WO2021023099A1 - 一种马钱子碱凝胶制剂及其制备方法 - Google Patents

一种马钱子碱凝胶制剂及其制备方法 Download PDF

Info

Publication number
WO2021023099A1
WO2021023099A1 PCT/CN2020/106108 CN2020106108W WO2021023099A1 WO 2021023099 A1 WO2021023099 A1 WO 2021023099A1 CN 2020106108 W CN2020106108 W CN 2020106108W WO 2021023099 A1 WO2021023099 A1 WO 2021023099A1
Authority
WO
WIPO (PCT)
Prior art keywords
gel
preparation
brucine
sodium
strychnine
Prior art date
Application number
PCT/CN2020/106108
Other languages
English (en)
French (fr)
Inventor
张保献
胡杰
吴珍珍
赵倩
薛春美
李文慧
曹瑛
Original Assignee
北京盈科瑞创新医药股份有限公司
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 北京盈科瑞创新医药股份有限公司 filed Critical 北京盈科瑞创新医药股份有限公司
Priority to US17/630,680 priority Critical patent/US20220313683A1/en
Priority to JP2022506060A priority patent/JP2022542304A/ja
Priority to EP20850549.5A priority patent/EP4008309A4/en
Priority to KR1020227004705A priority patent/KR20220042147A/ko
Publication of WO2021023099A1 publication Critical patent/WO2021023099A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a brucine gel preparation and a preparation method and application thereof.
  • Knee osteoarthritis is a disease based on degenerative pathological changes. When knee osteoarthritis occurs, the pain is severe, and this pain shows the characteristics of local severity and deep location, requiring drugs to quickly reach the disease Site, and lasting effect.
  • Maqianzi is bitter and warm in nature; it is very poisonous. It has the effects of dredging collaterals and relieving pain, dispelling masses and reducing swelling. Used for bruises, fractures, swelling and pain, rheumatism, numbness and paralysis.
  • the main active ingredients of Strychnine are total alkaloids, which include strychnine, strychnine, strychnine, strychnine, strychnine, ponytoside, and icatrin, etc.; among them, strychnine Alkali has anti-inflammatory and analgesic effects; strychnine basically has no anti-inflammatory and analgesic effects, and strychnine is the main toxic component of strychnine.
  • strychnine can be quickly eliminated after absorption, and its half-life is short, which is not conducive to the analgesic effect.
  • therapeutic dose of strychnine is close to the toxic dose, which is difficult to take orally. Controlling the optimal dose greatly limits its clinical application.
  • the related preparations of Strychoma spp. Oral 13-flavored Strychoma spp. Pills and St. Chrysanthemum powder are currently on the market.
  • the active ingredients in the related preparations are either the extracts of Strychnoma, or the total alkaloids of Strychnoma, or both Strychnine and strychnine, these preparations or doses are difficult to accurately control, resulting in the therapeutic dose and the toxic dose being close to each other, or contain strychnine, a toxic ingredient; there are few related topical applications that only contain strychnine monomer as the active ingredient Preparations exist.
  • strychnine is how to develop it into a safe and effective new medicinal dosage form, which can give full play to its analgesic, anti-inflammatory, anti-cancer and other biological activities, while avoiding central toxicity and making it Better serve the clinic.
  • azone skin penetration enhancers
  • Azone has a strong skin penetration promoting effect, but due to its high lipophilicity, long-term use will accumulate in the skin for a long time, destroy the stratum corneum, cause irreversible skin damage, and have a strong irritation.
  • the inventors found that for the gel formulation of a single strychnine monomer, the choice of excipients, especially the gel matrix material (gel matrix material), can greatly affect the pharmacokinetics of the obtained formulation.
  • Many commonly used matrix materials are not suitable for the preparation of brucine gel preparations, and the transdermal effect is often not ideal, or there are other shortcomings in the preparation properties, such as stability and viscosity.
  • the purpose of the present invention is to provide a new type of strychnine gel preparation with safety and excellent transdermal effect and its preparation method and application in view of the defects of the prior art.
  • a strychnine gel preparation calculated by weight percentage, the gel preparation contains 0.5%-1% strychnine and 0.5%-3% gel matrix Materials and 10%-30% co-solvent.
  • the gel matrix material is carbomer, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose HPMC, sodium alginate, gum arabic, tragacanth, gelatin, One or a combination of two or more of chitosan, polyacrylic acid and its sodium salt; preferably, the gel skeleton material is selected from carbomer, sodium carboxymethyl cellulose, hydroxypropyl methyl Base cellulose, gum arabic and sodium polyacrylate; more preferably, the gel matrix material is selected from carbomer, sodium polyacrylate and hydroxypropyl methylcellulose; more preferably, the gel matrix material is selected from From carbomer and hydroxypropyl methyl cellulose; particularly preferably, the gel matrix material is hydroxypropyl methyl cellulose.
  • the cosolvent is one or a combination of two or more of ethanol, benzyl alcohol, propylene glycol, glycerin, polyethylene glycol 400, and isopropanol.
  • the gel formulation may also include a pH adjuster.
  • the pH adjuster is selected from organic amines, sodium hydroxide, sodium bicarbonate, sodium carbonate, acetic acid, lemon Acid and phosphate buffers, more preferably, the organic amines are selected from triethanolamine, triethylamine, diethylamine and laurylamine.
  • the gel formulation may also contain 0.01%-0.1% of an antioxidant, and the antioxidant is preferably anhydrous sodium sulfite, sodium metabisulfite, and hydrogen sulfite.
  • an antioxidant is preferably anhydrous sodium sulfite, sodium metabisulfite, and hydrogen sulfite.
  • the gel formulation may also contain 0.01%-0.15% of a bacteriostatic agent, and the bacteriostatic agent is preferably chlorobutanol, paraben One or a combination of two or more of ester, benzyl alcohol, methyl paraben, butyl paraben, sorbic acid and its potassium salt, benzoic acid and its sodium salt.
