's disease and a variety of other conditions by inhibiting MAO in the brain. Blue metabolism does not produce amphetamines and does not cause unnecessary sympathomimetic effects. Compared with levodopa, rasagiline has better safety and can be used alone in the treatment of patients with early Parkinson's disease.
  • the marketed formulation of rasagiline mesylate is a common tablet with the trade name AZILECT, which was first listed in Israel in March 2005, in the United Kingdom in June, in Ireland in September, in the United States in 2006, and in 2017 in the United Kingdom.
  • the dosage form patents about rasagiline and its medicinal salt are all oral administration preparations, such as rasagiline oral disintegrating composition (CN101098685A), a rasagiline preparation and its preparation method (CN103315983A), Rasagiline tablet (CN105496979A), rasagiline tablet and preparation method thereof (CN107753446A), rasagiline oral solid preparation (CN1911211A), rasagiline or its medicinal salt orally disintegrating Dissolution and preparation method thereof (CN101874790A), Rasagiline soft gelatin capsules (EP2285214B1), Rasagiline formulations and processes for their preparation (US7619117B1), Rasagiline formulations (WO2010111264A2) and the like.
  • rasagiline oral disintegrating composition CN101098685A
  • a rasagiline preparation and its preparation method CN103315983A
  • Rasagiline tablet CN105496979A
  • rasagiline tablet and preparation method thereof CN107753446A
  • rasagiline oral solid preparation
  • Rasagiline is orally absorbed through the gastrointestinal tract, and patients are at risk of increased blood pressure at any dose if they consume a diet high in tyramine (FDA: (rasagiline) Tablets: Label).
  • FDA rasagiline
  • Parkinson's patients are usually accompanied by gastrointestinal motility disorders, mainly manifested as dysphagia, gastric emptying disorders and constipation (Wolfgang, H. Jost. "Gastrointestinal motility problems in patients with Parkinson's disease" Drugs & Aging, 10, pages 249–258 ( 1997)), prolonged its inhibitory effect on peripheral MAO, and then aggravated the "cheese effect".
  • Chinese patent application CN200910191252.6 discloses a stable rasagiline composition
  • its embodiment 11 discloses a film that is attached to the oral mucosa, but the obtained film has poor stability and can be stored at 60°C for 10
  • the impurity content is as high as 2.6 to 15.33%.
  • the technical problem to be solved by the present invention is to overcome the defect of poor stability of rasagiline preparations in the prior art, and provide a rasagiline or its medicinal salt sublingual film preparation and its preparation method and application.
  • the invention prepares the drug into a sublingual film with convenient administration and stable quality, which does not need to be taken with water, the film is rapidly dissolved, the drug is rapidly dissolved from the preparation, and the drug is absorbed through the oral mucosa, which can not only avoid the first-pass effect, but also improve the bioavailability. It can also avoid the "cheese effect" caused by the inhibition of peripheral MAO in the stomach and reduce side effects.
  • Rasagiline is easy to be oxidized, unstable under acidic and alkaline conditions, and easily soluble in water.
  • the dosage is small (below 1 mg), and the relative dosage of excipients is large, so the stability of the drug is greatly affected by excipients.
  • the inventors found that a variety of excipients are likely to interact with rasagiline, resulting in a significant increase in the content of oxidized impurities, and the addition of antioxidants still cannot effectively solve the stability problem.
  • the present invention solves the above technical problems through the following technical solutions.
  • the invention provides a rasagiline or its medicinal salt sublingual film, which comprises the following prescription components:
  • Described dextrin is one or more of maltodextrin, hydroxypropyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin;
  • the above percentages are the mass percentages of each component relative to the total prescription components of the rasagiline or its pharmaceutically acceptable salt sublingual film.
  • the rasagiline or its pharmaceutically acceptable salt is preferably rasagiline mesylate.
  • the polymer film-forming material can be a conventional water-soluble polymer material that can be used for film formation in the field, such as hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl Base Cellulose (HPC), Sodium Carboxymethyl Cellulose (CMC-Na), Polyvinylpyrrolidone (PVP), Polyethylene Oxide (PEO), Sodium Alginate, Pullulan, Bletilla Gum, Corn Starch and Carrageenan One or more of them, preferably hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (CMC-Na), seaweed One or more of sodium, pullulan and corn starch, such as a mixture of hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC) and carboxymethyl A mixture of sodium cellulose (CMC-
  • the polymer film-forming material is a mixture of hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA)
  • HPMC hydroxypropyl methylcellulose
  • PVA polyvinyl alcohol
  • the ratio can be (27.5-45):(22.5-40), eg, 45:40, 42.5:37.5, 37.5:32.5, 32.5:27.5, or 27.5:22.5.
  • the polymer film-forming material is a mixture of hydroxypropyl cellulose (HPC) and sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC) and sodium carboxymethyl cellulose (The mass ratio of CMC-Na) may be 40:(25-35), for example, 40:30.
  • the mass ratio of polyvinyl alcohol (PVA) and corn starch may be 30:(25-35), for example, 30:30.
  • the mass ratio of pullulan and polyvinyl alcohol (PVP) may be 20:(15-25), for example, 20 :20.
  • the mass ratio of hydroxypropyl methylcellulose (HPMC) and sodium alginate can be 20:(5 ⁇ 15), such as 20:10.
  • the dextrin is preferably the maltodextrin, the hydroxypropyl- ⁇ -cyclodextrin, the glucosyl- ⁇ -cyclodextrin, the sulfobutyl- ⁇ -cyclodextrin Dextrin, a mixture of the maltodextrin and glucosyl-beta-cyclodextrin, or a mixture of the maltodextrin and hydroxypropyl-beta-cyclodextrin.
  • the mass ratio of maltodextrin and glucosyl- ⁇ -cyclodextrin is preferably 1:(0.8-1.2), for example, 1 :1.
  • the mass ratio of maltodextrin and hydroxypropyl- ⁇ -cyclodextrin is preferably 1:(0.8 ⁇ 1.2) , for example 1:1.
  • the other adjuvants may be conventional adjuvants in the field, preferably including one or more of antioxidants, disintegrants, plasticizers, colorants and flavors.
  • the disintegrating agent can be sodium carboxymethyl starch CMS-Na.
