CN110167569B - 制备粉末组合物的方法 - Google Patents

制备粉末组合物的方法 Download PDF

Info

Publication number
CN110167569B
CN110167569B CN201780076659.7A CN201780076659A CN110167569B CN 110167569 B CN110167569 B CN 110167569B CN 201780076659 A CN201780076659 A CN 201780076659A CN 110167569 B CN110167569 B CN 110167569B
Authority
CN
China
Prior art keywords
powder composition
phospholipid
lipophilic extract
echinacea
lipophilic
Prior art date
Legal status (The legal status 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 status listed.)
Active
Application number
CN201780076659.7A
Other languages
English (en)
Other versions
CN110167569A (zh
Inventor
M·龙基
E·弗拉蒂尼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yidina Co ltd
Original Assignee
Yidina Co ltd
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 Yidina Co ltd filed Critical Yidina Co ltd
Publication of CN110167569A publication Critical patent/CN110167569A/zh
Application granted granted Critical
Publication of CN110167569B publication Critical patent/CN110167569B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/758—Zanthoxylum, e.g. pricklyash
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/40—Shaping or working of foodstuffs characterised by the products free-flowing powder or instant powder, i.e. powder which is reconstituted rapidly when liquid is added
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9068—Zingiber, e.g. garden ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0216—Solid or semisolid forms
    • A61K8/022—Powders; Compacted Powders
    • A61K8/0225—Granulated powders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q90/00—Cosmetics or similar toiletry preparations for specific uses not provided for in other groups of this subclass
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/35—Extraction with lipophilic solvents, e.g. Hexane or petrol ether
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mycology (AREA)
  • Botany (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Medical Informatics (AREA)
  • Inorganic Chemistry (AREA)
  • Birds (AREA)
  • Rheumatology (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及制备粉末组合物的方法，所述粉末组合物包含紫松果菊属物种(Echinacea spp.)的亲脂性提取物、姜(Zingiber officinale)的亲脂性提取物和磷脂。本发明还涉及可通过本发明的方法获得的粉末组合物和包含所述组合物的药物、营养保健和化妆美容制剂。本发明涉及粉末组合物及其制剂在预防和/或治疗炎症和疼痛状态中的用途。

