WO2016153365A1 - Compositions d'origine naturelle issues de calamus ornatus destinées à des applications anti-inflammatoires - Google Patents

Compositions d'origine naturelle issues de calamus ornatus destinées à des applications anti-inflammatoires Download PDF

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Publication number
WO2016153365A1
WO2016153365A1 PCT/PH2016/050002 PH2016050002W WO2016153365A1 WO 2016153365 A1 WO2016153365 A1 WO 2016153365A1 PH 2016050002 W PH2016050002 W PH 2016050002W WO 2016153365 A1 WO2016153365 A1 WO 2016153365A1
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WO
WIPO (PCT)
Prior art keywords
derivatives
ornatus
composition according
binucao
spirostanol
Prior art date
Application number
PCT/PH2016/050002
Other languages
English (en)
Inventor
Gracia Fe YU
Lourdes Cruz
Original Assignee
Yu Gracia Fe
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 Yu Gracia Fe filed Critical Yu Gracia Fe
Publication of WO2016153365A1 publication Critical patent/WO2016153365A1/fr

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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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • A61K36/8895—Calamus, e.g. rattan
    • 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)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • 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
    • 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

Definitions

  • This invention relates to the field of natural products, functional food and herbal- derived medicine, in particular to analgesics or pain-relieving substances.
  • Inflammatory conditions are very common medical problems. They include various forms of arthritides, sprains and strains, dysmenorrhea, toothaches, fractures and wounds, fatigue, post-surgical and dental operations, and local wound infections.
  • drugs have been developed for inflammatory and pain-relieving conditions, but most of them are limited by possible serious side effects.
  • the most commonly used are non-steroidal anti-inflammatory agents (NSAIDS), such as mefenamic acid, naproxen, ibuprofen, indomethacin, aspirin and diclofenac.
  • NSAIDS non-steroidal anti-inflammatory agents
  • COX cyclooxygenase
  • COX cyclooxygenase
  • COX-2-selective inhibitor drugs include celecoxib (Celebrex), rofecoxib (Vioxx), etoricoxib (Arcoxia) and lumiracoxib (Prexige).
  • the drugs block the inflammation-inducing COX-2 pathway with minimal inhibition of the COX-1 pathway, which, if inhibited, can result in gastric irritation and ulcers.
  • COX-2- selective inhibitor drugs retain a potent anti-inflammatory activity with lesser side effects (Pellicano, 2014).
  • the traditional NSAIDs (such as mefenamic acid and naproxen) cost significantly more than the traditional NSAIDs (such as mefenamic acid and naproxen).
  • the traditional NSAIDs such as mefenamic acid and naproxen.
  • Celecoxib and rofecoxib are associated with adverse cardiac-related side effects, such as myocardial infarction (Brueggemann et al., 2009). This could be due to the secondary targeting of coxibs on calcium signalling of vascular smooth muscle cells that is separate from their cyclooxygenase inhibition.
  • the objective of the present invention is to provide anti-inflammatory and anti-pain compositions with COX-2-selective inhibitory properties that are less expensive and have better safety potential. It has been determined that the enzyme COX-2 is selectively inhibited by rattan limuran (Calamus ornatus Blume var. philippinensis) shoot components, with minimal inhibition of COX-1. COX-2 is induced anywhere in the body in response to inflammation causing symptoms such as pain and swelling; thus, inhibition of COX-2 activity leads to the alleviation of these inflammatory manifestations. In contrast to the traditional NSAIDs, the lack of COX-1 inhibition prevents the occurrence gastrointestinal injury.
  • COX-1 constitutively expressed mainly in the digestive system and the genitourinary tract, has a major role in the protection of the mucosal linings (Pellicano, 2014). This explains why COX-2 selective inhibitory components have potent anti-inflammatory properties with lesser side effects.
  • COX-2 selective inhibitory components have potent anti-inflammatory properties with lesser side effects.
  • We present an invention that offers therapeutic and preventive solutions for the very common problems of inflammation and its associated pain. It offers several breakthroughs.
  • C. ornatus an indigenous and endemic plant in the Philippines.
  • the plant materials are food consumed by a Philippine ethnic group - Aytas - for centuries, attesting to its safety and availability as food. Typically, the plants grow in hills and forests away from polluted communities; thus the raw materials are cleaner and safer to consume.
  • G. binucao which lessens the anti-motility effect of C. ornatus preparations.
  • the G. binucao extract also neutralizes the bitter taste of C. ornatus.
  • G. binucao is also a traditional herbal-derived food for Aytas and has been tested in the laboratory to be very safe for oral intake.
  • rattan is a generic plant term for about 600 species that does not point specifically to C. ornatus. Moreover, the aforementioned invention is unlikely to be C. ornatus, simply because the plant is not endemic in China.
  • spirostanol saponins As for spirostanol saponins, several treatment indications are presented in the literature, such as Candida infection (MXMX/a/2007/014485), cardiovascular diseases (CN101035548), vulvovaginitis (US20050112218), hypoxia (CN102863501), and hyperglycemia (JP2005089419). However, the anti-inflammatory and/or analgesic action of the compounds have not been cited.
  • the present invention is a composition containing derivatives from extracts of C. ornatus shoot, either in the form of crude extracts or in a chemically purified form of the active chemical compounds with COX2- specific properties.