  • the amount of the disintegrant can be 3-7%, for example, 5%, and the percentage is the mass percentage relative to the total prescription components of the rasagiline or its pharmaceutically acceptable salt sublingual film.
  • the plasticizer can be PEG400.
  • the amount of the plasticizer can be 7-11%, for example, 9%, and the percentage is the mass percentage relative to the total formulation components of the rasagiline or its pharmaceutically acceptable salt sublingual film.
  • the colorant may be titanium dioxide.
  • the amount of the colorant can be 2-6%, for example, 4%, and the percentage is the mass percentage relative to the total prescription components of the rasagiline or its pharmaceutically acceptable salt sublingual film.
  • the flavor can be one or more of strawberry flavor, grape flavor and sweet orange flavor.
  • the amount of the flavor can be 1% or 3%, and the percentage is the mass percentage relative to the total prescription components of the rasagiline or its pharmaceutically acceptable salt sublingual film.
  • the other auxiliary materials may also include sweeteners.
  • the sweetener can be conventional in the art, preferably includes one or more of xylitol, maltitol, steviol glycosides, sodium saccharin, aspartame, acesulfame potassium and sodium cyclamate, more preferably xylose One or more of alcohol, maltitol, aspartame, cyclamate, and steviol glycosides, such as xylitol, maltitol, aspartame, cyclamate, or steviol glycosides.
  • the dosage of the sweetener can be conventional in the field, and can be 1%, 4%, 5%, 10% or 30%, preferably 3% to 30%, more preferably 5 to 20%;
  • the percentage is the mass percentage of the sweetener relative to the total formulation components of the rasagiline or its pharmaceutically acceptable salt sublingual film.
  • the dosage of rasagiline or its pharmaceutical salt may be 1%, 5%, 8%, 10% or 15%, preferably 1-8%.
  • the amount of the polymer film-forming material may be 30%, 40%, 50%, 60%, 70%, 80% or 85%, preferably 40-60%. If the amount of the polymer film-forming material is less than 30%, the film-forming property is not good, and the strength and toughness of the film may not meet the needs of use; The stability and taste of the orchid or its medicinal salt oral film cannot meet the requirements.
  • the amount of the dextrin can be 5%, 10%, 20%, 25%, 30% or 40%, preferably 10-30%. If the amount of the dextrin is less than 5%, the stability of the sublingual film of rasagiline or its medicinal salt cannot be significantly improved; if it is higher than 40%, the film is brittle and easily broken.
  • the dosage of the other auxiliary materials is preferably 2-20%, for example, 9%, 12%, 15% or 20%.
  • the present invention also provides a preparation method of the rasagiline or its medicinal salt sublingual film, which comprises the following steps: coating the slurry to make a film;
  • the slurry comprises the aforementioned formulation components of rasagiline or its pharmaceutically acceptable salt sublingual film and water.
  • the slurry can be prepared by conventional methods in the art, preferably prepared by the following method: adding formulation components other than the polymer film-forming material to water containing the polymer film-forming material In the slurry, mix evenly.
  • the mass concentration of the polymer film-forming material is preferably 10% to 40%, more preferably 13% to 30%.
  • the amount of water used in the slurry, can be conventional in the field, and is generally based on a solution that can be made into a certain viscosity and good fluidity.
  • the slurry is generally a uniform slurry. Before the slurry is coated and formed into a film, it is generally allowed to stand for defoaming.
  • the method of coating and film-making may be conventional in the field, for example, a conventional film coating machine in the field may be used for coating, drying and slitting.
  • the thickness of the film may be 0.3-0.5 mm, for example, 0.4 mm.
  • drying temperature may be 80-95°C.
  • the coating film speed may be 40-150 cm/min, for example, 50 cm/min.
  • the specifications of the film after slitting can be selected according to actual needs.
  • the present invention also provides an application of the rasagiline or its medicinal salt sublingual film in preparing a medicine for treating Parkinson's disease and Alzheimer's disease-related diseases.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the sublingual film of the present invention can be adhered to the administration site without water and quickly melted, the patient does not need to swallow, the compliance is good, and it is more convenient for nursing staff to help the administration.
  • the drug is absorbed through the oral mucosa, avoids the liver first-pass effect, has high bioavailability, and reduces the dose of the drug compared with oral preparations.
  • the sublingual film of the present invention has good stability, and the impurity content is still low after long-term storage.
  • the sublingual membrane of the present invention has better dissolution characteristics, and is characterized by rapid and complete dissolution of the drug, rapid absorption of the drug through the sublingual mucosa into the blood circulation, and rapid onset of effect.
  • Fig. 1 shows the dissolution profiles of formulation 1 in Example 1 and sublingual films of Examples 2 to 5.
  • Fig. 2 is the change curve of the plasma concentration of rasagiline with time after sublingual membrane, intravenous injection and intragastric administration of Example 3 respectively.
  • the raw materials and auxiliary materials used in the examples and comparative examples are all commercially available.
  • compositions and dosages of prescriptions 1-5 and comparative prescriptions are shown in Table 1.
  • Example 2 The prescription of Example 2 is shown in Table 2.
  • Example 3 The prescription of Example 3 is shown in Table 3.
  • Example 4 The formulation of Example 4 is shown in Table 4.
  • Example 5 The formulation of Example 5 is shown in Table 5.
  • Example 3 The maltodextrin in the recipe of Example 3 was replaced by PVA, and other recipe processes remained unchanged.
  • Example 1 Take prescription 1 in Example 1 and the films of Examples 2 to 5 (specification 0.5 mg, that is, each film contains 0.5 mg rasagiline) each 6 pieces, according to the dissolution assay method (Chinese Pharmacopoeia 2015 edition four general rules 0931 The second method), take 500ml of pH 6.8 phosphate buffer as the solvent, the rotation speed is 50 rpm, operate according to the law, after 1, 2, 3, 5, 10 and 15 minutes, take 1 ml of the solution and filter, accurately Measure 20uL of the continuous filtrate and measure it according to high performance liquid chromatography; calculate the dissolution amount at different times.
  • the dissolution profile is shown in Figure 1.
  • Fig. 1 shows that the rasagiline mesylate sublingual film of the present invention dissolves rapidly, and basically dissolves completely in 3 minutes.