Description

制备粉末组合物的方法
本发明的技术领域
本发明涉及制备粉末组合物的方法，所述粉末组合物包含紫松果菊属物种(Echinacea spp.)的亲脂性提取物、姜(Zingiber officinale)的亲脂性提取物和磷脂。
本发明还涉及可通过本发明的方法获得的粉末组合物和包含所述组合物的药物制剂。
根据本发明的粉末组合物及其制剂可用于预防和/或治疗炎症和疼痛状态。
发明背景
当局部或全身施用时，紫松果菊属物种、优选狭叶松果菊(Echinaceaangustifolia)的那些亲脂性提取物；花椒属物种(Zanthoxylum spp.)、优选花椒(Zanthoxylum bungeanum)的那些亲脂性提取物；金纽扣属物种(Acmella spp.)、优选千日菊(Acmella oleracea)的那些亲脂性提取物具有抗炎活性。已经证明它们的药理活性可归因于异丁酰胺，CB1和CB2大麻素受体的配体(Alkylamides from Echinacea are a newclass of cannabinomimetics；Stefan Raduner等人；J.Biol.Chem.(2006),281(20),14192-14206.Identification of CB1/CB2 Ligands from Zanthoxylum bungeanum；Katina S.S.Dossou等人；J.Nat.Prod.2013,76,2060-2064)。
姜的亲脂性提取物的主要活性成分由姜醇和姜烯酚组成。姜醇和姜烯酚是LPS(脂多糖)诱导的PGE2(前列腺素E2)产生的强效抑制剂和炎症部位的促炎细胞因子的脂氧化酶多效性下调剂。此外，姜醇和姜烯酚是有效的香草素受体(VR1)激动剂(Comparativeantioxidant and anti-inflammatory effects of[6]-gingerol,[8]-gingerol,[10]-gingerol and[6]-shogaol；Swarnalatha Dugasania等人；J.Ethnopharmacol.127(2010)515–520.Gingerols:a novel class of vanilloid receptor(VR1)agonists；VadimN.Dedov等人,Brit.J.Pharmacol.(2002)137,793-798.Echinacea alkylamides modulateTNF-a gene expression via cannabinoid receptor CB2 and multiple signaltransduction pathways；Juerg Gertscha等人；FEBS Letters 577(2004)563–569)。
已经描述了含有狭叶松果菊和姜的亲脂性提取物的制剂可用于减轻炎症和外周疼痛(EP 2 598 156 B1)和用于预防和治疗胃食管反流(EP 2 379095B1)。
考虑到狭叶松果菊(或花椒属或金纽扣属)和姜的亲脂性提取物为油性物理状态，软明胶胶囊代表了理想的口服施用制剂。众所周知，溶解性差的活性成分(其被配制为用于软明胶胶囊的基于脂质的填充物)的全身吸收可以通过甘油三酯的消化过程来介导和增强。此外，作为软明胶胶囊的基于脂质的填充物施用的溶解性差的活性成分的口服生物利用度也可以通过肠淋巴系统转运至全身循环来增强。
另一方面，软明胶胶囊制剂的特征在于一些缺点，因为由于活性物质和明胶壳之间的相互作用，活性成分通常更容易受化学降解和剂型的物理不稳定性影响。这尤其在用于植物提取物时发生，原因是植物提取物的多组分化学组成。此外，软明胶胶囊的生产需要特定的设施和设备，其仅可从有限数量的公司获得。
因此，仍然需要供选择的组合物，其特征在于活性成分的高度和快速吸收，其能容易地掺入稳定的制剂中。
发明概述
本发明涉及制备粉末组合物的方法，其包括以下步骤:
