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EP1651245A1 - Une composition pour reduire le risque des thromboses comprenant un melange de proanthocyanidines et de sesquiterpenes - Google Patents

Une composition pour reduire le risque des thromboses comprenant un melange de proanthocyanidines et de sesquiterpenes

Info

Publication number
EP1651245A1
EP1651245A1 EP04738122A EP04738122A EP1651245A1 EP 1651245 A1 EP1651245 A1 EP 1651245A1 EP 04738122 A EP04738122 A EP 04738122A EP 04738122 A EP04738122 A EP 04738122A EP 1651245 A1 EP1651245 A1 EP 1651245A1
Authority
EP
European Patent Office
Prior art keywords
pycnogenol
extract
ginger
haul
long
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.)
Withdrawn
Application number
EP04738122A
Other languages
German (de)
English (en)
Inventor
Michael Lehman
Adriana Burkard
Om P. Gulati
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.)
Pynogin GmbH
Original Assignee
Pynogin GmbH
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 Pynogin GmbH filed Critical Pynogin GmbH
Priority to EP04738122A priority Critical patent/EP1651245A1/fr
Publication of EP1651245A1 publication Critical patent/EP1651245A1/fr
Withdrawn legal-status Critical Current

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
    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • 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)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the invention refers to a newly developed, innovative health care product for decreasing the risk of Deep Vein Thrombosis (DVT) in leg veins, leg and/or feet oedema and motion sickness which may occur particularly in long-haul travellers by air, road or sea while sitting in the constrained position.
  • DVD Deep Vein Thrombosis
  • VTE Venous thrombo-embolism
  • a preparation including acetylsalicylic acid, which inhibits the aggregation of thrombocytes, is often administered to the patients as a remedy from their pain.
  • Such preparations involve the risk of inner bleeding out of the vascular capillaries into the surrounding tissue. It is known that ugly blue spots appear easily upon the skin in case such tissue is compressed from the exterior.
  • Pycnogenol ® includes among other active ingredients, procyanidins. Extended clinical tests confirmed that Pycnogenol ® is not only superior to acetylsalicylic acid in inhibiting aggregation but is also free of any side effects particularly it does not cause any inner bleeding. Preparation and qualities of Pycnogenol ® are disclosed in US Patent 5,720,956 listed as reference 5. This patent discloses a method of controlling human platelet reactivity by Pycnogenol ® .
  • Pycnogenol ® has been subject of a number of studies for finding out scientifically confirmed qualities and effects on the human body. Such studies are enlisted in Reference list (6-18). Regarding venous insufficiency & Oedema a double blind, placebo controlled study is disclosed in reference 6. This study shows that 4 days of Pycnogenol ® treatment statistically and significantly reduced the leg volume increase while remaining seated, while placebo had no significant effect. The authors conclude that Pycnogenol ® displays a significant inhibition of oedema during hydrostatic burden (Schmidtke and Shoop, 1984). Reference 7 presents a double blind, placebo controlled study.
  • Pycnogenol ® Clinical studies with Pycnogenol ® (reference 14) have shown with elevated platelet activity, such as smokers and elderly, that the activation of platelets is prevented. Pycnogenol ® was found to dose-dependently reduce platelet activity, with statistical significance after using a single dose of at least 100 mg Pycnogenol ® . The authors of that study propose that stimulation of nitric oxide production by Pycnogenol ® inhibits aggregation of platelets. Thus, Pycnogenol ® supports body- own mechanisms to maintain healthy platelet functions. In a dose range finding part of this study, it was shown that the maximum platelet inhibitory effect was evident at a dose of 200 mg (Putter etal, 1999).
  • a single dose of 100 mg of Pycnogenol ® was found to be as effective for reduction of platelet activity as acetyl-salicylic acid, a substance widely used for suppression of platelet aggregation.
  • acetyl-salicylic acid irreversibly inhibits the enzyme COX involved in platelet aggregation.
  • acetyl-salicylic acid dramatically increases the bleeding time causing severe adverse effects, primarily g astro- intestinal bleeding problems.
  • Pycnogenol ® does not significantly increase bleeding time allowing a long term use for preventing of thrombotic events.
  • Pycnogenol ® has been demonstrated in various studies to be one of the most powerful natural antioxidants.
  • One of the objects of the invention resides in creating a health care composition having improved platelet aggregation inhibiting function and being substantially free of side effects.
  • the invention provides for a health care product for decreasing the risk of thrombosis particularly within the human leg veins.
  • This includes a standardized mixture of Pycnogenol ® and Standardized Ginger Root Extract in a newly invented, well-defined proportion (1 :1.5) of these two innovative, Generally Recognized As Safe (GRAS) ingredients.
  • Tests showed that the adding of Standardized Ginger Root Extract, to Pycnogenol ® in a well defined proportion, allowed us to produce a preparation having improved platelet aggregation inhibiting function, relieving the symptoms of pain, oedema and inflammation, in addition to having beneficial effects in travel-induced motion sickness, which are of particular importance for passengers of long haul flights at increased altitudes.
  • references 20 - 23 report on the prophylaxis of nausea and vomiting associated with motion sickness, supported by clinical data related to ginger.