  • Intravenous injection 4 healthy Beagle dogs, half male and half male, were given 4ml of rasagiline mesylate solution (solvent is water) (0.5mg/ml, calculated as rasagiline) by intravenous injection respectively, that is, the dosage was 2mg.
  • rasagiline mesylate solution solvent is water
  • Sublingual membrane and gavage administration A two-period, double-crossover trial was used with a washout period of 1 week. 4 healthy Beagle dogs, half male and half male, were randomly divided into 2 groups, respectively sublingually administered with rasagiline mesylate sublingual film (Example 3) and intragastrically administered with rasagiline mesylate solution. The dose is 2 mg.
  • the plasma concentration of rasagiline in the sample was determined by LC-MS/MS, and the average drug-time curve was drawn (Fig. 2).
  • the non-compartmental model of DAS2.0 software was used to process the plasma concentration data to calculate the bioavailability of rasagiline.
  • the films (specification 0.5 mg) of the comparative formulations and formulations 1 to 5 in Example 1 were taken, the outer packaging was removed, and a high temperature test was carried out to investigate the stability of the samples.
  • the membrane was placed in a petri dish and placed at 60°C for 10 days, and samples were taken on the 5th and 10th days to detect the related substances of rasagiline in the membrane.
  • the test results show that the proportion of hydroxypropyl- ⁇ -cyclodextrin is in the range of 5-40%, and with the increase of the dosage of hydroxypropyl- ⁇ -cyclodextrin, the stability of the drug in high temperature environment is enhanced.
  • the amount of hydroxypropyl- ⁇ -cyclodextrin increases, the amount of film-forming material needs to be reduced accordingly, the strength of the film gradually decreases, and the toughness gradually deteriorates.
  • Table 8 The results are shown in Table 8.
  • Comparative Example 1 The films of Comparative Example 1, Comparative Example 2 and Examples 2 to 5 (specification 0.5 mg) were taken, the outer packaging was removed, and a high temperature test was performed to investigate the stability of the samples.
  • the membrane was placed in a petri dish, placed at 60°C for 10 days, and the samples were taken on the 5th and 10th days to detect the content of rasagiline, related substances and dissolution in the membrane (see Effect Example 2 for the dissolution method). ).
  • the test results show that during the investigation period, the sublingual films of rasagiline mesylate produced in Comparative Example 1 and Comparative Example 2 had a significant increase in related substances, and the results are shown in Tables 9-10.
  • the rasagiline mesylate sublingual film prepared by the present invention is Example 2 to Example 5. There is no obvious change in each index, and the product quality is stable. The results are shown in Tables 11 to 14.