a)将紫松果菊属物种的亲脂性提取物或含有烷基酰胺的植物亲脂性提取物与姜的亲脂性提取物分散在至少一种有机溶剂中，并进行混合直至获得溶液或混悬液；任选地加热；
b)然后将至少一种磷脂加入所述多个亲脂性提取物形成的溶液或混悬液中，并将该混合液进行混合；任选地加热；
c)然后除去有机溶剂，得到粉末组合物。
本发明还涉及可通过本发明的方法获得的粉末组合物以及包含所述组合物的药物制剂。
根据本发明的粉末组合物可用于预防和/或治疗炎症和疼痛状态。
发明详述
令人惊讶地发现根据本发明所述的制备方法制备的粉末组合物，其包含紫松果菊属物种的亲脂性提取物(或含烷基酰胺的其他植物提取物)和姜的亲脂性提取物以及磷脂，可用于制备固体制剂，诸如除了软凝胶之外的常规剂型，如片剂和硬明胶胶囊，且与包含相同活性成分的机械混合物的软明胶胶囊制剂相比，所得的固体制剂保证了相似或改善(更高和/或更快)的活性成分的吸收，导致药理作用的快速起效。
本发明涉及制备包含以下成分的粉末组合物的制备方法:紫松果菊属物种的亲脂性提取物(或包含烷基酰胺的其他植物提取物，如花椒属物种或金纽扣属物种)、姜的亲脂性提取物和磷脂，本发明的方法能确保亲脂性提取物和磷脂之间的紧密相互作用。通过加入磷脂之前亲脂性提取物在合适的有机溶剂中的全部或部分共溶解(co-solubilisation)，可以获得这种紧密的相互作用。
制备根据本发明的粉末组合物的制备方法包括以下步骤:
a)将紫松果菊属物种的亲脂性提取物或包含烷基酰胺的植物亲脂性提取物与姜的亲脂性提取物分散在至少一种合适的有机溶剂中，并进行混合直至获得溶液或混悬液；如果需要，任选地加热；
b)然后将至少一种磷脂加入所述多个亲脂性提取物形成的溶液中，并将该混合液进行混合；任选地加热；
c)然后除去有机溶剂，得到粉末组合物。
紫松果菊属物种的亲脂性提取物优选从狭叶松果菊或紫松果菊(Echinaceapurpurea)、更优选从狭叶松果菊获得。
可使用含烷基酰胺的其他植物亲脂性提取物，此类提取物可以是，例如，花椒属物种或金纽扣属物种的亲脂性提取物。优选地，花椒属物种的亲脂性提取物可以从花椒、胡椒木(Zanthoxylum piperitum)、美洲花椒(Zanthoxylum americanum)获得，金纽扣属物种的亲脂性提取物从千日菊获得。
适合的有机溶剂是导致亲脂性提取物全部或至少基本上溶解的极性有机溶剂，如极性质子溶剂或极性非质子溶剂。
优选地极性质子溶剂为直链或支链的C1-C8烷基醇，且极性非质子溶剂为直链或支链的C1-C8烷基酯或C1-C8二烷基酮。
磷脂在所选有机溶剂中的全部或部分溶解也是期望的。
优选的有机溶剂可选自乙醇、乙酸乙酯、丙酮、异丙醇、异丁醇及其组合。优选乙醇和乙酸乙酯。
任选地加热以促进溶解而不引起活性成分的任何降解。
磷脂可以选自得自大豆、向日葵或卵的卵磷脂，磷脂酰胆碱，磷脂酰丝氨酸，磷脂酰乙醇胺，其中酰基可以相同或不同并且主要得自棕榈酸、硬脂酸、油酸、亚油酸、亚麻酸；及其组合。优选地，磷脂是卵磷脂。
亲脂性提取物与磷脂的比率可以优选为0.2至2，更优选为0.5至1。
在步骤b)之后，可以将额外的成分添加到所获得的亲脂性提取物和磷脂的溶液(或混悬液)中，将其进行混合达合适的一段时间以促进不同成分的相互作用。
粉末组合物中可包含除卵磷脂外的第二种表面活性剂，例如，以进一步促进亲脂性提取物的活性成分的溶解并增强其快速吸收。第二种表面活性剂可选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚甘油酯、脱水山梨糖醇脂肪酸酯、蔗糖棕榈酸酯、蔗糖硬脂酸酯、D-α-生育酚聚乙二醇琥珀酸酯及其组合。
磷脂(例如卵磷脂)与第二种表面活性剂的比率可以优选为0.25至10，最优选为0.5至1。
可以在真空下除去溶剂。供选干燥方法也可用于除去有机溶剂，例如喷雾干燥和冷冻干燥。
然后通常调整(calibrate)所得粉末组合物并最终研磨以获得所需的粒度分布。