  • the prophylaxis of pernicious vomiting in pregnancy is subject of reference 24.
  • the studies according to references 25-26 refer to the prophylaxis of seasickness.
  • References 21 & 27-30 represent monographies on ginger revealing results as to the treatment of dyspepsia, flatulence, colic, vomiting, diarrhoea, spasms and other stomach complaints.
  • ginger may have beneficial effects on thrombosis, owing to its ability to inhibit platelet aggregation, thromboxane synthase and to act as a prostacyclin agonist causing vasodilatation and increase in blood flow.
  • Ginger can significantly scavenge O 2 - in hypoxanthinexanthine oxidase system and -OH in ultraviolet exposure of H 2 O 2 system.
  • the scavenger effects of ginger on O 2 - and -OH may contribute to explaining some of the physiological mechanisms of this active substance.
  • Ginger's action against oedema and anti-inflammatory activity of ginger are demonstrated in reference 41 according to which ginger (100 mg/kg) was effective as acetyl-salicylic acid (100 mg/kg) in reducing carrageenin induced oedema in rats (Jana et al., 1999). Similar results for the anti-inflammatory and analgesic activities of ginger (references 42 and 43) were reported by (Mascolo et al, 1989; Thomson et al., 2002). It is thought that these anti-inflammatory actions are a result of inhibition of prostaglandin release, and hence ginger may act in a similar fashion to other non-steroidal anti-inflammatory agents which interfere with prostaglandin release or biosynthesis.
  • Ginger has also been shown to produce decrease in fibrinogen levels and increased fibrinolytic activity (Verma and Bordia, 2001).
  • ginger decreases the levels of cholesterol, phospholipids and free fatty acids in tissues and serum. Serum glycerdies levels were also significantly reduced. Ginger increases the concentration of HDLs and decreases the concentrations of LDLs and VLDLs in serum (Murgaiah et al, 1999).
  • the health care composition Zinopin ® according to the present invention includes a well-proportioned and well-defined mixture of Pycnogenol ® and Standardized Ginger Root Extract.
  • the proposed mechanism of action in the proposed healthcare indication, "Long-haul Traveller's Syndrome" is included (see
  • Standardised Ginger Root Extract which includes a content of approximately 5% of the 150 weight units of gingeroles and approximately 1 ,.5% of the 150 weight units of shagoals.
  • the invention represents a unique combination of Pycnogenol ® and standardised Ginger Root Extract in a preferred and well-defined proportion (1 :1.5).
  • the invention offers the physiological benefits in newly defined syndrome in healthy subjects.
  • a newly invented term, "Long-haul Traveller's Syndrome (LTS)” is defined as "occurrence of deep vein thrombosis and/or oedema in legs and/or feet, associated with or without motion sickness, in travellers going on long-haul journey by air, land or sea", (see below script 4 for further explanation on this syndrome).
  • Zinopin ® inclusive of application of the unique formulation and ratio of 1 :1.5 Pycnogenol ® to Standardized Ginger Root Extract in a maintenance product application, in the Fast Moving Consumer Goods (FMCG) market for application as a flavouring and or nutraceutical agent in chewing gums, travel sweets, beverages and oral care (such as mouth sprays)
  • FMCG Fast Moving Consumer Goods
  • the Standardized Ginger Root Extract according to the invention is effective as an anti-nausea and anti-emetic: Clinical studies have demonstrated that the oral administration of ginger is more effective than dimenhydrinate in preventing the gastrointestinal symptoms of kinetosis (motion sickness). Having a Standardised Ginger Root Extract with a minimum 10:1 concentration to that of ginger rhizomes means the recommended posology of the WHO Monograph of .5 g 2-4 times daily is easily met with one capsule containing the medicament according to the invention offering the equivalent of 1.5 g of ginger rhizomes.
  • Zinopin ® reduces free radical damage during long haul flights: Pycnogenol ® and Ginger are both powerful antioxidants which help to reduce the damage caused by free radicals generated as a result of long haul flights. Cosmic radiation exposure is much higher for long haul flights due to the increased altitude of long haul flights as compared to short haul flights and this is particularly magnified near the respective poles. Further, research shows that the electromagnetic fields which are also pronounced on aircraft might actually increase the half life of free radicals which both oligomeric proanthocyanidins and ginger are known to scavenge. Several studies support the possibility that magnetic fields inhibit a cell's ability to protect itself from ionising radiation.
  • Zinopin ® is currently being taken by long-haul travellers, travelling for more than eight hours, and who are over eighteen years of age. There have been no exclusions from this study. Prior to entering the study, a full medical history is obtained, including a history of recent flights and the duration of those flights. Any current medication is noted and passengers are asked to record any use of medication during the study period. No specific advice about travel was given to any passenger, and the passengers took one Zinopin ® capsule the day before flight, two on the day of flight, and a further capsule on each of the two following days. On their return all passengers completed a questionnaire looking specifically for leg and chest symptoms. Passengers took the Zinopin ® on both the outward bound and the return flights.
  • Pycnogenol ® and Standardized Ginger Root Extract are blended in a weight ratio of 1 :1 to 1 :2, preferred 1 :1.5 weight units of such blend were granulated in a planetary mixer with a suspension of 10 to 15, preferred 11.7 weight units of Plasdone K 29 - 32 and 10 to 15, preferred 11.7 weight units of Aerosil 200 in 250 weight units isopropyl alcohol.