  • a bacteriostatic agent is preferably chlorobutanol, paraben One or a combination of two or more of ester, benzyl alcohol, methyl paraben, butyl paraben, sorbic acid and its potassium salt, benzoic acid and its sodium salt.
  • the gel formulation may contain 68%-80% water.
  • a method for preparing the gel formulation of the present invention includes the following steps: (1) swelling the gel matrix material to obtain the gel matrix I; (2) dissolving brucine and the cosolvent in Water to obtain brucine solution II; (3) mixing the gel matrix I and brucine solution II to obtain a brucine gel preparation.
  • a pH adjuster can be added in step (1) to adjust the pH to 5.5-6.5.
  • the pH can be adjusted by adding the pH adjuster to the solvent used for swelling.
  • step (2) antioxidants and/or bacteriostatic agents and/or transdermal agents can also be added, which can actually be added and dissolved in water.
  • a pH regulator can be added to adjust the pH value to 6.5-7.5 in step (3).
  • the application of brucine gel preparation in the preparation of medicine for treating knee osteoarthritis is provided.
  • the present invention has the following beneficial effects:
  • the strychnine gel preparation of the present invention uses simple pharmaceutical excipients, does not use skin penetration enhancers, but has excellent transdermal effect, easy spreading, good biological compatibility, good skin absorption, and good drug film adhesion , No irritation to skin and mucous membranes.
  • Test Example 1 Study on the properties of the brucine gel preparation of the present invention
  • Test Example 2 Study on the pharmacokinetics of the strychnine gel preparation of the present invention in the skin-administered joint fluid
  • Feeding conditions use artificial light for a 12-hour light-dark cycle, maintain an ambient temperature of 20-24°C, a humidity of 40%-70%, and breathe 15 times per hour; animals are kept in polycarbonate mouse cages, each cage is kept the same Group of 6 rats of the same sex; clean the animal cage and litter every 2 days.
  • Feed Growth maintenance feed for rats and mice, purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.
  • Drinking water drinking water for experimental animals, which can be taken freely by animals. New water bottles and fresh water are replaced daily.
  • Example 4 Example 5, and Comparative Examples 1-4, Gel 1, Gel 2, Gel 3, Gel 4, Gel 5, Gel 6, and Gel 7 were obtained respectively.
  • Chloral hydrate manufacturer: Shanghai Shanpu Chemical Co., Ltd.
  • the concentration of strychnine in the dialysate samples was analyzed by Beijing Yingkerui Pharmaceutical Safety and Effectiveness Research Co., Ltd., and the analysis used the non-confirmed liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
  • the standard curve range of Gel 1-7 is 0.2 to 200 ng/mL, and the lower limit of quantification is 0.2 ng/mL.
  • Mobile phase B acetonitrile/formic acid (99.9/0.1, v/v); injection volume: 10 ⁇ L; column temperature: 40°C
  • Ion source ESI
  • scan type positive ion MRM (multiple reaction monitoring)
  • the plasma concentration-time data of individual animals were analyzed with WinNonlin (Professional Edition, Version 5.2; Pharsight) software.
  • the non-compartmental model was used for concentration analysis.
  • the pharmacokinetic parameters in the present invention are summarized as follows:
  • AUC0-inf(ng*h/mL) The area under the drug concentration-time curve after administration of the test product
  • the microdialysis sampling device was adjusted to sample at a flow rate of 1 ⁇ L/min. Before sample collection, the probe was perfused and equilibrated for 1 hour, and one sample was collected every 30 minutes for a total of 10 hours (the rats were placed on an electric blanket at 38°C to observe the breathing rate and adjust the temperature). The dialysate was stored at -80°C until analysis. During the experiment, the animals were anesthetized with chloral hydrate, and if the rats were awake during the collection process, 0.3 mL 10% chloral hydrate (intraperitoneal injection) was added.
  • Table 3 Summary of the main pharmacokinetic parameters of the synovial fluid administered with brucine gel skin
  • Gel 1, gel 2, and gel 3 all have good pharmacokinetic properties, and the exposure amount (AUC) of gel 1 is higher than that of gel 2 and gel 3. It can be seen that gel 1 has better Pharmacokinetic properties, fast absorption and high exposure, high transdermal effect; unexpectedly, we found strychnine-containing strychnine (ie total strychnine) (gel 5, comparative example) 2) The transdermal effect is significantly lower than the gel made from strychnose monomer (Gel 1, Example 3).
  • Test Example 3 Experiment of the treatment effect of brucine gel preparation of the invention on joint swelling
  • CFA Complete Freund's Adjuvant
  • Example 4 According to the preparation methods of Example 3, Example 4, Example 5, and Comparative Example 2, Gel 1, Gel 2, Gel 3, and Gel 5 were obtained respectively.
  • CFA complete Freund's adjuvant
  • Swelling rate measurement The thickness of the left hind foot plantar was measured once before modeling, once before grouping, and once a week after administration to calculate the swelling rate.
  • Transdermal administration of Voltaren (Diclofenac sodium diethylamine; positive control group G3) and brucine gel (Example 3, gel 1 group; Example 4, gel 2 group; Example 5, gel Gel 3 group), Strychlamys japonicus total alkali gel (Comparative Example 2, Gel 5 group) can all reduce swelling, and gel 1 group is significantly better than the other groups.
  • Voltaren Diclofenac sodium diethylamine; positive control group G3
  • brucine gel Example 3, gel 1 group; Example 4, gel 2 group; Example 5, gel Gel 3 group
  • Strychlamys japonicus total alkali gel (Comparative Example 2, Gel 5 group) can all reduce swelling, and gel 1 group is significantly better than the other groups.

