WO2018189100A1 - Compositions comprenant des huiles essentielles - Google Patents

Compositions comprenant des huiles essentielles Download PDF

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Publication number
WO2018189100A1
WO2018189100A1 PCT/EP2018/059014 EP2018059014W WO2018189100A1 WO 2018189100 A1 WO2018189100 A1 WO 2018189100A1 EP 2018059014 W EP2018059014 W EP 2018059014W WO 2018189100 A1 WO2018189100 A1 WO 2018189100A1
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WO
WIPO (PCT)
Prior art keywords
compositions
essential oil
citrus
phospholipid
insomnia
Prior art date
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PCT/EP2018/059014
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English (en)
Inventor
Ezio Bombardelli
Paolo Morazzoni
Massimo Ronchi
Pietro Allegrini
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Indena S.P.A.
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Publication date
Application filed by Indena S.P.A. filed Critical Indena S.P.A.
Publication of WO2018189100A1 publication Critical patent/WO2018189100A1/fr

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Classifications

    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • 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)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to solid powdered compositions comprising at least one phospholipid and at least one essential oil deriving from citrus fruits or Lavandula officinalis, which are useful in the treatment of insomnia and anxiety, and in reducing appetite and stimulating the metabolism.
  • Anxiety, depression and obesity are among the most common disorders of the modern era, affecting a large proportion of the population ranging from infancy to adulthood.
  • Sleep disorders have a significant incidence in the oncological and pre-operative fields, and are added to problems liable to cause a deterioration in the patient's quality of life.
  • Anxiety and depression are often directly or indirectly correlated with metabolic disorders, leading to problems in personal relationships.
  • Excess weight is also one of the major health problems because it is positively correlated with an increased risk of numerous serious disorders, such as cardiovascular diseases, diabetes and cancer.
  • insomnia is a very widespread problem, which affects a growing number of individuals of working age, between 30 and 50, as a result of stress-induced anxiety, which makes the individual tired and irascible; hence the need for non-sedative tranquillisers with a calming, sleep-inducing function which act in the most physiological way possible.
  • Sleep and specifically good sleep quality, is one of the essential ingredients for a good quality of life, in order to maintain the individual's physical, social, emotional and functional well-being.
  • Insomnia is a sleep disorder characterised by inability to sleep, even though the body has a real physiological need for sleep.
  • Insomnia can be defined as the subjective perception of difficulty with the beginning, duration and consolidation of sleep, leading to a reduction in its quality, which takes place despite sufficient opportunities for rest, and leads to impairment during the day.
  • insomnia refers to chronic insomnia, which has been present for at least a month; otherwise the disorder is known as acute or transient insomnia, which can last for periods ranging from days to weeks.
  • insomnia can be found in about 33% to 50% of the adult population; when associated with stress or weakness they are present in between 10 and 15%) of cases, whereas insomnia associated with specific disorders affects between 5 and
  • Risk factors for insomnia include aging, female sex, the presence of co-morbidities (medical, psychiatric, etc.), shift work, and the onset of devastating socio-economic situations.
  • insomnia The main disorders characteristic of insomnia relate to difficulty in getting to sleep, lengthy periods of waking during the night, and non-restorative or poor-quality sleep, with individual variables associated with the methods of onset, duration, frequency and perpetuation of the triggers, the type of present and past treatments used, and their efficacy.
  • insomnia Common problems associated with insomnia are an average sleep onset latency >30 minutes, periods of night waking with a total duration >30 minutes, and sleep duration of less than 6 hours per night.
  • Hypersomnia is not a common situation, whereas chronic insomnia is very frequent and alters the natural sleep cycle, which is difficult to restore, partly because sufferers try to sleep when they can during the day and then remain awake at night, thus disrupting the circadian rhythms.
  • sleep deprivation can cause physical and mental problems which are so serious as to require corrective medicaments; however, like all drugs which act on the central nervous system, they are not free of major side effects.
  • Insomnia in its various forms is a problem which has been known since ancient times.