  • the rasagiline oral film preparation does not require water or other liquids when taking it, and the packaging bag is torn open with dry hands, the medicine film is taken out, and it is placed in the oral cavity until it is completely dissolved.
  • This product should not be folded, chewed or swallowed. Avoid eating or drinking within 10 minutes after taking the drug.
  • Films with different water contents were prepared according to the recipe and preparation method of Example 3, sealed and packaged in PET/Al/PE bags, and placed at 60°C for 10 days. Take samples every day to detect related substances in the membrane. The test results are shown in Table 15.

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Abstract

一种雷沙吉兰或其药用盐的舌下膜剂及其制备方法、应用。舌下膜剂包括下述处方组分：雷沙吉兰或其药用盐0.5～15％，高分子成膜材料30～85％，糊精5％～40％，其它辅料0～30％且不为0，糊精为麦芽糊精、羟丙基-β-环糊精、葡糖基-β-环糊精和磺丁基-β-环糊精的一种或多种；百分比为各组分分别相对于舌下膜剂的处方总组分的质量百分比。

Description

雷沙吉兰或其药用盐舌下膜剂及其制备方法、应用
本申请要求申请日为2020年10月23日的中国专利申请2020111451096的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种雷沙吉兰或其药用盐舌下膜剂及其制备方法、应用。
背景技术
帕金森病(PD)作为第二大神经退行性疾病，多发于40岁以上的人群，65岁以上的老年人中有2～3％受这种疾病的折磨。每个帕金森病人的症状都不同，最常见的症状是运动障碍和骨骼肌僵直、震颤、运动迟缓、平衡差和步态障碍。另外还常常伴有抑郁、睡眠障碍、眩晕、痴呆、言语障碍、呼吸系统疾病和吞咽困难，而且症状会逐年加重，甚至导致死亡。
目前治疗帕金森病的药物主要有左旋多巴、DA受体激动剂、MAO-B抑制剂、COMT抑制剂和抗胆碱能类制剂等。其中最常见的是左旋多巴，左旋多巴虽然能迅速改善帕金森症状，有其不可取代的优越性，但其优越性仅仅只在治疗初期的几年里，长期使用之后临床效果会明显减弱且出现严重的副作用，包括运动障碍、药效波动(俗称“开关效应”)以及精神混乱等症状。
甲磺酸雷沙吉兰是一种强效、选择性不可逆MAO-B抑制剂，通过抑制脑中的MAO，用于治疗帕金森病、阿尔茨海默症和多种其他病症，雷沙吉兰代谢不产生安非他明，不会引起不必要的拟交感作用。相对于左旋多巴，雷沙吉兰具有更好的安全性，可以单独用于早期帕金森病患者的治疗。目前甲磺酸雷沙吉兰的上市制剂为普通片剂，商品名称AZILECT，2005年3月首次在以色列上市，6月在英国上市，9月在爱尔兰上市，2006年在美国上市，2017年在中国正式上市，规格为0.5mg和1mg(以雷沙吉兰计)。关于雷沙吉兰及其药用盐的剂型专利均为口服给药制剂，例如雷沙吉兰经口崩解组合物(CN101098685A)、一种雷沙吉兰制剂及其制备方法(CN103315983A)、一种雷沙吉兰片剂(CN105496979A)、一种雷沙吉兰片剂及其制备方法(CN107753446A)、雷沙吉兰口服固体制剂(CN1911211A)、雷沙吉兰或者其药用盐口腔崩解片及其制备方法(CN101874790A)、Rasagiline soft gelatin capsules(EP2285214B1)、Rasagiline formulations and processes for their preparation(US7619117B1)、Rasagiline formulations(WO2010111264A2)等。
甲磺酸雷沙吉兰口服后受肝脏首过效应影响，生物利用度较低，约为36％。且雷沙 吉兰在使用中主要风险来源是高血压，通常称为“奶酪效应”。(Simpson.G.M.and White K.,“Tyramine studies and the safety of MAOI drugs”,The Journal of Clinical Psychiatry,01 Jul 1984,45(7 Pt 2):59-61)。该效应是由外周MAO的抑制引起的，而在胃中发现高浓度的外周MAO。雷沙吉兰口服经胃肠道吸收，患者如果摄入高酪胺饮食的话，在任何剂量下均有血压升高的风险(FDA：
Figure PCTCN2021083192-appb-000001
(rasagiline)Tablets：Label)。另外，帕金森患者通常伴有胃肠运动障碍，主要表现为吞咽困难、胃排空障碍和便秘(Wolfgang,H.Jost."Gastrointestinal motility problems in patients with Parkinson’s disease"Drugs&Aging,10,pages249–258(1997))，延长了其对外周MAO的抑制作用时间，继而加重“奶酪效应”。
中国专利申请CN200910191252.6公开了一种稳定的雷沙吉兰组合物，其实施例11公开了一种贴于口腔黏膜处的膜剂，但是其制得的膜剂稳定性差，60℃存放10天杂质含量高达在2.6～15.33％。
发明内容
本发明所要解决的技术问题是克服了现有技术中雷沙吉兰制剂稳定性差的缺陷，而提供了一种雷沙吉兰或其药用盐舌下膜剂及其制备方法、应用。本发明将药物制成给药方便、质量稳定的舌下膜，无需用水送服，膜剂迅速溶化，药物迅速从制剂中溶出，药物经口腔黏膜吸收，不仅可避免首过效应，提高生物利用度；还可避免因胃中外周MAO抑制引起“奶酪效应”，减轻副作用。