  • the chemical structures of the active compounds were determined to be consistent with spirostanol saponin- 1, spirostanol saponin 2, spirostanol saponin-3, and diosgenin. More importantly, the safety of the compositions has been verified through standard animal protocols, and has been considered to be very safe. Since the plant itself is used traditionally as food and medicine to humans, it is very likely that this plant material is safe for consumption. Part of the findings used for this invention has been published by the study group that includes the author (Yu et al., 2008). However, no data has come for human application, and the present formulation using G. binucao is not included.
  • Figure 1 refers to the anti-inflammatory activity profile of the different proportions of C. ornatus - G. binucao extract formulation.
  • Figure 2 refers to the anti-inflammatory profile of G. binucao at 300, 150 and 75 mg/kg.
  • Figure 4 refers to the COX inhibitory activities of spirostanol saponin -1, -2, -3 and diosgenin at 28.2, 24.2, 21.2 and 60.4 ⁇ , and the methanol extract at 250 ug/mL.
  • Commercial antiinflammatory drugs, aspirin, celecoxib (CelebrexTM) and rofecoxib (VioxxTM) were used as positive control and tested at 60 ⁇ , 26 nM, and 32 nM concentrations, respectively. All compounds and the crude methanol extract from C. ornatus exhibited significant anti-inflammatory activity, which is comparable with celecoxib (CelebrexTM).
  • the concentrations of positive controls used were based on their IC50.
  • the collected edible shoots were immediately washed with water and boiled for 5 min. After cooling, the boiled shoots with water extracts were osterized and lyophilized. The lyophilized shoot was stored in the freezer. This boiled C. ornatus shoot can be eaten by itself or in combination with other food.
  • the G. binucao leaves were washed with water and boiled for 5 min.
  • the water extract lyophilized was stored in the freezer.
  • the G. binucao extract was incorporated producing a tea or smoothie.
  • the most preferred preparation is 3parts of C. ornatus and lpart of G. binucao to be combined.
  • the proportions of C. ornatus: G. binucao may range from 1: 1 to 7: 1.
  • Water and/or sugar or any sweetener can be added to suit the sweet taste of the consumer.
  • One hundred grams (lOOg) of lyophilized shoot of C. ornatus was extracted 3 consecutive times at least 6 hours each with methanol solvent. The extraction may also be done 1-4 times.
  • the solvent-free methanol extract was obtained by rotary evaporation after which the extracts were stored in the freezer.
  • the 3g of methanol extract was passed through the gel column chromatography using 6:4 chloroform: methanol: solvent system to fractionate the different components. Depending on the capacity or targeted yield, the initial amount of methanol extract may vary. After rotary evaporation, each fraction was subjected to inflammatory testing. Fractions showing the bioactivity were pooled and were further isolated using the preparative thin layer chromatography preferably using 4:2 chloroform:methanol solvent system, but may range from 2: 1 to 1: 1. The TLC bands scraped were collected and re-extracted from the paper with the same solvent system. The solvents were removed using rotary evaporator and dissolved with chloroform:methanol combination for structural elucidation using NMR.
  • C. ornatus shoot has LD50 of 2,460 mg/kg body weight which denotes that this food is not harmful.
  • the LD50 of boiled C. ornatus shoot: G. binucao extract formulation was more than 2000 mg/ kg body weight (OECD protocol) confirming the former LD50 for C. ornatus.
  • OECD protocol body weight
  • G. binucao was likewise subjected to anti-inflammatory assay using Paw Method in mice ( Figure 3). It can be deduced from Fig. 6 the significant effect of G. binucao even at the lowest dose of 75mg/kg of G. binucao extracts at different concentrations. At the dose range of 75 to 300 mg/mL, its activity profile was comparable to the positive control, indomethacin (49.37%) reducing the inflammation by an a average value of 51.26%. The percent increase in paw thickness of the negative control was measured 120%.
  • the preferred formulation of the invention is a combination of processed limuran C. ornatus shoot and aqueous leaf extract of G. binucao that makes the product acceptable, safe and more effective as a supplement and/or a drug.
  • the presence of G. binucao extracts lessens the possibility of constipation due to C. ornatus and enhances the taste of the preparation.
  • the C. ornatus: G. binucao proportion ranges from 1: 1 to 7:1 parts, most preferably at 3: 1.
  • the bioactive derivatives are also obtainable from other parts of the plants, both from C. ornatus or from G. binucao.
  • compositions containing C. ornatus shoots or the derived bioactive compounds - spirostanol saponin -1, spirostanol saponin -2, spirostanol saponin -3, and diogenin - also produces similar anti-inflammatory effect regardless of the presence of G. binucao.
  • G. binucao by itself has a significant anti- inflammatory effect, and may therefore be used in compositions that ameliorate inflammatory symptoms.
  • the derived products from the extracts and compounds from the invention can be in the form of capsules, tablets, syrup, liquid preparations, tea and functional food. Because of the high likelihood of safety of the extracts and compounds, the translation to the market can be immediate if provided as tea, herbal supplement or functional food. Processes related to drug-development are promising with potential significant contribution local economy, with implication for worldwide distribution.
  • plants extracts and compounds can be added as fortificants to various food products, such as in bread or soy sauce) as functional food anti-inflammatory supplements.