  • numerous plants have been identified which, taken individually or in, even complex, mixtures, seem to improve the psychosomatic state.
  • the placebo effect is significant. Extracts with psycho metabolic effects can also be used to regulate the appetite and body weight, with psychosomatic repercussions.
  • Products which are widely used orally are those derived from plants belonging to the Papaveraceae and Valerianaceae families, which have a hypnotic effect, or families of plants containing sedative flavonoids, such as passion flower, hawthorn, chamomile or plants rich in essential oils, such as Lavandula, Citrus and others.
  • the Valerianaceae are widely used although they do not have clinically supported activities, as in the case of many other commonly used plants.
  • WO 2008/155592 (INVENCIO-21 GYOGYHATASU KE SZITMEN YEKET GYARTOKFT), published on December 24, 2008, relates to liposome compositions containing essential oils and vitamins.
  • this document discloses a liposome composition comprising a citrus essential oil and lavender oil of pharmaceutical grade, ethoxylated castor oil and a phospholipid.
  • the compositions are prepared by mixing the essential oils, vitamins, ethoxylated castor oil and a phospholipid, followed by:
  • compositions of WO 2008/155592 are said to be useful for the treatment of skin injuries.
  • WEISSPAPIR MICHAEL published on February 14, 2013, discloses compositions comprising essential oils, including lavender oil and bergamot oil, in the form of oil-in-water emulsions, for the treatment of infections of the urinary tract.
  • Fisk, I.D. et al. disclose particles obtained by spray-drying of an emulsion obtained from an oil, water, a carrier (oxylsuccinated starch or lecithin) and D-limonene. This document focuses on formulation issues of volatile lipophilic actives, and does not mention any medicinal or nutraceutical applications of the particles.
  • PC soybean phosphatidylcholine
  • WO 2017/009711 discloses phospholipid compositions for the improvement of sleep; this document does not disclose or suggest combinations with essential oils, and refers to functional foods or discrete dosage units, powders, granules, solutions, suspensions, syrups or elixirs as administration forms.
  • compositions (C) comprising at least one phospholipid [phospholipid (PL)] and at least one essential oil [essential oil (O)] deriving from citrus fruits or from Lavandula officinalis.
  • compositions (C) to prepare pharmaceutical or nutraceutical formulations [formulations (F)] which are useful in the prevention and/or treatment of insomnia and anxiety, in appetite reduction and metabolic stimulation, treatment of excess weight and obesity, and body weight reduction.
  • compositions (C)] comprising at least one phospholipid [phospholipid (PL)] and at least one essential oil deriving from citrus fruits or Lavandula officinalis [essential oil (O)] are useful in the treatment of insomnia and anxiety, in appetite reduction and metabolic stimulation.
  • compositions (C) are in the form of powders in which the at least one essential oil (O) is homogeneously dispersed in the at least one phospholipid (PL).
  • compositions (C) also comprise at least one additional ingredient [ingredient (I)] that improves the physical and technological characteristics of compositions (C) and allows easier manufacturing of pharmaceutical or nutraceutical formulations [formulations (F)] for oral or topical administration.
  • essential oil (O) excludes hydroalcoholic extracts from citrus fruits or from Lavandula officinalis; the expression "at least one essential oil
  • compositions (C) can contain one single essential oil or mixtures of essential oils; alternatively, as explained in greater detail below, in compositions (C) the at least one essential oil (O) can be replaced by one or more pure active ingredients of said essential oils (O);
  • At least one phospholipid (PL) denotes one single phospholipid or a mixture of phospholipids obtained from one single vegetable or animal source, or a mixture of phospholipids obtained from different vegetable or animal sources.
  • the essential oils are preferably obtained from the fruit of Citrus bergamia, Citrus Union, Citrus paradisi and Lavandula ojficinalis. Said oils can be obtained traditionally by distillation in steam current, extraction with hypercritical gases or solvents, or pressing.
  • the essential oil is preferably obtained from Citrus bergamia fruits.
  • Essential oil of Citrus bergamia can be prepared by pressing, and preferably contains 35% linalool, 30% linalyl acetate and 20% limonene, together with small amounts of other terpenes.
  • Essential oil of Citrus paradisi can be prepared by pressing and distillation.
  • Essential oil of Lavandula ojficinalis preferably contains linalool and linalyl acetate in about the same ratio, together with a small portion of other monoterpenes.
  • compositions (C) can contain, instead of essential oil (O), one or more pure active ingredients contained in said essential oils (O), such as linalool, linalyl acetate and limonene.