本发明还涉及可通过本发明的制备方法获得的粉末组合物，其包含紫松果菊属物种的亲脂性提取物或含烷基酰胺的其他植物亲脂性提取物、姜的亲脂性提取物和一种或多种磷脂。
所得组合物为粉末形式，并且它们可通过常规制造方法容易地掺入固体剂型中，如片剂、硬明胶胶囊和颗粒剂。粉末组合物的特征在于活性成分的快速和有效吸收，以及随后其药理活性的快速起效。因此，从定量和动力学观点两个角度看，在胃环境中改善的和更快的溶解可以进一步增强姜醇、姜烯酚和烷基酰胺在体循环中的吸收，促进更高的生物利用度和其药理学活性的快速起效。
还可以向粉末组合物中加入另外的成分，目的是进一步提高活性成分的全身吸收的程度和速度，并改善组合物的技术特性，以促进它们通过常规制造方法掺入固体剂型中。所述成分可选自，例如，微晶纤维素、磷酸钙、粉状纤维素、硫酸钙、硫酸镁、甲基纤维素、羟丙基纤维素、羧甲基纤维素、羟丙基甲基纤维素、果糖、甘露糖醇、麦芽糖糊精、环糊精、异麦芽酮糖醇、糊精、菊粉。
还可以向粉末组合物中添加其他成分以改善其流动性。所述赋形剂可以是例如二氧化硅和滑石粉。
本发明还涉及药物制剂，其包含通过本发明的制备方法获得的粉末组合物和至少一种生理学上可接受的赋形剂和/或载体。
优选地，制剂用于口服施用。
生理学上可接受的赋形剂和/或载体可以是，例如，崩解剂、润滑剂、粘合剂、包衣剂、着色剂、吸收增强剂、增溶剂、稳定剂、矫味剂、甜味剂、抗菌剂、防腐剂、抗氧化剂等。
本发明制剂的剂型的实例可以是片剂、可咀嚼片剂、硬明胶胶囊、用于重构的粉末剂。
粉末组合物本身或包含在固体剂型中的粉末组合物的特征在于：亲脂性植物提取物的活性成分的有效和快速的吸收、这些活性成分的高口服生物利用度和因此的它们的药理活性的快速起效。
通过本发明所述的制备方法获得的粉末组合物及其固体制剂，即含有粉末组合物的剂型，可用于预防和/或治疗不同的炎症和疼痛状态，特别是当需要药理作用快速起效时。
测试根据本发明中描述的制备方法获得的干粉组合物以评价活性成分的溶解度。在水和/或生物相关介质(在禁食和进食条件下模拟胃液和肠液)中测量溶解度，并与配制成软明胶胶囊填充物的油性亲脂性提取物的溶解度以及与所述成分的物理(机械)混合物的溶解度进行比较。
通过HPLC分析粉末组合物，以测定亲脂性提取物和残留溶剂的活性成分的含量。
以下非限制性实施例进一步描述了本发明。
实施例
实施例1-粉末组合物的制备
将50g姜亲脂性提取物和10g狭叶松果菊亲脂性提取物在搅拌下溶于2000mL乙酸乙酯中。得到澄清的溶液。
将60g向日葵卵磷脂加入所述多个亲脂性提取物得到的溶液中，在60℃混合2小时直至卵磷脂几乎完全溶解。
将250g微晶纤维素和24g羟丙基甲基纤维素加入亲脂性提取物和卵磷脂的溶液中，混合约1小时。
然后减压除去溶剂，至乙酸乙酯残余物低于5000ppm。
将8g二氧化硅加入干燥的粉末中以改善其流动性。
通过1mm筛网调整所得固体，得到呈褐色的可流动粉末。
实施例2-粉末组合物的制备
将37.5g姜亲脂性提取物和7.5g千日菊亲脂性提取物在搅拌下溶于2500mL乙醇中。得到澄清的溶液。
将45g向日葵卵磷脂加入所述多个亲脂性提取物得到的溶液中，在60℃混合2小时直至卵磷脂几乎部分溶解。
将235g微晶纤维素和18g羟丙基纤维素加入得到的有机混悬液中，混合约1小时。
然后减压除去溶剂，至乙醇残余物低于5000ppm。
将7g二氧化硅加入干燥的粉末中以改善其流动性。
通过1mm筛网调整所得固体，得到呈褐色的可流动粉末。
实施例3-粉末组合物的制备
将125g姜亲脂性提取物和25g狭叶松果菊亲脂性提取物在搅拌下溶于5L乙酸乙酯中。得到澄清的溶液。·
将150g向日葵卵磷脂加入所述多个亲脂性提取物形成的溶液中，在60℃混合约2小时直至卵磷脂几乎完全溶解。
将125g蔗糖棕榈酸酯加入得到的溶液中，在60℃混合约15分钟。然后将750g微晶纤维素加入得到的溶液中，混合约15分钟。
然后减压除去溶剂直至乙酸乙酯的残余物低于5000ppm。将20g二氧化硅加入得到的粉末中。