雷沙吉兰易氧化，在酸性及碱性条件下均不稳定，且易溶于水，剂量小(1mg以下)，辅料的相对用量大，因而药物的稳定性受辅料影响较大。发明人发现多种辅料易与雷沙吉兰发生相互作用，引起氧化杂质含量明显增加，加入抗氧剂仍不能有效解决稳定性问题。雷沙吉兰或其药物盐制得的舌下膜剂处方中，发明人通过创造性劳动偶然发现，加入一定含量的麦芽糊精、羟丙基-β-环糊精、葡糖基-β-环糊精或磺丁基-β-环糊精的一种或多种，和处方中其它组分相互配合，可有效改善膜剂的稳定性以及有效增强药物在长期放置过程中的稳定性。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种雷沙吉兰或其药用盐舌下膜剂，其包括下述处方组分：
Figure PCTCN2021083192-appb-000002
所述的糊精为麦芽糊精、羟丙基-β-环糊精、葡糖基-β-环糊精和磺丁基-β-环糊精的一 种或多种；
上述百分比为各组分分别相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
本发明中，所述的雷沙吉兰或其药用盐优选为甲磺酸雷沙吉兰。
本发明中，所述的高分子成膜材料可为本领域常规的可用于成膜的水溶性高分子材料，例如羟丙基甲基纤维素(HPMC)、聚乙烯醇(PVA)、羟丙基纤维素(HPC)、羧甲基纤维素钠(CMC-Na)、聚乙烯吡咯烷酮(PVP)、聚氧化乙烯(PEO)、海藻酸钠、普鲁兰多糖、白芨胶、玉米淀粉和卡拉胶中的一种或多种，优选为羟丙基甲基纤维素(HPMC)、聚乙烯醇(PVA)、羟丙基纤维素(HPC)、羧甲基纤维素钠(CMC-Na)、海藻酸钠、普鲁兰多糖和玉米淀粉中的一种或多种，例如羟丙基甲基纤维素(HPMC)和聚乙烯醇(PVA)的混合物，羟丙基纤维素(HPC)和羧甲基纤维素钠(CMC-Na)的混合物、聚乙烯醇(PVA)和玉米淀粉的混合物、普鲁兰多糖和聚乙烯醇(PVP)的混合物，或者，羟丙基甲基纤维素(HPMC)和海藻酸钠的混合物。
当所述的高分子成膜材料为羟丙基甲基纤维素(HPMC)和聚乙烯醇(PVA)的混合物时，羟丙基甲基纤维素(HPMC)和聚乙烯醇(PVA)的质量比可为(27.5～45)：(22.5～40)，例如45:40、42.5:37.5、37.5:32.5、32.5:27.5或者27.5:22.5。
当所述的高分子成膜材料为羟丙基纤维素(HPC)和羧甲基纤维素钠(CMC-Na)的混合物时，羟丙基纤维素(HPC)和羧甲基纤维素钠(CMC-Na)质量比可为40：(25～35)，例如40:30。
当所述的高分子成膜材料为聚乙烯醇(PVA)和玉米淀粉的混合物时，聚乙烯醇(PVA)和玉米淀粉的质量比可为30:(25～35)，例如30:30。
当所述的高分子成膜材料为普鲁兰多糖和聚乙烯醇(PVP)的混合物时，普鲁兰多糖和聚乙烯醇(PVP)质量比可为20:(15～25)，例如20:20。
当所述的高分子成膜材料为羟丙基甲基纤维素(HPMC)和海藻酸钠的混合物时，羟丙基甲基纤维素(HPMC)和海藻酸钠质量比可为20:(5～15)，例如20:10。
本发明中，所述的糊精优选为所述麦芽糊精、所述羟丙基-β-环糊精、所述葡糖基-β-环糊精、所述磺丁基-β-环糊精、所述麦芽糊精和葡萄糖基-β-环糊精混合物、或者，所述麦芽糊精和羟丙基-β-环糊精的混合物。
当所述的糊精为所述麦芽糊精和葡萄糖基-β-环糊精混合物时，麦芽糊精和葡萄糖基-β-环糊精质量比优选为1：(0.8～1.2)，例如1:1。
当所述的糊精为所述麦芽糊精和羟丙基-β-环糊精的混合物时，麦芽糊精和羟丙基-β-环糊精质量比优选为1：(0.8～1.2)，例如1:1。
本发明中，所述其它辅料可为本领域常规辅料，优选包括抗氧剂、崩解剂、增塑剂、着色剂和香精中的一种或多种。
其中，所述崩解剂可为羧甲基淀粉钠CMS-Na。所述崩解剂用量可为3～7％，例如5％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
其中，所述增塑剂可为PEG400。所述增塑剂用量可为7～11％，例如9％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
其中，所述着色剂可为二氧化钛。所述着色剂的用量可为2～6％，例如4％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
其中，所述香精可为草莓香精、葡萄香精和甜橙香精中的一种或多种。所述香精的用量可为1％或者3％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
本发明中，所述其它辅料中还可包括甜味剂。所述甜味剂可为本领域常规，优选包括木糖醇、麦芽糖醇、甜菊糖苷、糖精钠、阿斯巴坦、安赛蜜和甜蜜素中的一种或多种，更优选为木糖醇、麦芽糖醇、阿斯巴坦、甜蜜素和甜菊糖苷中的一种或多种，例如木糖醇、麦芽糖醇、阿斯巴坦、甜蜜素或甜菊糖苷。
其中，所述的甜味剂的用量可为本领域常规，可为1％、4％、5％、10％或者30％，优选为3％～30％，更优选为5～20％；上述百分比为甜味剂相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
本发明中，所述的雷沙吉兰或其药物盐的用量可为1％、5％、8％、10％或者15％，优选为1～8％。
本发明中，所述的高分子成膜材料的用量可为30％、40％、50％、60％、70％、80％或者85％，优选为40～60％。若所述高分子成膜材料的用量低于30％，成膜性不佳，膜的强度和韧性可能不能满足使用的需要；若高于85％，则其它辅料的比例太小，雷沙吉兰或其药用盐口腔膜剂的稳定性、口味等方面无法满足要求。
本发明中，所述的糊精的用量可为5％、10％、20％、25％、30％或者40％，优选为10～30％。若所述糊精的用量低于5％，雷沙吉兰或其药用盐舌下膜的稳定性不能得到明显改善；若高于40％，膜较脆、易碎裂。
本发明中，所述其它辅料的用量优选为2～20％，例如9％、12％、15％或者20％。
本发明还提供了一种所述雷沙吉兰或其药用盐舌下膜剂的制备方法，其包括下述步骤：将浆料涂布制膜，即可；
其中，所述浆料包括如前所述的雷沙吉兰或其药用盐舌下膜剂的处方组分和水。
本发明中，所述浆料可通过本领域常规方法制得，优选通过下述方法制得：将除所 述高分子成膜材料以外的处方组分加入含有所述高分子成膜材料的水料浆中，混合均匀即可。
其中，所述含有所述高分子成膜材料的水料浆中，所述高分子成膜材料的质量浓度优选为10％～40％，更优选为13％～30％。
本发明中，所述浆料中，水的用量可为本领域常规，一般是以能够制成有一定粘稠度且流动性好的溶液为准。
本发明中，所述的浆料一般为均匀的浆液。所述浆料在进行涂布制膜前，一般进行静置消泡。