Abstract

一种马钱子碱凝胶制剂及其制备方法和应用。该凝胶制剂包含0.5％-1％的马钱子碱，0.5％-3％的凝胶骨架和10％-30％的助溶剂。所述马钱子碱水凝胶不含透皮促进剂但透皮效果优异，易涂展、生物相溶性好、皮肤吸收良好、药膜附着性好、对皮肤和黏膜无刺激性。

Description

一种马钱子碱凝胶制剂及其制备方法
交叉引用
本申请要求发明名称为“一种马钱子碱凝胶制剂及其制备方法”于2019年8月2日提交到中国专利局的中国专利申请201910709653.x的优先权，其内容通过引用以整体并入本文。
技术领域
本发明属于药物制剂领域，具体涉及一种马钱子碱凝胶制剂及其制备方法和用途。
背景技术
膝骨关节炎是一种以退行性病理改变为基础的疾患，膝骨关节炎发作时，疼痛剧烈，而且这种疼痛显现出局部的程度重、部位深的特点，需要药物能快速达到患病部位，并且持久起效。
马钱子性苦，温；有大毒。具有通络止痛，散结消肿的功效。用于跌打损伤，骨折肿痛，风湿顽痹，麻木瘫痪等。马钱子的主要有效成分是总生物碱，其包括马钱子碱、士的宁、番木鳖次碱、马钱子新碱、番木鳖甙、依卡精等；其中，马钱子碱具有抗炎、镇痛作用；士的宁基本无抗炎、镇痛作用，并且，士的宁是马钱子的主要毒性成分。
马钱子及其制剂的药动学研究表明，马钱子碱吸收后能够被快速消除，半衰期较短，不利于镇痛作用的发挥，而且马钱子的治疗剂量和中毒剂量接近，口服难以控制最佳剂量，大大限制了它的临床应用。
目前，已上市的马钱子相关制剂有口服十三味马钱子丸和马钱子散，相关制剂中的活性成分或者是马钱子提取物，或者是马钱子总生物碱，或者同时包含马钱子碱和士的宁，这些制剂或者剂量难以准确控制导致治疗剂量和中毒剂量接近，或者同时包含了毒性成分士的宁；几乎没有仅包含马钱子碱单体作为活性成分的相关外用制剂存在，有关马钱子碱的研究趋势是如何将其开发成安全、有效的药用新剂型，充分发挥其镇痛、抗炎、抗癌等生物活性,同时又能避免中枢毒性，使其更好地服务于临床。
对于凝胶制剂而言，如何提高活性成分的透皮效果是面临的主要问题。目前在凝胶制剂的处方中通常要加入透皮促进剂以提高活性成分的透皮效果，例如氮酮。氮酮有很强的皮肤促渗作用，但由于氮酮具有高亲脂性，长期使用会在皮肤中长期蓄积，破坏角质层， 导致不可逆的皮肤损伤，具有很强的刺激性。本发明人发现，对于单独马钱子碱单体的凝胶剂处方来说，辅料的选择，尤其是凝胶基质材料(凝胶骨架材料)可以在很大程度上影响所得制剂的药代动力学性质，并且多种通常采用的基质材料不适合制备马钱子碱的凝胶制剂，其透皮效果往往不够理想，或者存在其他制剂性质上的缺点，诸如稳定性、粘性等。
因此，现有技术中迫切需要一种安全、透皮效果优异的马钱子碱透皮制剂。
发明内容
本发明的目的就是针对现有技术存在的缺陷，提供一种安全、透皮效果优异的新型马钱子碱凝胶制剂及其制备方法和用途。
本发明在第一个方面，提供了一种马钱子碱凝胶制剂，按重量百分比计算，该凝胶制剂包含0.5％-1％的马钱子碱，0.5％-3％的凝胶骨架材料和10％-30％的助溶剂。
上述马钱子碱凝胶制剂中，所述凝胶骨架材料为卡波姆、羧甲基纤维素钠、羟丙基甲基纤维素HPMC、海藻酸钠、阿拉伯胶、西黄芪胶、明胶、壳聚糖、聚丙烯酸及其钠盐中的一种或两种或两种以上的组合；优选的，所述凝胶骨架材料选自卡波姆、羧甲基纤维素钠、羟丙基甲基纤维素、阿拉伯胶和聚丙烯酸钠；更优选地，所述凝胶骨架材料选自卡波姆、聚丙烯酸钠和羟丙基甲基纤维素；更优选地，所述凝胶骨架材料选自卡波姆和羟丙基甲基纤维素；特别优选地，所述凝胶骨架材料为羟丙基甲基纤维素。
上述马钱子碱凝胶制剂中，所述助溶剂为乙醇、苯甲醇、丙二醇、甘油、聚乙二醇400、异丙醇中的一种或两种或两种以上的组合。
上述马钱子碱凝胶制剂中，所述凝胶制剂还可以包含pH调节剂，优选地，所述pH调节剂选自有机胺类、氢氧化钠、碳酸氢钠、碳酸钠、醋酸、柠檬酸和磷酸盐缓冲液，更优选地，所述有机胺类选自三乙醇胺、三乙胺、二乙胺和月桂胺。
上述马钱子碱凝胶制剂中，按重量百分比计算，所述凝胶制剂还可以包含0.01％-0.1％的抗氧剂，所述抗氧剂优选为无水亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、叔丁基对羟基茴香醚、二丁基苯酚、维生素C、维生素C棕榈酸酯、乙二胺四乙酸及其钠盐中的一种或两种或两种以上的组合。
上述马钱子碱凝胶制剂中，按重量百分比计算，所述凝胶制剂还可以包含0.01％-0.15％的抑菌剂，所述抑菌剂优选为三氯叔丁醇、尼泊金乙酯、苯甲醇、尼泊金甲酯、尼泊金丁酯、山梨酸及其钾盐、苯甲酸及其钠盐中的一种或两种或两种以上的组合。
上述马钱子碱凝胶制剂中，按重量百分比计算，所述凝胶制剂中可以含有68％-80％的 水。
在本发明的另一方面，提供了本发明凝胶制剂的制备方法，包括以下步骤：(1)溶胀凝胶骨架材料得到凝胶基质I；(2)使马钱子碱和助溶剂溶解于水，得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合得到马钱子碱凝胶制剂。
其中，根据凝胶基质的酸碱性不同，可在步骤(1)中加入pH调节剂调节pH值至5.5-6.5，实际可以通过将pH调节剂加入到溶胀所用的溶剂中来调节pH值。
步骤(2)中还可以加入抗氧剂和/或抑菌剂和/或透皮剂，实际可以将所述抗氧剂、抑菌剂和/或透皮剂加入并溶解于水中。