  • the mass is wetted with additional 400 weight units isopropyl alcohol for better granulation.
  • the wet mass was sieved for this preparation through a 10.8 mm sieve and dried on hurdles at 40 - 45°C.
  • the dry granules were sieved for this preparation again through a 0.8 mm sieve.
  • the mass was thereafter encapsulated.
  • the material may be granulated and dried in a ROTO vacuum mixer and drier with inlet air of 60°C and the product temperature up to 30 - 40°C.
  • the standardised ginger root extract is a concentrated form from 5:1 to 15:1, preferred 10:1. Therefore, at 10: 1 concentration 150 mg of standardised ginger extract in each capsule is equivalent to 1500 mg of ginger rhizome material satisfying the recommended posology of the WHO Monograph.
  • Dyspepsia 2-4 g daily as powdered plant material or extracts.
  • the initial formulation comprised: - 250 mg of Dried Ground Rhizomes Powder 50 mg of OPC's blend (Oligomeric Proanthocyanidins ) from Pinus Maritima (pine bark extract) 25% & Vitis Vinifera (grape seed extract) 75%.
  • the formulation for the first pilot trial comprised: - 250 mg of Dried Ground Ginger Rhizomes - 100 mg of a blend of OPC's (Oligomeric Proanthocyanidis) from Pinus Maritima (pine bark extract) 25% & Vitis Vinifera (grape seed extract) 75%. Encapsulated in a size 0 vegetable capsule (8900 capsules test, which was effected on scaled down machine that replicated full production) Pack of 3 blisters of 10 vegetable capsules.
  • Pycnogenol ® was chosen at this stage because of it being relatively more potent and more researched particularly on clinical aspects in venous area (chronic venous insufficiency) with a USA Patent 5,720,956 on "Decreasing platelet reactivity ".
  • the powder characteristics of the new materials were different to the former products (i.e. OPC blend & dried ground ginger powder).
  • the new blend resulted in being much finer and suitable for formulation. Also the flow and filling characteristics were not sufficient for a production run. It was tried to encapsulate the new blend, but stopped after 1500 capsules because of insufficient capacity of the machine and strong deviation in the uniformity of the capsules mass.
  • the product was again reformulated.
  • the addition of excipients alone was not sufficient. Therefore the materials were granulated to increase the density and flow characteristics.
  • the blend was granulated with a solution of 0.5% Povidone and 0.5% Silicone Dioxide in isopropanol, in a planetary mixer. After drying and sieving a granulate with sufficient encapsulation characteristic resulted. The colour of the granulate was a little darker than a blend without granulation but acceptable.
  • Figure 4 shows the Zinopin ® dosage schedule and the recommended posology for long haul travel.
  • the 1 capsule the day before the trip was introduced to prime the metabolism prior to the journey and to already have a beneficial effect on the blood.
  • Zinopin ® is also long lasting so even after a journey of 10 -12 hours, therapeutic levels of Zinopin ® are still extant in the blood.
  • an effective dosage of 300mg of Standardized Ginger Root Extract with a 10:1 concentration i.e. two capsules of 150 mg of Standardized Ginger Root
  • Extract each) complies with the WHO Monograph's posology for motion sickness in ginger root equivalent i.e. "for motion sickness in adults and children more than 6 years: 0.5g, 2-4 times daily.
  • Long-haul travelerr's syndrome is defined a occurrence of Deep vein thrombosis and/or oedema in legs and/or feet associated with or without motion sickness.
  • Oxidative stress and/or other kind of chemical stimuli released due to venous stasis cause endothelial cell injury producing platelets adhesions and aggregation producing micro-thrombus. Increased, fibrinogen levels, haemo-concentration and blood viscosity further contribute to clot formation in the veins producing deep vein thrombosis.
  • Physiological activities of Pycnogenol ® • Potent antioxidant, • Anti-oedema & anti-inflammatory, • Provides endothelial cell protection, • inhibits platelet aggregation & improves microcirculation.
  • Physiolgical activities of Standarized Ginger extract ® Strong anti-nausea and anti-motion sickness profile, Antioxidant, Anti-inflammatory, Inhibits platelets aggregation, • Fibrinolytic action. It seems both active components Pycnogenol® and standardized ginger extract work in synergistic manner by virtue of their multiple factor physiological actions target towards one or more of the sites on the patho-physiolgical axis of Long-haul Traveller's Syndrome. SCRIPT NO. 4 " Long-haul Traveller's Syndrome"
  • Zinopin ® Maintenance product this product is presently being developed and is aimed at people who are constantly traveling or sat immobile for extended periods of time. The dosage of Pycnogenol ® and standardized ginger will be reduced although the ratio of 1 :1.5 of Pycnogenol ® to Standardized Ginger Root extract will be maintained. People will be able to take a daily maintenance dose and still reduce the risks associated with Traveler's Syndrome at an affordable price.
  • Zinopin ® Beverage application and flavoring inclusion It is proposed to have Zinopin® as a flavor ingredient, with GRAS status, with inclusion in beverage formats since airlines (for instance) may still wish to hand their passengers a beverage on long haul flights.
  • Zinopin® Confectionary and Chewing gum...Zinopin ® can also be included in confectionary and chewing gum applications so people obtain a benefit for reducing the risk of Traveler's Syndrome from the likes of Travel Sweets for instance.
  • Zinopin® spectrum Drink & Ampoule, Daily Shot Dosages” Table 5.
  • Zinopin application Confectionary, Chewing gum, Mouthspray Flavoring Ingredients Dosages