通过1mm筛网调整所得固体，得到可流动的呈褐色的粉末。
实施例4-粉末组合物的制备
将37.5g姜亲脂性提取物和7.5g千日菊亲脂性提取物在搅拌下溶于4L乙醇中。得到澄清的溶液。
将45g向日葵卵磷脂加入所述多个亲脂性提取物形成的溶液中，在60℃混合约2小时直至卵磷脂几乎部分溶解。
将35g蔗糖棕榈酸酯加入得到的有机混悬液中，在60℃混合约15分钟。然后将200g微晶纤维素和18g羟丙基纤维素加入到所得溶液中，混合约15分钟。
然后减压除去溶剂，直至残留的乙醇低于5000ppm。将7g二氧化硅加入得到的粉末中。
通过1mm筛网调整所得固体，得到可流动的呈褐色的粉末。
实施例5–溶解度研究
将约200mg实施例3中所述的粉末组合物混悬于10ml模拟胃液中并在室温下在合适的容器中磁力搅拌2小时。然后将混悬液通过0.2μm PTFE一次性注射器过滤器过滤，将澄清的水相直接注入HPLC系统进行分析。
相同的方法还用于物理(机械)混合物，其含有与实施例3中所述制剂相同的组分。
得到以下结果，表示为姜醇和姜烯酚的总量的浓度，姜黄和姜烯酚是生姜提取物的活性成分：
●根据实施例3的制剂＝0.035mg/ml
·物理(机械)混合物＝0.024mg/ml
与物理(机械)混合物相比，对于根据实施例3获得的制剂，观察到姜醇+姜烯酚的溶解度增加约46％。活性成分在胃液中的更快和更高的溶解可以增强它们的快速吸收和药理活性更快起效，这在疼痛控制中特别有用。
实施例6–溶解度研究
将约200mg实施例3中得到的粉末组合物混悬在10ml模拟胃液中并在室温在合适的容器中磁力搅拌2小时。然后将混悬液通过0.2μm PTFE一次性注射器过滤器过滤，将澄清的水相直接注入HPLC系统进行分析。
相同的方法还用于物理(机械)混合物，其含有与实施例3中所述制剂相同的组分。
得到以下结果，表示为烷基酰胺8的浓度，其是狭叶松果菊亲脂性提取物中最相关的活性成分之一:
●根据实施例3制剂＝0.027mg/ml
●物理混合物＝0.012mg/ml
与物理(机械)混合物相比，观察到实施例3中获得的制剂的烷基酰胺8的溶解度显著增加。活性成分在胃液中的更快和更高的溶解可以增强它们的快速吸收和药理活性更快起效，这在疼痛控制中特别有用。
实施例7
测量来自实施例3中描述的组合物的姜醇和姜烯酚在模拟胃液中的溶解度，并与来自适于填充在软明胶胶囊中的油性组合物的姜醇和姜烯酚的溶解度进行比较。众所周知，软明胶胶囊制剂可以促进溶解性差的活性成分的生物利用度。实验结果如下，表示为姜醇和姜烯酚总量的浓度:
●根据实施例3的制剂＝0.344mg/ml
●用于软明胶胶囊的油性组合物＝0.090mg/ml
来自实施例3中描述的制剂姜醇和姜烯酚在模拟肠液中的浓度(总和)比来自适于软明胶胶囊的油性组合物的姜醇和姜烯酚的浓度高3.8倍。
实施例8–溶解度研究
测量来自实施例1中描述的制剂的姜醇和姜烯酚在模拟肠液中的溶解度，并与来自适于填充在软明胶胶囊中的油性组合物的姜醇和姜烯酚的溶解度进行比较。实验结果表示为姜醇和姜烯酚总量的浓度，报告如下:
●根据实施例1的制剂＝0.444mg/ml
·用于软明胶胶囊的油性组合物＝0.149mg/ml
结果显示，来自实施例1中描述的制剂的姜醇和姜烯酚在模拟肠液中的浓度(总和)比来自用于软明胶胶囊的油性组合物的姜醇和姜烯酚的浓度高三倍。
实施例9–片剂剂型
将实施例1中所述的粉末组合物与微晶纤维素、磷酸二钙二水合物和交联羧甲基纤维素钠在合适的混合器中混合10分钟。然后将硬脂酸镁和二氧化硅加入到所得混合物中，并再混合2分钟。将得到的混合物在配备有直径为10mm的圆形凹面冲头的旋转压片机中压制，配制500mg片剂。所得片剂的特征在于合适的硬度、脆碎度和崩解时间。
实施例10–硬明胶胶囊剂型
将实施例4中所述的粉末组合物与无水磷酸二钙和聚乙烯基聚吡咯烷酮在合适的混合器中混合10分钟。然后将山嵛酸甘油酯和二氧化硅加入到所得混合物中，并再混合2分钟。将得到的混合物装入1号硬明胶胶囊中，配制350mg胶囊。