根据测定马钱子碱凝胶制剂的pH值，步骤(3)中还可以加入pH调节剂调节pH值至6.5-7.5。
上述制备方法仅对本发明所提制法进行列举，但不应将此理解为本发明制备方法仅仅限于上述所列举方法。
在本发明的第三个方面，提供了马钱子碱凝胶制剂在制备用于治疗膝骨关节炎的药物中的应用。
与现有技术相比，本发明具有以下有益效果：
1、马钱子碱口服治疗关节炎毒副作用大，开发马钱子碱局部外用的凝胶制剂，避免了口服毒性，提高药物的生物利用度，提高治疗效果。
2、本发明的马钱子碱凝胶制剂，使用简单的药用辅料，不使用透皮促进剂但透皮效果优异，易涂展，生物相溶性好、皮肤吸收良好、药膜附着性好、对皮肤和黏膜无刺激性。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
配方 用量(g)
马钱子碱 10.0
卡波姆 8.3
无水乙醇 166.7
丙二醇 250.0
5M氢氧化钠 0.05
乙二胺四乙酸 0.83
尼泊金乙酯 1.67
水 1230.0
制备方法：
(1)将8.3g卡波姆加入水中溶胀完全，用5M氢氧化钠调pH值至6左右，得到凝胶基质I；(2)将1.67g尼泊金乙酯溶于丙二醇得溶液a，将0.83g乙二胺四乙酸溶于适量水得溶液b，将10g马钱子碱溶于无水乙醇和溶液a得到溶液c，将溶液c和溶液b混合均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，得到马钱子碱凝胶制剂。
实施例2
配方 用量(g)
马钱子碱 10.0
羟丙基甲基纤维素 33.33
无水乙醇 250.0
丙二醇 250.0
0.1M柠檬酸 0.08
乙二胺四乙酸 0.83
尼泊金乙酯 1.67
水 1120.0
制备方法：
(1)将33.33g羟丙基甲基纤维素加入水中溶胀完全得到凝胶基质I；(2)将1.67g尼泊金乙酯溶于丙二醇得溶液a，将0.83g乙二胺四乙酸溶于适量水得溶液b，将10.0g马钱子碱溶于无水乙醇和溶液a得到溶液c，将溶液c和溶液b混合均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，加入0.1M柠檬酸调pH值至7左右，得到马钱子碱凝胶制剂。
实施例3
配方 用量(g)
马钱子碱 10.0
羟丙基甲基纤维素 40.0
无水乙醇 200.0
丙二醇 300.0
0.1M柠檬酸 0.10
水 1450.0
制备方法：
(1)将40g羟丙基甲基纤维素加入水中溶胀完全得到凝胶基质I；(2)将10g马钱子碱溶于无水乙醇和丙二醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，加入0.1M柠檬酸调pH值至7左右，得到马钱子碱凝胶制剂。
实施例4
配方 用量(g)
马钱子碱 10.0
卡波姆 10.0
无水乙醇 200.0
丙二醇 300.0
5M氢氧化钠 0.04
水 1480.0
制备方法：
(1)将10g卡波姆加入水中溶胀完全，用5M氢氧化钠调pH值至6左右得到凝胶基质I；(2)将10g马钱子碱溶于无水乙醇和丙二醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，得到马钱子碱凝胶制剂。
实施例5
配方 用量(g)
马钱子碱 10.0
聚丙烯酸钠 20.0
无水乙醇 200.0
丙二醇 300.0
水 1470.0
制备方法：
(1)将20g聚丙烯酸加入水中溶胀完全得到凝胶基质I；(2)将10g马钱子碱溶于无水乙醇和丙二醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，得到马钱子碱凝胶制剂。
实施例6
配方 用量(g)
马钱子碱 10.0
羧甲基纤维素钠 30.0
无水乙醇 100.0
甘油 100.0
水 760.0
制备方法：
(1)将30g羧甲基纤维素钠加入水中溶胀完全得到凝胶基质I；(2)将10g马钱子碱溶于无水乙醇和甘油，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，得到马钱子碱凝胶制剂。
实施例7
配方 用量(g)
马钱子碱 10.0
羟丙基甲基纤维素 25.0
聚乙二醇400 300.0
0.1M柠檬酸 0.02
水 665.0
制备方法：
(1)将25g羟丙基甲基纤维素加入水中溶胀完全得到凝胶基质I；(2)将10g马钱子碱溶于聚乙二醇400，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，加入0.1M柠檬酸调pH值至7左右，搅 拌均匀，得到马钱子碱凝胶制剂。
实施例8
配方 用量(g)
马钱子碱 10.0
阿拉伯胶 8.33
苯甲醇 167.0
水 1480.0
制备方法：
(1)将8.33g阿拉伯胶加入水中溶胀完全得到凝胶基质I；(2)将10g马钱子碱溶于苯甲醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，得到马钱子碱凝胶制剂。
实施例9
配方 用量(g)
马钱子碱 10.0
卡波姆 30.0
甘油 100.0
异丙醇 400.0
5M氢氧化钠 0.06
水 1460.0
制备方法：