  • the compositions can comprise linalool, linalyl acetate and limonene, preferably in a weight ratio of 1 : 1 : 1.
  • a composition (C) comprises a single essential oil deriving from citrus fruits, preferably an essential oil of Citrus bergamia. According to another preferred aspect, a composition (C) only comprises essential oil of Lavandula officinalis.
  • the at least one phospholipid (PL) can be selected from the group comprising lecithins obtained from soy, sunflower or egg, phosphatidyl choline, phosphatidyl serine or phosphatidyl ethanolamine, wherein the acyl groups, being the same or different, are mostly derived from palmitic, stearic, oleic, linoleic, linolenic acids or combinations thereof.
  • the phospholipid (PL) is a lecithin; more preferably, the lecithin is soy lecithin or sunflower lecithin; even more preferably, the lecithin is sunflower lecithin.
  • the essential oil (0):phospholipid (PL) ratio ranges from 2: 1 to 1 : 10, preferably from 1 : 1 to 1 :5.
  • compositions (C) can be a surfactant other than a phospholipid [surfactant (S)] or a non- surfactant ingredient [non- surfactant (NS)].
  • compositions (C) contain at least one surfactant (S) other than a phospholipid (PL) and at least one non- surfactant (NS).
  • surfactant (S) is a surfactant having an HLB value equal to or higher than 12.
  • Surfactant (S) enhances incorporation and homogeneous dispersion of essential oil (O) in the manufacturing process of composition (C) and maximises the interaction of essential oil (O) with the selected phospholipid (PL).
  • surfactant (S) enhances the wettability and fast dispersion of composition (C) in the gut fluids and promotes faster and higher absorption and, therefore, higher bioavailability of the active ingredient(s) of essential oil (O).
  • Surfactant (S) is preferably selected from the group comprising sucrose esters, polysorbates, polyoxyethylene castor oil derivatives, polyoxy ethylene stearates, D-a-tocopheryl polyethylene glycol succinate and combinations thereof, sucrose esters being preferred.
  • Non- surfactant ingredient (NS) can be:
  • a soluble or insoluble filler preferably selected from cellulose powder, microcrystalline cellulose, calcium carbonate, calcium phosphate, mannitol, cyclodextrins, typically maltodextrins, sorbitol, xylitol, fructose, isomalt, inulin and combinations thereof, and/or
  • methylcellulose hydroxypropylmethyl cellulose, hydroxypropyl cellulose, natural gums, silicon dioxide, talc, stearic acid and magnesium stearate and combinations thereof.
  • Compositions (C) are typically prepared by a manufacturing method [method (M)] which comprises mixing at least one essential oil (O) with at least one phospholipid (PL) to obtain a homogeneous mixture, and optionally adding at least one additional ingredient (I), preferably at least one surfactant (S) and at least one non-surfactant (NS).
  • method (M) comprises mixing at least one essential oil (O) with at least one phospholipid (PL) to obtain a homogeneous mixture, and optionally adding at least one additional ingredient (I), preferably at least one surfactant (S) and at least one non-surfactant (NS).
  • method (M) consists of the following steps:
  • method (M) consists of the following steps: mixing at least one essential oil (O) with at least one phospholipid (PL) to obtain an oil (0)/phospho lipid (PL) mixture [mixture (MX-1)];
  • composition (C) adding at least one filler (F) to mixture (MX-1)] and mixing to obtain a composition (C).
  • Method (M) can be carried out by a person skilled in the art with conventional equipment; a person skilled in the art will be able to select additional ingredients (I) and mixing times according to the selected essential oil (O) and its final concentration in the target composition (C).
  • the ratio between the essential oils and the additional ingredients ranges between
  • 1 : 1 and 1 :30 preferably between 1 :10 and 1 :30.
  • compositions (C) are useful in the treatment of insomnia and anxiety, in appetite reduction and metabolic stimulation.
  • Compositions (C) by reducing the appetite and/or stimulating the metabolism, are consequently useful in weight reduction in general, and may be used in the treatment of excess weight and obesity in particular.
  • the treatment may be given one to three times a day, administering the composition orally or sublingually or in retro auricular patches at doses to be established on the basis of the patient's body weight.
  • compositions (C) were tested on a preliminary basis on rats, monitoring the electroencephalogram before and during the treatment and placing the laboratory animal in a controlled atmosphere of active ingredient, as reported in the literature to evaluate its efficacy in aromatherapy.
  • compositions (C) according to the invention give rise to a drastic reduction in the amount of essential oil (O) to be administered, therapeutic effect being equal, thus eliminating the side effects associated with the use of essential oils. Moreover, the effect obtainable by treatment with compositions (C) is immediate, and produces a rapid response. Compositions (C) unpredictably exhibit an early plasma peak of the active ingredients.