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention a trait à l'utilisation de Pycnogenol® et un extrait de gingembre normalisé en une proportion bien définie (par exemple, 1:1,5) dans un nouveau produit de combinaison sous la forme d'une composition de soins de santé portant le nom commercial de Zinopin®, destinée à la prévention du syndrome de voyageurs long-courrier chez des passagers voyageant par avion, bateau ou sur terre. Les principes actifs se combinent de manière synergique pour réduire le risque de thrombose veineuse profonde et/ou d'oedème associée avec ou sans mal de mouvement. Le mécanisme de l'action de la combinaison dans le syndrome de voyageurs long-courrier est présenté dans le contexte d'effets physiologiques établis des deux en tant que constituants actifs GRAS. L'invention a également trait aux étapes inventives menant au développement de Zinopin® et des plages de doses et des formes préférées.
EP04738122A 2003-07-31 2004-08-02 Une composition pour reduire le risque des thromboses comprenant un melange de proanthocyanidines et de sesquiterpenes Withdrawn EP1651245A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04738122A EP1651245A1 (fr) 2003-07-31 2004-08-02 Une composition pour reduire le risque des thromboses comprenant un melange de proanthocyanidines et de sesquiterpenes

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP03017345A EP1502594A1 (fr) 2003-07-31 2003-07-31 Une composition pour réduire le risque des thromboses comprenant un mélange de proanthocyanidines et de sesquiterpenes
PCT/CH2004/000482 WO2005009452A1 (fr) 2003-07-31 2004-08-02 Compositions pour la réduction du risque du syndrome de voyageur long-courrier comportant un mélange de pycnogenol et d'extrait de racine de gingembre normalisé
EP04738122A EP1651245A1 (fr) 2003-07-31 2004-08-02 Une composition pour reduire le risque des thromboses comprenant un melange de proanthocyanidines et de sesquiterpenes