(1)将30g卡波姆加入水中溶胀完全，用5M氢氧化钠调pH值至6左右得到凝胶基质I；(2)将10g马钱子碱溶于甘油和异丙醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，搅拌均匀，得到马钱子碱凝胶制剂。
实施例10
配方 用量(g)
马钱子碱 10.0
羟丙基甲基纤维素 30.0
甘油 100.0
0.1M柠檬酸 0.02
水 880.0
制备方法：
(1)将30g羟丙基甲基纤维素加入水中溶胀完全得到凝胶基质I；(2)将10g马钱子碱溶于甘油，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合，加入0.1M柠檬酸调pH值至7左右，搅拌均匀，得到马钱子碱凝胶制剂。
对比例1
配方 用量(g)
马钱子碱 10.0
聚乙烯醇 40.0
无水乙醇 200.0
丙二醇 300.0
0.1M柠檬酸 0.04
透明质酸钠 20.0
水 1430.0
制备方法：
(1)将40.0g聚乙烯醇、20g透明质酸钠加入水中溶胀完全得到凝胶基质I；(2)10g马钱子碱溶于无水乙醇和丙二醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)凝胶基质I与马钱子碱溶液II混合，搅拌均匀，再加入0.1M柠檬酸调pH值至7左右，搅拌均匀，得到马钱子碱凝胶制剂。
对比例2
配方 用量(g)
马钱子总碱 含有10.0g马钱子碱和10.0g士的宁
羟丙基甲基纤维素 40.0
无水乙醇 200.0
丙二醇 300.0
0.1M柠檬酸 0.10
水 1440.0
制备方法：
(1)将40g羟丙基甲基纤维素加入水中溶胀完全得到凝胶基质I；(2)20g马钱子总碱溶于无水乙醇和丙二醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)凝胶基质I与马钱子碱溶液II混合，搅拌均匀，加入0.1M柠檬酸调pH值至7左右，得到马钱子总碱凝胶制剂。
对比例3
配方 用量(g)
马钱子碱 10.0
黄原胶 40.0
无水乙醇 200.0
丙二醇 300.0
0.1M柠檬酸 0.06
水 1450.0
制备方法：
(1)将40g黄原胶加入水中溶胀完全得到凝胶基质I；(2)10g马钱子碱溶于无水乙醇和丙二醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)凝胶基质I与马钱子碱溶液II混合，搅拌均匀，加入0.1M柠檬酸调pH值至7左右，即得。
对比例4
配方 用量(g)
马钱子碱 10.0
泊洛沙姆 300.0
无水乙醇 200.0
丙二醇 300.0
0.1M柠檬酸 0.06
水 1190.0
制备方法：
(1)将300g泊洛沙姆加入水中溶胀完全得到凝胶基质I；(2)10g马钱子碱溶于无水乙醇和丙二醇，混入剩余处方量的水，搅拌均匀得到马钱子碱溶液II；(3)凝胶基质I与马钱子碱溶液II混合，搅拌均匀，加入0.1M柠檬酸调pH值至7左右，即得。
试验例1：本发明马钱子碱凝胶制剂的性状研究
对根据实施例1-10、对比例1-4制备的凝胶制剂进行物理性状的肉眼观察。
表1：凝胶制剂的物理性状
凝胶 肉眼观察
实施例1 粘度适中
实施例2 粘度适中
实施例3 粘度适中
实施例4 粘度适中
实施例5 粘度适中
实施例6 粘度适中
实施例7 粘度适中
实施例8 粘度适中
实施例9 粘度适中
实施例10 粘度适中
对比例1 粘度适中
对比例2 粘度适中
对比例3 粘度适中
对比例4 粘度适中
结果显示，所有产品均符合凝胶制剂的粘度要求。
试验例2：本发明马钱子碱凝胶制剂皮肤给药关节液药代动力学研究
1、实验动物、药物与仪器
1.1实验动物
Wistar大鼠，SPF级(无特定病原体级实验动物)：体重210-250g，雌性，动物年龄10-11周，购自斯贝福(北京)生物技术有限公司；许可证编号：11401500036047。
动物房：试验期间动物饲养于北京盈科瑞药物安全有效性研究有限公司，实验设施许可证：SYXK(京)2017-0026；设施管理遵循中华人民共和国国家标准GB14925-2001《实验动物环境及设施》。
喂养条件：采用人工光照12小时明暗周期，环境温度维持在20～24℃，湿度在40％～70％，每小时换气15次；动物饲养于聚碳酸酯小鼠饲养笼，每笼饲养同组的6只同性别大鼠；每2天更换一次清洁动物笼和垫料。
饲料：大小鼠生长维持饲料，购自斯贝福(北京)生物技术有限公司
饮用水：试验动物饮用水，动物可自由摄取，每日更换新的水瓶和新鲜水。
1.2药物
根据实施例3、实施例4、实施例5、对比例1-4制备方法分别得到凝胶1、凝胶2、凝胶3、凝胶4、凝胶5、凝胶6、凝胶7。
1.3仪器与试剂
仪器：
三重四级杆-离子阱质谱仪AB Sciex QTRAP5500 Applied Biosystem公司；液相：超高效液相色谱ExionLC AC Applied Biosystem公司；微透析采样设备：CMA微透析采样系统
试剂和药品：
水合氯醛，生产厂家：上海山浦化工有限公司
1.4分析方法
1.4.1 LC-MS/MS测定马钱子碱在大鼠关节液中药物浓度的分析方法
透析液样品中马钱子碱的浓度在北京盈科瑞药物安全有效性研究有限公司分析，分析使用非确证的液相色谱-串联质谱联用方法(LC-MS/MS)。凝胶1-7的标准曲线范围均为0.2至200ng/mL，定量下限均为0.2ng/mL。