本发明中，所述涂布制膜的方式可为本领域常规，例如可采用本领域常规涂膜机进行涂布后，干燥、分切。
其中，所述涂布制膜过程中，铺膜厚度可为0.3～0.5mm，例如0.4mm。
其中，所述干燥的温度可为80～95℃。
其中，所述涂布制膜过程中，涂膜速度可为40～150cm/min，例如50cm/min。
其中，所述分切后膜的规格可根据实际需求进行选择。
本发明还提供了一种所述雷沙吉兰或其药用盐舌下膜剂在制备用于治疗帕金森病、阿尔茨海默症有关的疾病的药物中的应用。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
1)本发明舌下膜无需用水即可黏附于给药部位并快速溶化，患者无需吞咽，顺应性好，也更便于护理人员帮助给药。
2)药物经口腔黏膜吸收，避免了肝脏首过效应，生物利用度高，与口服制剂相比降低药物的剂量。
3)药物在口腔中溶解、经口腔黏膜吸收而不经过胃肠道，有可能避免“奶酪效应”，减轻不良反应。
4)本发明舌下膜剂稳定性好，长期储存后杂质含量仍较低。
5)本发明舌下膜具有较好的溶出特性，表现为药物溶出迅速、完全，药物迅速经舌下黏膜吸收进入血液循环，起效快。
附图说明
图1为实施例1中的处方1和实施例2～5舌下膜的溶出曲线。
图2为实施例3舌下膜、静脉注射和灌胃给药分别给药后雷沙吉兰的血药浓度随时间的变化曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例和对比例中所采用的原料和辅料均为常规市售可得。
效果实施例中稳定性考察、相容性实验、溶出曲线的测试等均按照药典规定中实验条件和检测方法进行。
实施例1
处方1-5和对比处方的组成及用量如表1所示。
表1
Figure PCTCN2021083192-appb-000003
制备工艺：
1、制备成膜材料的水浆料：按照处方比例，将HPMC和PVP溶解于水中，配成质量浓度为25％的水料浆。
2、将甲磺酸雷沙吉兰、羟丙基-β-环糊精、甜菊糖苷、二氧化钛、草莓香精加入上述水浆料中，搅拌均匀。
3、静置消泡，在铺膜厚度为0.4mm，干燥温度为85℃的条件下涂膜，涂布制膜的速度为50cm/min。
4、按0.5mg/片的规格进行分切包装。
由表1可知，(1)本发明处方1-3膜的物理性能与处方4-5膜的物理性能相比，强度和韧性较好。(2)虽然本发明处方4-5膜的物理性能与对比处方膜的物理性能相比相对差，但是由效果实施例4可知，对比处方高温稳定性较差，不合格。具体地，60℃下放置5天后，对比处方有关物质含量高达1.33％，远高于本发明处方1-5；60℃下放置10天后，对比处方有关物质含量高达2.35％，远远高于本发明处方1-5。
实施例2
实施例2的处方如表2所示。
表2
原辅料名称 质量百分比％
甲磺酸雷沙吉兰 5
羟丙基纤维素HPC 40
羧甲基纤维素钠CMC-Na 30
麦芽糊精 5
葡萄糖基-β-环糊精 5
麦芽糖醇 10
二氧化钛 4
葡萄香精 1
合计 100
制备工艺：
1、制备成膜材料的水浆料：将40gHPC和30gCMC-Na溶解于水中，配成质量浓度约为20％的水料浆。
2、将甲磺酸雷沙吉兰、麦芽糊精、葡萄糖基-β-环糊精、麦芽糖醇、二氧化钛、葡萄香精加入上述水浆料中，搅拌均匀。
3、静置消泡，在铺膜厚度为0.4mm，干燥温度为85℃的条件下涂膜，涂布制膜的速度为50cm/min。
4、按0.5mg/片的规格进行分切包装。
实施例3
实施例3的处方如表3所示。
表3
原辅料名称 质量百分比％
甲磺酸雷沙吉兰 8
聚乙烯醇PVA 30
玉米淀粉 30
麦芽糊精 20
阿斯巴坦 5
二氧化钛 4
甜橙香精 3
合计 100
制备工艺：
1、制备成膜材料的水浆料：将30gPVA和30g玉米淀粉溶解于水中，配成质量浓度约为16％的水料浆。
2、将甲磺酸雷沙吉兰、麦芽糊精、阿斯巴坦、二氧化钛、甜橙香精加入上述水浆料中，搅拌均匀。
3、静置消泡，在铺膜厚度为0.4mm，干燥温度为85℃的条件下涂膜，涂布制膜的速度为50cm/min。
4、按0.5mg/片的规格进行分切包装。
实施例4
实施例4的处方如表4所示。
表4
原辅料名称 质量百分比％
甲磺酸雷沙吉兰 10
普鲁兰多糖 20
聚乙烯醇PVP 20
磺丁基-β-环糊精 30
木糖醇 10
二氧化钛 4
草莓香精 1
崩解剂：羧甲基淀粉钠CMS-Na 5
合计 100
制备工艺：
1、制备成膜材料的水浆料：将20g普鲁兰多糖和30gPVA溶解于水中，配成质量浓度约为14％的水料浆。
2、将甲磺酸雷沙吉兰、磺丁基-β-环糊精、木糖醇、二氧化钛、草莓香精、CMS-Na加入上述水浆料中，搅拌均匀。
3、静置消泡，在铺膜厚度为0.4mm，干燥温度为85℃的条件下涂膜，涂布制膜的速度为50cm/min。
4、按0.5mg/片的规格进行分切包装。
实施例5
实施例5的处方如表5所示。
表5
原辅料名称 质量百分比％
甲磺酸雷沙吉兰 15
羟丙基甲基纤维素HPMC 20
海藻酸钠 10
麦芽糊精 20
羟丙基-β-环糊精 20
甜蜜素 1
二氧化钛 4
草莓香精 1
增塑剂：PEG400 9
合计 100
制备工艺：
1、制备成膜材料的水浆料：将20gHPMC和10g海藻酸钠溶解于水中，配成质量浓度约为10％的水料浆。
2、将甲磺酸雷沙吉兰、麦芽糊精、羟丙基-β-环糊精、甜蜜素、二氧化钛、草莓香精、PEG400加入上述水浆料中，搅拌均匀。
3、静置消泡，在铺膜厚度为0.4mm，干燥温度为85℃的条件下涂膜，涂布制膜的速度为50cm/min。
4、按0.5mg/片的规格进行分切包装。
对比实施例1
将实施例3处方中的麦芽糊精用PVA代替，其他处方工艺不变。
对比实施例2
将实施例4处方中的磺丁基-β-环糊精用普鲁兰多糖代替，其他处方工艺不变。
效果实施例1原辅料相容性试验
高分子成膜材料等辅料与药物按一定比例混合后，加纯化水研磨均匀，铺膜、干燥，置60℃条件下放置10天，于第5天和第10天取样，考察有关物质的变化。结果见表6。
表6原辅料相容性试验结果-高分子成膜材料
Figure PCTCN2021083192-appb-000004
Figure PCTCN2021083192-appb-000005
如表6所示，单独采用HPMC、PVA成膜材料，或者将HPMC分别与EDTA、焦硫酸钠、抗坏血酸、亚硫酸氢钠诸多常规稳定剂进行复配时，其总杂质含量远高于HPMC与“麦芽糊精或羟丙基-β-环糊精”进行复配时的总杂质含量。
其它辅料与药物按一定比例混合后，置60℃条件下放置10天，于第5天和第10天取样，考察有关物质的变化。结果见表7。
表7主辅料相容性试验结果-其它辅料
Figure PCTCN2021083192-appb-000006
表6-7的结果表明，甲磺酸雷沙吉兰与多种辅料配伍稳定性差，加各种常规的稳定剂仍无改善，而加糊精后稳定性明显增强。