  • Compositions (C) are particularly useful in paediatrics, as the waking/sleep problem is particularly significant in growing children.
  • Essential oils are also characterised by an analgesic activity which can be useful in states of anxiety and insomnia, especially when associated with chronic pain in the elderly and in long-term oncological patients, before moving on to appropriate painkilling treatments.
  • the target of the active ingredients is mainly the limbic system of the hypothalamus, from which biochemical and neuronal messages are transmitted to specific sites.
  • the hypothalamic-pituitary-adrenal axis is involved in metabolic regulation as well as insomnia.
  • compositions (C) for the manufacture of formulations for pharmaceutical or nutraceutical use [formulations (F)].
  • a still further embodiment of the invention is a method [method (Ml)] for treating insomnia and anxiety, for reducing appetite and/or for stimulation of metabolism, said method comprising administering a composition (C) or a formulation (F) to a subject in need thereof.
  • Formulations (F) can be designed for oral or topical administration.
  • formulations (F) for oral administration include tablets, capsules and dispersible granules, optionally for sublingual administration
  • topical formulations (F) are gels and patches, preferably patches, more preferably patches to be applied to the retroauricular skin.
  • Formulations (F) can be prepared by a person skilled in the art according to conventional techniques, such as those described in Remington's Pharmaceutical Handbook, Mack Publishing Co., N.Y., USA.
  • compositions (C) When required, one or more excipients of nutraceutical grade may be added to compositions (C) for the manufacture of formulations (F).
  • the amount of the at least one essential oil (O) may range from 2 to 20% w/w, and preferably ranges from 2 to 10% w/w of the total weight of the formulation.
  • the amount of essential oil (O) per dose when administered orally may vary from 5 to 20 mg, and preferably amounts to 10 mg; when administered by the sublingual and/or retroauricular route it may range from 2 to 10 mg, and preferably amounts to 3 mg.
  • Essential oil of Citrus paradisi may be administered in daily doses ranging from 5 to 25 mg, preferably 10 mg.
  • Tablets containing 300 mg of the composition of Example 1 were prepared.
  • compositions per dosage unit Composition per dosage unit
  • the resulting product is calibrated on a 40-mesh screen and mixed for a further 5 minutes with silicon dioxide and magnesium stearate.
  • the resulting mixture is compressed with a rotary tablet press equipped with rounded convex punches having a diameter of 11 mm.
  • Hard gelatin capsules were prepared containing 180 mg of the composition of Example 2, corresponding to 10 mg of essential oil of Lavandula officinalis.
  • Example 5 Efficacy test
  • compositions according to the invention in clinical pharmacology was evaluated by examining parameters relating to induced anxiety, depression and mood parameters, evaluating the amount of circulating Cortisol measured in the saliva by a known clinical procedure.
  • the evaluation criterion used was the Leeds Sleep Evaluation Questionnaire (SEQ), a tool designed to evaluate the effects of psychoactive drugs on sleep, which consists of a self-assessment with a visual analogue technique.
  • SEQ Leeds Sleep Evaluation Questionnaire
  • the SEQ explores 10 aspects of sleep, including the following four:
  • GTS Getting to sleep
  • QOS Quality of sleep
  • Awakening from sleep (AFS)
  • composition of example 3 produced a mediated global difference of 39% compared with the placebo, and a difference of 71 ⁇ 18% compared with the baseline.
  • the patients were treated with a hard gelatin capsule, prepared according to example 4, half an hour before the two main meals, and reported in a questionnaire on their sensations of hunger/satiety, state of health, changes in diuresis since the baseline, effect on mood, and on the state of anxiety in general.
  • Citrus paradisi essential oil was administered, and the patients were monitored with the Haber scale.
  • the composition of example 2 was administered to 42 patients, mainly women, in a double-blind trial; after randomisation, the patients were treated with the placebo or with the composition of example 2 for 60 days, 10 minutes before the main meals.
  • the Haber scale was used, which has appetite as primary endpoint and psychosomatic parameters as secondary endpoints.
  • the Haber scale is a visual scale scored from -10 to +10, wherein -10 represents maximum hunger and +10 represents maximum satiety.
  • composition of example 2 is therefore much more effective than the placebo.
  • Appetite reduction and body metabolism stimulation using a composition of example 2 according to the invention was reflected by a reduction in body weight.