Claims (14)

1.制备粉末组合物的制备方法，其包括以下步骤:
a)将紫松果菊属物种的亲脂性提取物或金纽扣属物种的亲脂性提取物、与姜的亲脂性提取物分散于至少一种极性有机溶剂中，并进行混合直至获得溶液或混悬液；任选地加热；其中有机溶剂是直链或支链的C1-C8烷基醇、直链或支链的C1-C8烷基酯或C1-C8二烷基酮；
b)然后将至少一种磷脂加入所述多个亲脂性提取物形成的溶液或混悬液中，并将该混合液进行混合；任选地加热；其中亲脂性提取物与磷脂的比率为0.2至2；
c)然后除去有机溶剂，得到粉末组合物；
其中在步骤b)之后加入除磷脂外的第二种表面活性剂，且磷脂与第二种表面活性剂的比率为0.25至10；其中第二种表面活性剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚甘油酯、脱水山梨糖醇脂肪酸酯、蔗糖棕榈酸酯、蔗糖硬脂酸酯、D-α-生育酚聚乙二醇琥珀酸酯及其组合；
其中在步骤b)之后，可以将另外的成分添加到所获得的亲脂性提取物和磷脂的溶液或混悬液中；其中所述另外的成分选自微晶纤维素、磷酸钙、粉状纤维素、硫酸钙、硫酸镁、甲基纤维素、羟丙基纤维素、羧甲基纤维素、羟丙基甲基纤维素、果糖、甘露糖醇、麦芽糖糊精、环糊精、异麦芽酮糖醇、糊精、菊粉；
其中紫松果菊属物种的亲脂性提取物从狭叶松果菊或紫松果菊获得；且
其中金纽扣属物种的亲脂性提取物从千日菊获得。
2.根据权利要求1的制备方法，其中然后调整得到的粉末组合物，并任选研磨以获得所需的粒度分布。
3.根据权利要求1-2中任一项的制备方法，其中紫松果菊属物种的亲脂性提取物从狭叶松果菊获得。
4.根据权利要求1-2中任一项的制备方法，其中有机溶剂选自乙醇、乙酸乙酯、丙酮、异丙醇、异丁醇及其组合。
5.根据权利要求1-2中任一项的制备方法，其中有机溶剂选自乙醇和乙酸乙酯。
6.根据权利要求1-2中任一项的制备方法，其中磷脂选自得自大豆、向日葵或卵的卵磷脂，磷脂酰胆碱，磷脂酰丝氨酸，磷脂酰乙醇胺，及其组合。
7.根据权利要求1-2中任一项的制备方法，其中磷脂是卵磷脂。
8.根据权利要求1-2中任一项的制备方法，其中亲脂性提取物与磷脂的比率为0.5至1。
9.根据权利要求1-2中任一项的制备方法，其中磷脂与第二种表面活性剂的比率为0.5至1。
10.能通过权利要求1-9中任一项的制造方法获得的粉末组合物。
11.固体剂型，其包含根据权利要求10的粉末组合物。
12.用于口服施用的固体剂型，其包含根据权利要求10的粉末组合物。
13.药物制剂，其包含根据权利要求10的粉末组合物和至少一种生理学上可接受的赋形剂和/或载体。
14.根据权利要求10的粉末组合物或根据权利要求13的药物制剂在制备用于预防和/或治疗炎症和疼痛状态的产品中的用途。
CN201780076659.7A 2016-12-15 2017-11-30 制备粉末组合物的方法 Active CN110167569B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP16204459.8 2016-12-15
EP16204459.8A EP3335716A1 (en) 2016-12-15 2016-12-15 Process for the preparation of powder compositions
PCT/EP2017/080967 WO2018108549A1 (en) 2016-12-15 2017-11-30 Process for the preparation of powder compositions