效果实施例2溶出曲线
取实施例1中的处方1和实施例2～5的膜(规格0.5mg，即每片膜含0.5mg雷沙吉兰)各6片，照溶出度测定法(中国药典2015年版四部通则0931第二法)，以pH6.8的磷酸盐缓冲液500ml为溶剂，转速为每分钟50转，依法操作，经1、2、3、5、10和15min时，各取溶液1ml滤过，精密量取续滤液20uL，照高效液相色谱法测定；计算出不同时间的溶出量。溶出曲线见图1。
图1的结果表明，本发明的甲磺酸雷沙吉兰舌下膜，溶出迅速，3min基本溶出完全。
效果实施例3 Beagle犬药代动力学试验
静脉注射：4只健康Beagle犬，雌雄各半，分别静脉注射给予甲磺酸雷沙吉兰溶液(溶剂为水)(0.5mg/ml，以雷沙吉兰计)4ml，即给药剂量为2mg。
舌下膜和灌胃给药：采用双周期双交叉试验，清洗期为1周。4只健康Beagle犬，雌雄各半，随机分为2组，分别舌下给予甲磺酸雷沙吉兰舌下膜(实施例3)和灌胃给予 甲磺酸雷沙吉兰溶液，给药剂量为2mg。
给药前禁食16h，自由饮水。给药4h后自由饮水，并给予食物。给药前(0h)及给药后0.033、0.083、0.167、0.25、0.333、0.5、0.75、1、1.5、2、3、4、6h于前肢或后肢静脉取血2ml，置肝素钠抗凝管中。采集的血液样品立即离心(1006×g，10min)，分离血浆，-20℃保存。以盐酸司来吉兰为内标、采用乙腈蛋白沉淀方法处理后，LC-MS/MS测定样品中雷沙吉兰的血药浓度，绘制平均药-时曲线(图2)所示。采用DAS2.0软件的非房室模型处理血药浓度数据，计算雷沙吉兰的生物利用度。
图2的结果表明，将甲磺酸雷沙吉兰灌胃给予Beagle犬后，由于首过效应，生物利用度低，绝对生物利用度为11.8％±3.3％(n＝4)。舌下给予本发明的甲磺酸雷沙吉兰舌下膜，药物经舌下黏膜吸收，生物利用度明显增加，绝对生物利用度为77.8％±9.7％(n＝4)；增加至灌胃给药的6.9±1.3倍(n＝4)；且起效迅速，Tmax为(0.07±0.02)h(n＝4)。
效果实施例4处方中含不同比例糊精的样品稳定性考察
取实施例1中对比处方和处方1～5的膜(规格0.5mg)，去除外包装，进行高温试验，考察样品的稳定性。
将膜置培养皿中，在60℃条件下放置10天，于第5天和第10天取样，检测膜中雷沙吉兰的有关物质。试验结果表明，羟丙基-β-环糊精的比例在5～40％范围内，随羟丙基-β-环糊精的用量增加，药物在高温环境下的稳定性增强。但随羟丙基-β-环糊精的用量增大，需要相应减少成膜材料的用量，膜的强度逐渐减小，韧性逐渐变差。结果见表8。
表8实施例1稳定性考察结果
Figure PCTCN2021083192-appb-000007
效果实施例5
不同处方样品稳定性考察
取对比实施例1、对比实施例2和实施例2～5的膜(规格0.5mg)，去除外包装，进行高温试验，考察样品的稳定性。
将膜置培养皿中，在60℃条件下放置10天，于第5天和第10天取样，检测膜中雷沙吉兰的含量、有关物质和溶出度(溶出度方法见效果实施例2)。试验结果表明，在考察期间，对比实施例1和对比实施例2生产的甲磺酸雷沙吉兰舌下膜，其有关物质有明显增长，结果见表9-10。本发明制备的甲磺酸雷沙吉兰舌下膜即实施例2～实施例5，各项指标无明显变化、产品质量稳定，结果见表11～14。
表9对比实施例1稳定性考察结果
考察项目 原始 60℃5天 60℃10天
有关物质(％) 0.10 1.27 1.96
3分钟溶出度(％) 98.7 97.5 96.2
含量(％) 100.2 98.9 97.4
表10对比实施例2稳定性考察结果
考察项目 原始 60℃5天 60℃10天
有关物质(％) 0.14 1.46 2.59
3分钟溶出度(％) 99.6 97.5 96.1
含量(％) 101.3 99.2 98.1
表11实施例2稳定性考察结果
考察项目 原始 60℃5天 60℃10天
有关物质(％) 0.07 0.41 0.64
3分钟溶出度(％) 99.6 98.9 98.1
含量(％) 101.0 100.5 100.6
表12实施例3稳定性考察结果
考察项目 原始 60℃5天 60℃10天
有关物质(％) 0.09 0.37 0.52
3分钟溶出度(％) 99.6 98.8 99.4
含量(％) 101.8 100.5 101.4
表13实施例4稳定性考察结果：
考察项目 原始 60℃5天 60℃10天
有关物质(％) 0.05 0.33 0.41
3分钟溶出度(％) 99.8 98.5 99.3
含量(％) 100.5 101.2 100.4
表14实施例5稳定性考察结果：
考察项目 原始 60℃5天 60℃10天
有关物质(％) 0.08 0.36 0.49
3分钟溶出度(％) 98.9 97.4 98.3
含量(％) 101.3 100.0 101.2
表9-14的结果表明，本发明的甲磺酸雷沙吉兰舌下膜，由于各组分协同配合作用，高温60℃储存10天总杂质均未超过1％，且糊精比例增加，稳定性增强。与未添加糊精的对比实施例1和对比实施例2相比，高温放置后，溶出度和含量未见明显变化，有关物质的增加明显减少，稳定性明显增强。
本发明中，所述的雷沙吉兰口腔膜剂，服用时不需要水或其它液体，以干手撕开包装袋，取出药膜，放在口腔中至完全溶解。不应折叠本品，不应咀嚼或吞咽本品。用药后10min内应避免进食或饮水。
效果实施例6
不同水分样品稳定性考察
不同水分样品稳定性考察
按照实施例3的处方及制备方法分别制备不同含水量的膜(如下表第2列)，用PET/Al/PE袋密封包装，在60℃条件下放置10天，于第5天和第10天取样，检测膜中有关物质。试验结果见表15。
表15不同水分膜稳定性考察结果
Figure PCTCN2021083192-appb-000008
表15的结果表明，水分对本发明的甲磺酸雷沙吉兰舌下膜稳定性有影响，随着水分增大，本发明舌下膜稳定性增强。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅 是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (10)

  1. 一种雷沙吉兰或其药用盐舌下膜剂，其特征在于，其包括下述处方组分：
    Figure PCTCN2021083192-appb-100001
    所述的糊精为麦芽糊精、羟丙基-β-环糊精、葡糖基-β-环糊精和磺丁基-β-环糊精的一种或多种；
    上述百分比为各组分分别相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