大鼠关节腔透析液添加华法林内标后，通过LC-MS/MS分析。
待测透析液样品直接取10μL再加2μL乙腈处理。将标曲(浓度分别为0.20ng/mL、0.60ng/mL、2.00ng/mL、6.00ng/mL、20.0ng/mL、60.0ng/mL、200ng/mL)(除Double Blank外)、质控和待测样本，加入100μL内标(华法林，100ng/mL)，涡旋混匀；取10μL Double Blank样本，加入102μL乙腈，涡旋混匀；吸取上清液，按顺序放置于进样盘，进样测定。所有的透析液均存储于-80℃冰箱中。
HPLC条件：
HPLC色谱柱：ACQUITY UPLC BEH C8 1.7um 2.1×50mm Colume(Waters)
流速：0.5mL/min；流动相A：水/甲酸(99.9/0.1,v/v)
流动相B：乙腈/甲酸(99.9/0.1,v/v)；进样量：10μL；柱温：40℃
运行时间：3.0分钟
MS条件：
离子源：ESI；扫描类型：正离子MRM(多反应监测)；
CUR Gas：30.00；喷雾电压：5500.00；源温度：500℃；
GS1:55.00；GS2:55.00；CAD:Medium
表2：马钱子碱和内标的监测离子参数
Figure PCTCN2020106108-appb-000001
计算：
通过Analyst 1.6.3软件线性程序拟合，在权重为1/x2下马钱子碱与内标峰面积比和浓度之间拟合一个线性方程(标准曲线)，此方程用于推算马钱子碱在透析液中 的浓度。
1.4.2药代动力学数据分析
个体动物的血浆浓度-时间数据用WinNonlin(专业版，版本5.2；Pharsight公司)软件进行分析。非房室模型被用于浓度分析。本发明中的药代动力学参数总结如下：
Cmax(ng/mL)：最大(峰值)透析液药物浓度
Tmax(h)：达峰时间
t1/2(h)：半衰期
AUC0-inf(ng*h/mL)：给予受试品后，药物浓度-时间曲线下面积
2、实验方法
取SD大鼠，雄性，随机分组为4组，每组12只。
研究分为三组各组动物分别组单次经皮给药(给与凝胶1-7)，剂量均为10mg/kg。动物在实验前无需禁食。
各组动物在给药后，调节微透析采样设备以1μL/min流速采样。样品收集前探针灌流平衡1h，每30min采集一个样，共采集10h(采集时大鼠置于38℃电热毯上观测呼吸频率，调节温度)，透析液放于-80℃保存直到分析。实验过程中，采用水合氯醛对动物进行麻醉，采集过程中若大鼠清醒，补0.3mL 10％水合氯醛(腹腔注射)。
表3：马钱子碱凝胶皮肤给药关节液的主要药代动力学参数总结
Figure PCTCN2020106108-appb-000002
凝胶1、凝胶2、凝胶3均具有较好的药代动力学特性，且凝胶1的暴露量(AUC)高于凝胶2与凝胶3，可见凝胶1具有更好的药代动力学特性，吸收快且暴露量高，透皮效果高；出乎意料的是，我们发现含有士的宁的马钱子碱(即马钱子总碱)(凝胶5，对比例2)透皮效果显著低于由马钱子单体制成的凝胶(凝胶1，实施例3)。
试验例3：本发明马钱子碱凝胶制剂的治疗关节肿胀效果实验
1、实验动物与药物
1.1实验动物和药物同试验例2
1.2药物
完全弗氏佐剂(CFA)，生产厂家：碧云天生物技术有限公司
扶他林(双氯芬酸二乙胺乳胶剂)，生产厂家：北京诺华制药有限公司
根据实施例3、实施例4、实施例5、对比例2制备方法分别得到的凝胶1、凝胶2、凝胶3、凝胶5。
2、实验方法
动物使用麻醉机麻醉后，在每只大鼠左后足趾皮内注射0.1ml完全弗氏佐剂(CFA)，其中卡介苗(BCG)浓度为10mg/ml，以诱发关节炎的发生。
根据大鼠关节炎临床评分随机分组，分为空白对照组、模型对照组、阳性对照组(扶他林、50mg/kg)、凝胶1组(5mg/kg)、凝胶2组(5mg/kg)、凝胶3组(5mg/kg)、凝胶5组(5mg/kg)。
称取不同量凝胶涂抹于大鼠左侧足及踝关节周围，注意轻轻按摩数下，用离型纸包裹，先用一层医用橡皮膏粘上，再缠上医用橡皮膏防止药物脱落。4h后去医用橡皮膏等，洗净大鼠左足。所有组每日均给药1次，连续给药7天，给药开始时间每天基本一致。
关节炎临床评分：建模前一次、分组时一次、分组后一次。采用0-4级评分法，测量右后足和左后足，每足最高得分4分，评分标准如下：
0分：无红肿
1分：趾关节红肿及脚面轻度红肿
2分：趾关节和足趾肿胀
3分：踝关节以下的足爪肿胀
4分：包括踝关节在内的全部足爪肿胀
肿胀率测定：造模前一次、分组前一次、给药后每周一次测定左后足足跖厚度，计算肿胀率。
肿胀率＝(造模后每次测定数据-造模前/造模前)×100％
结果如下：
表4：马钱子碱凝胶制剂治疗关节肿胀的肿胀率结果
Figure PCTCN2020106108-appb-000003
与空白组比： ◆◆P＜0.01， ◆P＜0.05；与模型组相比： ■■P＜0.01， ■P＜0.05
从表中可以看出，大鼠左足底皮内注射0.1ml完全弗氏佐剂后模型组(G2)大鼠足趾肿胀度、左后足趾关节肿胀度均与空白组有极显著差异(P＜0.01)，说明模型构建成功；
经皮给予扶他林(双氯酚酸钠二乙胺；阳性对照组G3)和马钱子碱凝胶(实施例3，凝胶1组；实施例4，凝胶2组；实施例5，凝胶3组)、马钱子总碱凝胶(对比例2，凝胶5组)均能减轻肿胀度，其中凝胶1组显著优于其他各组。