Publications (2)

Publication Number Publication Date
CN110167569A CN110167569A (zh) 2019-08-23
CN110167569B true CN110167569B (zh) 2024-01-19

Family

ID=57708351

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201780076659.7A Active CN110167569B (zh) 2016-12-15 2017-11-30 制备粉末组合物的方法

Country Status (18)

Country Link
US (1) US11123394B2 (zh)
EP (2) EP3335716A1 (zh)
JP (1) JP2020502101A (zh)
KR (1) KR102353858B1 (zh)
CN (1) CN110167569B (zh)
AU (1) AU2017377595B2 (zh)
BR (1) BR112019012307B1 (zh)
CA (1) CA3045207A1 (zh)
DK (1) DK3554523T3 (zh)
ES (1) ES2862917T3 (zh)
HU (1) HUE053275T2 (zh)
IL (1) IL267198B (zh)
MX (1) MX2019007078A (zh)
PL (1) PL3554523T3 (zh)
PT (1) PT3554523T (zh)
RU (1) RU2768108C2 (zh)
SI (1) SI3554523T1 (zh)
WO (1) WO2018108549A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1308541A (zh) * 1998-07-07 2001-08-15 因迪纳有限公司 花椒的提取物,含有它们的药物和化妆品制剂
CN103096907A (zh) * 2010-07-26 2013-05-08 因德纳有限公司 可用于减轻炎症和外周疼痛的含有狭叶紫锥菊和姜的提取物的制剂

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1220680B1 (en) * 1999-09-30 2008-03-12 Factors R & D Technologies Ltd. Echinacea supplement and method of manufacture
US8658202B2 (en) * 2001-04-25 2014-02-25 Western University Of Health Sciences Coated drug delivery formulations
DE10205362A1 (de) * 2002-02-08 2003-08-21 Abbott Gmbh & Co Kg Verfahren zur Herstellung wasserdispergierbarer Trockenpulver von in Wasser schwer löslichen Verbindungen
MXPA06005593A (es) * 2003-11-20 2007-02-12 Zomanex Llc Metodos y formulaciones para el tratamiento de condiciones medicas relacionadas con la dihidrotestosterona elevada.
US7491414B2 (en) 2005-10-12 2009-02-17 Gaia Herbs, Inc. Anti-inflammatory substances extracted from Echinacea
KR100928726B1 (ko) * 2006-03-22 2009-11-27 유니크인터네셔널 주식회사 아토피성 피부 질환 치료용 천연 특수 한방 조성물 및 그제조방법
IT1392535B1 (it) * 2008-11-17 2012-03-09 Herbal & Antioxidant Derivatives S R L In Forma Abbreviata H&Ad S R L Fitocomplesso da frutto di bergamotto, procedimento di preparazione e impiego quale integratore alimentare e nel settore farmaceutico.
ITMI20090049A1 (it) * 2009-01-20 2010-07-21 Indena Spa Composizioni a base di estratti lipofili di zingiber officinale e di echinacea angustifolia per la prevenzione e il trattamento del riflusso gastro-esofageo e dell'emesi indotta da chemioterapici
ITMI20121317A1 (it) * 2012-07-27 2014-01-28 Indena Spa Composizioni per il trattamento della fatica oncologica
RU2501549C1 (ru) * 2012-08-30 2013-12-20 Авва Девелопмент Лтд Фармацевтическая композиция для лечения гастроэзофагеальной рефлюксной болезни
US9860529B2 (en) * 2013-07-16 2018-01-02 Qualcomm Incorporated Processing illumination compensation for video coding
WO2015099842A1 (en) * 2013-12-23 2015-07-02 Abbott Laboratories Hot beverage fortifier

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1308541A (zh) * 1998-07-07 2001-08-15 因迪纳有限公司 花椒的提取物,含有它们的药物和化妆品制剂
CN103096907A (zh) * 2010-07-26 2013-05-08 因德纳有限公司 可用于减轻炎症和外周疼痛的含有狭叶紫锥菊和姜的提取物的制剂