  2. 如权利要求1所述的雷沙吉兰或其药用盐舌下膜剂，其特征在于，所述雷沙吉兰或其药用盐为甲磺酸雷沙吉兰；
    和/或，所述的高分子成膜材料为羟丙基甲基纤维素HPMC、聚乙烯醇PVA、羟丙基纤维素HPC、羧甲基纤维素钠CMC-Na、聚乙烯吡咯烷酮PVP、聚氧化乙烯PEO、海藻酸钠、普鲁兰多糖、白芨胶、玉米淀粉和卡拉胶中的一种或多种，
    和/或，所述的糊精为所述麦芽糊精、所述羟丙基-β-环糊精、所述葡糖基-β-环糊精、所述磺丁基-β-环糊精、所述麦芽糊精和葡萄糖基-β-环糊精混合物、或者，所述麦芽糊精和羟丙基-β-环糊精的混合物；
    和/或，所述其它辅料包括抗氧剂、崩解剂、增塑剂、着色剂、香精和甜味剂中的一种或多种。
  3. 如权利要求2所述的雷沙吉兰或其药用盐舌下膜剂，其特征在于，所述的高分子成膜材料为羟丙基甲基纤维素HPMC、聚乙烯醇PVA、羟丙基纤维素HPC、羧甲基纤维素钠CMC-Na、海藻酸钠、普鲁兰多糖和玉米淀粉中的一种或多种，优选羟丙基甲基纤维素HPMC和聚乙烯醇PVA的混合物，羟丙基纤维素HPC和羧甲基纤维素钠CMC-Na的混合物、聚乙烯醇PVA和玉米淀粉的混合物、普鲁兰多糖和聚乙烯醇PVP的混合物，或者，羟丙基甲基纤维素HPMC和海藻酸钠的混合物。
  4. 如权利要求2或3所述的雷沙吉兰或其药用盐舌下膜剂，其特征在于，当所述的高分子成膜材料为羟丙基甲基纤维素HPMC和聚乙烯醇PVA的混合物时，羟丙基甲基纤维素HPMC和聚乙烯醇PVA的质量比为(27.5～45)：(22.5～40)，例如45:40、42.5:37.5、37.5:32.5、32.5:27.5或者27.5:22.5；
    当所述的高分子成膜材料为羟丙基纤维素HPC和羧甲基纤维素钠CMC-Na的混合 物时，羟丙基纤维素HPC和羧甲基纤维素钠CMC-Na质量比为40：(25～35)，例如40:30；
    当所述的高分子成膜材料为聚乙烯醇PVA和玉米淀粉的混合物时，聚乙烯醇PVA和玉米淀粉的质量比为30:(25～35)，例如30:30；
    当所述的高分子成膜材料为普鲁兰多糖和聚乙烯醇PVP的混合物时，普鲁兰多糖和聚乙烯醇PVP质量比为20:(15～25)，例如20:20；
    当所述的高分子成膜材料为羟丙基甲基纤维素HPMC和海藻酸钠的混合物时，羟丙基甲基纤维素HPMC和海藻酸钠质量比为20:(5～15)，例如20:10。
  5. 如权利要求2～4中至少一项所述的雷沙吉兰或其药用盐舌下膜剂，其特征在于，当所述的糊精为所述麦芽糊精和葡萄糖基-β-环糊精混合物时，麦芽糊精和葡萄糖基-β-环糊精质量比为1：(0.8～1.2)，例如1:1；
    当所述的糊精为所述麦芽糊精和羟丙基-β-环糊精的混合物时，麦芽糊精和羟丙基-β-环糊精质量比为1：(0.8～1.2)，例如1:1。
  6. 如权利要求2～5中至少一项所述的雷沙吉兰或其药用盐舌下膜剂，其特征在于，所述崩解剂为羧甲基淀粉钠CMS-Na；所述崩解剂用量优选为3～7％，例如5％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比；
    和/或，所述增塑剂为PEG400；所述增塑剂用量优选为7～11％，例如9％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比；
    和/或，所述着色剂为二氧化钛；所述着色剂的用量优选为2～6％，例如4％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比；
    和/或，所述香精为草莓香精、葡萄香精和甜橙香精中的一种或多种；所述香精的用量优选为1～3％，百分比为相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比；
    和/或，所述甜味剂包括木糖醇、麦芽糖醇、甜菊糖苷、糖精钠、阿斯巴坦、安赛蜜和甜蜜素中的一种或多种，优选木糖醇、麦芽糖醇、阿斯巴坦、甜蜜素和甜菊糖苷中的一种或多种，例如木糖醇、麦芽糖醇、阿斯巴坦、甜蜜素或甜菊糖苷；
    其中，所述的甜味剂的用量例如1％、4％、5％、10％或者30％，优选为3％～30％，更优选为5～20％；上述百分比为甜味剂相对于所述雷沙吉兰或其药用盐舌下膜剂的处方总组分的质量百分比。
  7. 如权利要求1～6中至少一项所述的雷沙吉兰或其药用盐舌下膜剂，其特征在于，所述的雷沙吉兰或其药物盐的用量为1％、5％、8％、10％或者15％，优选为1～8％；
    和/或，所述的高分子成膜材料的用量为30％、40％、50％、60％、70％、80％或者85％， 优选为40～60％；
    和/或，所述的糊精的用量为5％、10％、20％、25％、30％或者40％，优选为10～30％；
    和/或，所述其它辅料的用量为2～20％，例如9％、12％、15％或者20％。
  8. 一种如权利要求1～7中至少一项所述的雷沙吉兰或其药用盐舌下膜剂的制备方法，其特征在于，其包括下述步骤：将浆料涂布制膜，即可；
    其中，所述浆料包括所述的雷沙吉兰或其药用盐舌下膜剂的处方组分和水。
  9. 如权利要求8所述的雷沙吉兰或其药用盐舌下膜剂的制备方法，其特征在于，所述浆料通过下述方法制得：将除所述高分子成膜材料以外的处方组分加入含有所述高分子成膜材料的水料浆中，混合均匀即可；
    其中，所述含有所述高分子成膜材料的水料浆中，所述高分子成膜材料的质量浓度优选为10％～40％，更优选为13％～30％；
    所述涂布制膜过程中，铺膜厚度优选为0.3～0.5mm，例如0.4mm；
    所述涂布制膜过程中，涂膜速度优选为40～150cm/min，例如50cm/min。
  10. 一种如权利要求1～7中至少一项所述雷沙吉兰或其药用盐舌下膜剂在制备用于治疗帕金森病、阿尔茨海默症有关的疾病的药物中的应用。
PCT/CN2021/083192 2020-10-23 2021-03-26 雷沙吉兰或其药用盐舌下膜剂及其制备方法、应用 WO2022083063A1 (zh)

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EP21881489.5A EP4233852A4 (en) 2020-10-23 2021-03-26 SUBLINGUAL FILM DOSAGE OF RASAGILIN OR PHARMACEUTICALLY APPROPRIATE SALT THEREOF, AND METHOD OF MANUFACTURE THEREOF AND USE THEREOF
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