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne des compositions solides en poudre comprenant au moins un phospholipide et au moins une huile essentielle dérivée des agrumes ou de la Lavandula officinalis. Les compositions selon l'invention sont utiles dans la prévention et/ou le traitement de l'insomnie et de l'anxiété, et dans la réduction de l'appétit et la stimulation du métabolisme. La présente invention concerne également des formulations pharmaceutiques ou nutraceutiques pour une administration orale ou topique contenant lesdites compositions.
PCT/EP2018/059014 2017-04-12 2018-04-09 Compositions comprenant des huiles essentielles WO2018189100A1 (fr)

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IT102017000040828A IT201700040828A1 (it) 2017-04-12 2017-04-12 Composizioni comprendenti oli essenziali

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2762993A1 (fr) 1997-05-06 1998-11-13 Inst Rech Biolog Sa Nouvelle utilisation de phospholipides d'origine animale en therapeutique et/ou dietetique
WO2008155592A2 (fr) 2007-06-19 2008-12-24 Invenció-21 Gyógyhatású Készitményeket Gyártó Kft Composition liposomale
US20130039978A1 (en) 2011-08-09 2013-02-14 Joseph Schwarz Medicinal compositions and method for treatment of urinary tract infections
WO2017009711A1 (fr) 2015-07-13 2017-01-19 Enzymotec Ltd. Préparations à base de phospholipides pour l'amélioration du sommeil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2762993A1 (fr) 1997-05-06 1998-11-13 Inst Rech Biolog Sa Nouvelle utilisation de phospholipides d'origine animale en therapeutique et/ou dietetique
WO2008155592A2 (fr) 2007-06-19 2008-12-24 Invenció-21 Gyógyhatású Készitményeket Gyártó Kft Composition liposomale
US20130039978A1 (en) 2011-08-09 2013-02-14 Joseph Schwarz Medicinal compositions and method for treatment of urinary tract infections
WO2017009711A1 (fr) 2015-07-13 2017-01-19 Enzymotec Ltd. Préparations à base de phospholipides pour l'amélioration du sommeil

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"Remington's Pharmaceutical Handbook", MACK PUBLISHING CO.
CLAESON (COMMITTEE ON HERBAL MEDICINAL PRODUCTS, EMA): "Assessment report Glycine max (L) merr. lecithinum", 31 January 2017 (2017-01-31), pages 1 - 27, XP055483717, Retrieved from the Internet <URL:http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2017/11/WC500238847.pdf> [retrieved on 20180613] *
COMMITTEE ON HERBAL MEDICINAL PRODUCTS, EMA: "assessment report on Lavandula angustifolia Miller", 27 March 2012 (2012-03-27), pages 1 - 46, XP055483691, Retrieved from the Internet <URL:http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2012/06/WC500128642.pdf> [retrieved on 20180613] *
DAMIÃO DE SOUSA ET AL: "A Systematic Review of the Anxiolytic-Like Effects of Essential Oils in Animal Models", MOLECULES, vol. 20, no. 10, 14 October 2015 (2015-10-14), pages 18620 - 18660, XP055414278, DOI: 10.3390/molecules201018620 *
DE MOURA LINCK ET AL., PHYTOMEDICINE, vol. 16, 2009, pages 303 - 307
DE SOUSA D.P. ET AL., MOLECULES, vol. 20, 2015, pages 18620 - 18660
FISK, I.D. ET AL., FOOD RESEARCH INTERNATIONAL, vol. 54, 2013, pages 861 - 866
KASPER, EUROPEAN NEUROPSYCOPHARMACOLOGY, vol. 25, 2015, pages 1960 - 67
LAVELA: "LAVELA WS 1265 (TM) CLINICALLY STUDIED LAVENDER OIL", INT CLIN PSYCHOPHARMACOL PHYTOMEDICINE HIDALGO RB J PSYCHOPHARMACOL, 12 March 2015 (2015-03-12), pages 1 - 2, XP055483909, Retrieved from the Internet <URL:http://data.integrativepro.com/product-literature/info/lavela-ws-1265-info-sheet.pdf> [retrieved on 20180613] *
LEE H.S. ET AL., LIFE SCIENCES, vol. 118, 2014, pages 7 - 14
NAGAI K. ET AL., AUTONOMIC NEUROSCIENCE: BASIS AND CLINICAL, vol. 185, 2014, pages 29 - 35
NAVARRA M. ET AL., FRONTIERS IN PHARMACOLOGY, vol. 6, 2015
SHEN ET AL., NEUROSCIENCE LETTERS, vol. 383, 2005, pages 188 - 193
SIEGFRIED KASPER ET AL: "Lavender oil preparation Silexan is effective in generalized anxiety disorder - a randomized, double-blind comparison to placebo and paroxetine", INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, vol. 17, no. 06, 23 January 2014 (2014-01-23), Cambridge, pages 859 - 869, XP055483897, ISSN: 1461-1457, DOI: 10.1017/S1461145714000017 *
WOELK, PHYTOMEDICINE, vol. 12, 2010, pages 94 - 99

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