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Antinociceptiveeffectsofethanolicextractfromthe flowers of Acmella oleracea (L.) R.K.Janseninmice;Ellen Cristine Ogata Nomura，et al;《Journal ofEthnopharmacology》;20130916;第583-584页 *
Ellen Cristine Ogata Nomura，et al.Antinociceptiveeffectsofethanolicextractfromthe flowers of Acmella oleracea (L.) R.K.Janseninmice.《Journal ofEthnopharmacology》.2013, *
上海医药工业研究院药物制剂研究中心等.药用辅料应用技术.《药用辅料应用技术》.2002,(第2版), *

Also Published As

Publication number Publication date
EP3554523A1 (en) 2019-10-23
SI3554523T1 (sl) 2021-03-31
PL3554523T3 (pl) 2021-06-14
US11123394B2 (en) 2021-09-21
RU2019121947A3 (zh) 2021-03-12
BR112019012307A2 (pt) 2019-11-12
PT3554523T (pt) 2021-03-17
RU2019121947A (ru) 2021-01-18
IL267198B (en) 2021-10-31
US20200085901A1 (en) 2020-03-19
AU2017377595A1 (en) 2019-07-11
RU2768108C2 (ru) 2022-03-23
DK3554523T3 (da) 2021-01-18
WO2018108549A1 (en) 2018-06-21
EP3554523B1 (en) 2020-12-30
KR102353858B1 (ko) 2022-01-21
CA3045207A1 (en) 2018-06-21
BR112019012307B1 (pt) 2022-10-04
EP3335716A1 (en) 2018-06-20
IL267198A (en) 2019-08-29
CN110167569A (zh) 2019-08-23
JP2020502101A (ja) 2020-01-23
ES2862917T3 (es) 2021-10-08
AU2017377595B2 (en) 2023-08-24
KR20190097089A (ko) 2019-08-20
HUE053275T2 (hu) 2021-06-28
MX2019007078A (es) 2019-08-16

Similar Documents

Publication Publication Date Title
US20160151440A1 (en) A Novel Composition of Curcumin with Enhanced Bioavailability
CN111787909B (zh) 包含小檗碱的组合物
ES2613381T3 (es) Nuevos extractos de Cynara scolymus, Coffea spp. y Olea Europaea para el tratamiento de síndrome metabólico
Karataş et al. Phyto-phospholipid complexes as drug delivery system for herbal extracts/molecules
EP2806866B1 (en) Pharmaceutical compositions containing phosphatidylserine sodium salt and curcumin
CN110167569B (zh) 制备粉末组合物的方法
CN113573722A (zh) 包含姜黄素和辅酶q10的组合物
Khan et al. Phospholipids: a novel adjuvant in herbal drug delivery systems
WO2017021974A2 (en) Novel and synergistic composition of lecithin and lysolecithin for improving bioavailability and solubility of hydrophobic compounds and extracts
Kumar et al. Phytosomes: a noval phyto-phospholipid carriers: an overview
US20160015813A1 (en) Novel and synergistic composition of lecithin and lysolecithin for improving bioavailability and solubility of hydrophobic compounds and extracts
AU2017370956B2 (en) Powder solid compositions, process for their preparation, formulations and use thereof
WO2009064151A1 (es) Método para obtener un extracto seco de galphimia glauca, composiciones farmacéuticas que comprenden dicho extracto y uso de las composiciones para el tratamiento de la ansiedad
Dwivedi et al. Phytosomes an Emerging Technology for Herbal Drug Delivery: an Approach To Hepatoprotection
WO2022101841A1 (en) Solid dispersions of cannabidiol
TW201943413A (zh) 含薑黃酮醇a及／或薑黃酮醇b之組合物

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40012558

Country of ref document: HK

CB02 Change of applicant information

Address after: Italy, Milan

Applicant after: Yidina Co.,Ltd.

Address before: Italy, Milan

Applicant before: INDENA S.P.A.

CB02 Change of applicant information
GR01 Patent grant
GR01 Patent grant