Claims (13)

  1. 一种马钱子碱凝胶制剂，其中按重量百分比计算，所述凝胶制剂包含0.5％-1％的马钱子碱、0.5％-3％的凝胶骨架材料和10％-30％的助溶剂。
  2. 根据权利要求1所述的凝胶制剂，其中所述凝胶骨架材料为卡波姆、羧甲基纤维素钠、羟丙基甲基纤维素、海藻酸钠、阿拉伯胶、西黄芪胶、明胶、壳聚糖、聚丙烯酸及其钠盐中的一种或两种或两种以上的组合。
  3. 根据权利要求1或2所述的凝胶制剂，其中所述凝胶骨架材料选自卡波姆、羧甲基纤维素钠、羟丙基甲基纤维素、阿拉伯胶和聚丙烯酸钠。
  4. 根据权利要求1-3中任一项所述的凝胶制剂，其中所述凝胶骨架材料选自聚丙烯酸钠、卡波姆和羟丙基甲基纤维素。
  5. 根据权利要求1-4中任一项所述的凝胶制剂，其中所述凝胶骨架材料为羟丙基甲基纤维素。
  6. 根据权利要求1-5中任一项所述的凝胶制剂，其中所述助溶剂为乙醇、苯甲醇、丙二醇、甘油、聚乙二醇400、异丙醇中的一种或两种或两种以上的组合。
  7. 根据权利要求1-6中任一项所述的凝胶制剂，其中所述凝胶制剂还包含pH调节剂，所述pH调节剂选自有机胺类、氢氧化钠、碳酸氢钠、碳酸钠、醋酸、柠檬酸和磷酸盐缓冲液；优选的，所述有机胺类选自三乙醇胺、三乙胺、二乙胺和月桂胺。
  8. 根据权利要求1-7中任一项所述的凝胶制剂，其中，按重量百分比计算，所述凝胶制剂还包含0.01％-0.1％的抗氧剂，所述抗氧剂为无水亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、叔丁基对羟基茴香醚、二丁基苯酚、维生素C、维生素C棕榈酸酯、乙二胺四乙酸及其钠盐中的一种或两种或两种以上的组合。
  9. 根据权利要求1-8中任一项所述的凝胶制剂，其中，按重量百分比计算，所述凝胶制剂还包含0.01％-0.15％的抑菌剂，所述抑菌剂为三氯叔丁醇、尼泊金乙酯、苯甲醇、尼泊金甲酯、尼泊金丁酯、山梨酸及其钾盐、苯甲酸及其钠盐中的一种或两种或两种以上的组合。
  10. 根据权利要求1-9中任一项所述的凝胶制剂，其中，按重量百分比计算，所述凝胶制剂中含有68％-80％的水。
  11. 权利要求1-10中任一项所述的凝胶制剂的制备方法，包括以下步骤：(1)溶胀所述凝胶骨架材料得到凝胶基质I；(2)使马钱子碱和助溶剂溶解于水，得到马钱子碱溶液II；(3)将凝胶基质I与马钱子碱溶液II混合得到马钱子碱凝胶制剂。
  12. 根据权利要求11的制备方法，
    其中，步骤(1)中还可以加入pH调节剂调节pH值至5.5-6.5；
    步骤(2)中还可以加入抗氧剂、抑菌剂和透皮剂；
    步骤(3)中还可以加入pH调节剂调节pH值至6.5-7.5。
  13. 权利要求1-10中任一项的马钱子碱凝胶制剂在制备用于治疗膝骨关节炎的药物中的应用。
PCT/CN2020/106108 2019-08-02 2020-07-31 一种马钱子碱凝胶制剂及其制备方法 WO2021023099A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US17/630,680 US20220313683A1 (en) 2019-08-02 2020-07-31 Brucine gel formulation and preparation method therefor
JP2022506060A JP2022542304A (ja) 2019-08-02 2020-07-31 ブルシンゲル製剤及びその製造方法
EP20850549.5A EP4008309A4 (en) 2019-08-02 2020-07-31 BRUCINE GEL FORMULATION AND METHOD FOR PREPARING IT
KR1020227004705A KR20220042147A (ko) 2019-08-02 2020-07-31 브루신 겔 제형 및 그 제조 방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910709653.X 2019-08-02
CN201910709653.XA CN112386565A (zh) 2019-08-02 2019-08-02 一种马钱子碱凝胶制剂及其制备方法

Publications (1)

Publication Number Publication Date
WO2021023099A1 true WO2021023099A1 (zh) 2021-02-11

Family

ID=74503248

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/106108 WO2021023099A1 (zh) 2019-08-02 2020-07-31 一种马钱子碱凝胶制剂及其制备方法

Country Status (6)