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

Abstract

L'invention concerne des dérivés d'extraits de Calamus ornatus et des dérivés de composés purs compatibles avec des saponines de spirostanol en tant qu'inhibiteurs sélectifs de la cyclo-oxygénase 2 (COX-2). L'activation de CO2-2 est impliquée dans l'inflammation et la douleur sévères, ainsi que dans d'autres processus biologiques tels que l'angiogenèse et l'oncogenèse, et même dans le transit intestinal. De ce fait, une telle action de ces compositions contre COX-2 en fait un agent anti-inflammatoire prometteur. Du fait de sa structure différente des inhibiteurs de COX-2 classiques, ainsi que de l'utilisation de la plante source comme source alimentaire classique, il est également vraisemblable que l'invention puisse être d'une meilleure sécurité d'utilisation, que cette dernière soit utilisée de façon aiguë ou chronique.
PCT/PH2016/050002 2015-03-24 2016-03-23 Compositions d'origine naturelle issues de calamus ornatus destinées à des applications anti-inflammatoires WO2016153365A1 (fr)

Applications Claiming Priority (2)

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PH1-2015-000091 2015-03-24
PH2015209007 2015-03-24

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WO2016153365A1 true WO2016153365A1 (fr) 2016-09-29

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005089419A (ja) 2003-09-19 2005-04-07 Noevir Co Ltd ニンニクエキス
US20050112218A1 (en) 2001-12-12 2005-05-26 ALEXIS Brian Treatment of vulvovaginitis with spirostanol enriched extract from Tribulus Terrestris
CN101035548A (zh) 2004-09-30 2007-09-12 成都地奥制药集团有限公司 甾体皂苷药物组合物及其制备方法和用途
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CN102813867A (zh) 2012-08-21 2012-12-12 吴绍章 一种治疗风湿性关节炎的中药膏贴
CN102863501A (zh) 2012-08-01 2013-01-09 广东工业大学 一种螺甾皂苷类化合物及其用途和制备方法
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Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050112218A1 (en) 2001-12-12 2005-05-26 ALEXIS Brian Treatment of vulvovaginitis with spirostanol enriched extract from Tribulus Terrestris
JP2005089419A (ja) 2003-09-19 2005-04-07 Noevir Co Ltd ニンニクエキス
MX2007001448A (es) 2004-08-05 2008-03-04 Schott Ag Absorbedor solar.
CN101035548A (zh) 2004-09-30 2007-09-12 成都地奥制药集团有限公司 甾体皂苷药物组合物及其制备方法和用途
CN102863501A (zh) 2012-08-01 2013-01-09 广东工业大学 一种螺甾皂苷类化合物及其用途和制备方法
CN102813867A (zh) 2012-08-21 2012-12-12 吴绍章 一种治疗风湿性关节炎的中药膏贴
CN103800618A (zh) 2014-01-24 2014-05-21 王有亮 一种治疗腰腿关节痛的口服丸剂及其制备方法

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ZHANG S; YANG R; LI H; YIN Z; ZHOU H; LI X; JIN Y; YANG S: "Separation and bio-activities of spirostanol saponin from Tribulus terrestris", CHEM. RES. CHINESE UNIVERSITIES, vol. 26, no. 6, 2010, pages 915 - 921, XP055279898

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