Publications (1)

Publication Number Publication Date
EP1651245A1 true EP1651245A1 (fr) 2006-05-03

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EP03017345A Withdrawn EP1502594A1 (fr) 2003-07-31 2003-07-31 Une composition pour réduire le risque des thromboses comprenant un mélange de proanthocyanidines et de sesquiterpenes
EP04738122A Withdrawn EP1651245A1 (fr) 2003-07-31 2004-08-02 Une composition pour reduire le risque des thromboses comprenant un melange de proanthocyanidines et de sesquiterpenes

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Application Number Title Priority Date Filing Date
EP03017345A Withdrawn EP1502594A1 (fr) 2003-07-31 2003-07-31 Une composition pour réduire le risque des thromboses comprenant un mélange de proanthocyanidines et de sesquiterpenes

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Country Link
EP (2) EP1502594A1 (fr)
WO (1) WO2005009452A1 (fr)

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DE102005020846A1 (de) * 2005-05-02 2006-11-09 Hürth, Franz Martin, Dr.med. Darreichungsform für einen homöopathisch wirksamen Wirkstoff
EP2522347A1 (fr) * 2005-06-29 2012-11-14 Mars Incorporated Induction de la vasodilatation d'un vaisseau sanguin périphérique
FR2950804B1 (fr) * 2009-10-01 2011-12-23 Oreal Composition, utilisation et procede de conservation
FR2950884B1 (fr) 2009-10-01 2011-11-11 Oreal Utilisation de derives de vanilline comme conservateur, procede de conservation, composes et composition
FR2951079B1 (fr) 2009-10-08 2012-04-20 Oreal Composition photoprotectrice a base d'un compose 2-alcoxy-4-alkylcetone phenol ; utilisation dudit compose pour augmenter le facteur de protection solaire
PT3673896T (pt) * 2018-12-28 2022-02-03 Dr Rolf Lambert Pharma Consulting Gmbh Solução de colírio lipossomal e utilizações da mesma para o tratamento da síndrome do olho seco

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CN1104900A (zh) * 1994-01-04 1995-07-12 张建中 一种可对人体进行全面调理的中成药及其制备方法
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Also Published As

Publication number Publication date
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WO2005009452A1 (fr) 2005-02-03

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