Country Link
US (1) US20220313683A1 (zh)
EP (1) EP4008309A4 (zh)
JP (1) JP2022542304A (zh)
KR (1) KR20220042147A (zh)
CN (1) CN112386565A (zh)
WO (1) WO2021023099A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2023551417A (ja) * 2020-11-20 2023-12-08 セーリング ファーマシューティカル テクノロジー グループ カンパニー リミテッド ブルシンゲルプラスター、その製造方法および使用
CN114931548A (zh) * 2022-05-19 2022-08-23 季华实验室 一种驳骨酒凝胶膏剂的制备方法
CN115919754B (zh) * 2023-01-06 2023-09-12 广州家安化妆品有限公司 一种用于灭活病毒的粘膜消毒凝胶及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102008476A (zh) * 2010-11-22 2011-04-13 南京中医药大学 一种马钱子碱的羟丙基-β-环糊精包合物及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102008476A (zh) * 2010-11-22 2011-04-13 南京中医药大学 一种马钱子碱的羟丙基-β-环糊精包合物及其制备方法

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
WU PING, LIANG QIN, FENG PEI, LI CHUNYAN, YANG CHUNGUANG, LIANG HONGSUO, TANG HUAIBO, SHUAI CIJUN: "A Novel Brucine Gel Transdermal Delivery System Designed for Anti-Inflammatory and Analgesic Activities", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 18, no. 4, pages 757, XP055780285, DOI: 10.3390/ijms18040757 *
XIANG-TAO DENG, XIAO-DONG RUAN, HAI-JUN HAO: "Study on matrix sustained release tablets of brucine solid lipid nanoparticles", CHINESE TRADITIONAL AND HERBAL DRUGS, vol. 49, no. 22, 30 November 2018 (2018-11-30), pages 5298 - 5304, XP055780281, DOI: 10.7501/j.issn.0253-2670.2018.22.012 *
ZHANG WEI-HUA, JIE HU, ZHEN-ZHEN WU, YONG ZHENG: "Effects of Different Penetration Enhancers on in vitro Permeability of Brucine Vesicles Gels", CHINESE JOURNAL OF EXPERIMENTAL TRADITIONAL MEDICAL FORMULAE, vol. 21, no. 7, 1 April 2015 (2015-04-01), pages 14 - 16, XP055780279 *
ZHANG WEI-HUA, JIE HU, ZHEN-ZHEN WU, YONG ZHENG: "Effects of Different Penetration Enhancers on in vitro Permeability of Brucine Vesicles Gels", CHINESE JOURNAL OF EXPERIMENTAL TRADITIONAL MEDICAL FORMULAE, vol. 21, no. 7, 1 April 2015 (2015-04-01), pages 14 - 16, XP055780287 *
ZHENZHEN WU, HENGCHUN REN, YANYING LI, JIAJIA FU, XIAOJUN LIU, JIE HU: "Tissue distribution and pharmacokinetics of brucine niosomal gels in rats after topical and oral application", JOURNAL OF CHINESE PHARMACEUTICAL SCIENCES, vol. 27, no. 2, 31 December 2018 (2018-12-31), pages 92 - 98, XP055780283 *
ZHI-PENG CHEN, WEN LIU, HONG-XUAN CHEN, BAO-CHANG CAI: "Brucine chitosan thermosensitive hydrogel for intra-articular injection", ACTA PHARMACEUTICA SINICA, vol. 47, no. 5, 1 January 2012 (2012-01-01), pages 652 - 656, XP055780280, DOI: 10.16438/j.0513-4870.2012.05.006 *

Also Published As

Publication number Publication date
JP2022542304A (ja) 2022-09-30
KR20220042147A (ko) 2022-04-04
US20220313683A1 (en) 2022-10-06
CN112386565A (zh) 2021-02-23
EP4008309A1 (en) 2022-06-08
EP4008309A4 (en) 2023-08-23

Similar Documents

Publication Publication Date Title
JP6434104B2 (ja) ジクロフェナク製剤
WO2021023099A1 (zh) 一种马钱子碱凝胶制剂及其制备方法
US20210196783A1 (en) New pharmaceutical use
EP3785698B1 (en) Edaravone pharmaceutical composition
CN113274342A (zh) 一种秋水仙碱外用组合物
US9468618B2 (en) Topical pharmaceutical gel composition of diclofenac sodium
CN111825548A (zh) 一种含有芳基丙酸类化合物的药物组合物
CN110693860B (zh) 一种含酮洛芬的凝胶贴膏及其制备方法
US20220105082A1 (en) New formulations containing leukotriene receptor antagonists
WO2016137411A1 (en) Topical spray composition comprising ibuprofen and lidocaine
Jiang et al. Preparation and evaluation of dissolving tofacitinib microneedles for effective management of rheumatoid arthritis
CN110693861A (zh) 一种硫酸特布他林雾化吸入用溶液制剂及其制备方法
US20240100042A1 (en) Brucine gel plaster and preparation method and use thereof
JPH09157161A (ja) 皮膚疾患治療剤
WO2023016583A1 (zh) 一种芦可替尼组合物及其用途
US20230331792A1 (en) New multi-functional oligopeptides
WO2024088153A1 (zh) 托品酸及其衍生物在制备治疗银屑病药物中的用途
JP2024518462A (ja) 新しい製剤及び使用
US9468617B2 (en) Topical pharmaceutical gel composition of diclofenac sodium
CN117860670A (zh) 一种千层纸素外用制剂及其在银屑病治疗上的应用
TR2022007380A2 (tr) Korti̇kosteroi̇d i̇hti̇va eden merhem formülasyonlari
Arhewoh et al. Formulation of Powder Dosage Form of Insulin for Intranasal Delivery
CN115279360A (zh) 局部用双氯芬酸组合物和方法
KR20120059545A (ko) 세티리진염산염 약용액

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: 20850549

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022506060

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20227004705

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020850549

Country of ref document: EP

Effective date: 20220302