WO2013186220A1 - Compositions comprenant de l'hespéridine et/ou de l'apigénine destinées entre autres à un usage médical ou au traitement de troubles du sommeil - Google Patents
Compositions comprenant de l'hespéridine et/ou de l'apigénine destinées entre autres à un usage médical ou au traitement de troubles du sommeil Download PDFInfo
- Publication number
- WO2013186220A1 WO2013186220A1 PCT/EP2013/062046 EP2013062046W WO2013186220A1 WO 2013186220 A1 WO2013186220 A1 WO 2013186220A1 EP 2013062046 W EP2013062046 W EP 2013062046W WO 2013186220 A1 WO2013186220 A1 WO 2013186220A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- hesperidin
- composition according
- treatment
- apigenin
- Prior art date
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- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 title claims abstract description 124
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- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical group N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
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- SGEWCQFRYRRZDC-VPRICQMDSA-N vitexin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C=CC(O)=CC=1)=CC2=O SGEWCQFRYRRZDC-VPRICQMDSA-N 0.000 description 1
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
-
- 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
-
- 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
Definitions
- This present invention relates to compositions with sedative, sleep inducing and/or anxiolytic effects, more specifically using new application strategies of natural extracts, fractions and substances from orange peels, parsley, celery, dandelion roots, valerian and other potential botanic sources.
- the invention relates to a composition
- a composition comprising hesperidin and/or apigenin, said composition for sublingual and/or buccal administration, said composition for use as a medicament, preferably for the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increasing relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic.
- valerian root preparations have been available as very mild sedatives and an online search for relevant scientific articles reveals more than 100 hits since the 1950s. More recently, studies have been carried out to identify the composition of valerian extracts and which substances in this composition may be responsible for the reported effects: in 2003, a method for fractioning the active compounds from valerian roots was described and patented (WO03061678A1 ). In this description, the sedative effects were attributed to a number of flavonoids, especially Linarin, 6-methyl-Apigenin, and Hesperidin.
- compositions comprising hesperidin that can be orally administered, while maintaining their sedative, sleep enhancing and/or anxiolytic effects.
- composition comprising hesperidin and/or apigenin.
- compositions with Hesperidin are capable to induce sedative, sleep enhancing and/or anxiolytic effects, despite the fact that such formulations are orally administered.
- new means of oral administration and specifically designed compositions yield an orally administered product that can be used as an anxiolytic as well as for sleep management.
- Modes of administration include: - Sub-lingual films, tablets, or lozenges (tablets that slowly dissolve in the mouth) that ensure uptake of Hesperidin through the sublingual and/or buccal mucosa, bypassing the intestinal microflora and hepatic circulation.
- this object has been by a composition comprising hesperidin and apeginin.
- compositions with Hesperidin are capable of inducing sedative, sleep enhancing and/or anxiolytic effects, despite being orally administered.
- present invention comprises novel specifically designed
- compositions and/or dosage forms that yield an orally effective product to be used as an anxiolytic or sedative, which may be used in e.g. sleep management.
- the present invention is directed towards a composition for promoting sleep and/or reducing stress.
- 'sleep' for the purposes of the present invention is defined as a natural or artificially induced state of suspension of sensory and motor activity in an individual.
- improvements in sleep may be of a quantitative nature e.g. an increase in the length of sleep, a decreased time in the time of sleep onset, and/or of a qualitative nature e.g. a deeper, more restful, more undisturbed period of sleep. Improvement of sleep may consist of any of the improvements mentioned herein, any combination thereof, and/or any other factor that is a scientifically accepted
- sleep will be directly improved by the administration of a substance, which is known to induce sleep or to reduce time to sleep onset. Sleep may be indirectly improved, for example, by the administration of a substance, which is known to result in feelings of relaxation and calmness.
- 'Stress' is defined as the mental or physical response to a mental of physical challenge, including all hormonal and mental responses. For example, when a mental challenge is presented, or a physical work has to be performed, this leads to the activation of the hypothalamus-pituitary-adrenal axis and ultimately an increased production of the hormone Cortisol. Physically, effects can in some cases exhibit themselves as felt sensations, including but not limited to heart palpitations, faster heart rate, shortness of breath, and/or more moderate similar effects. At the same time, fear, increased alertness, reduced sleepiness, restlessness, excitement, irritability and/or increased capacity for physical work may be experienced mentally. 'Stress' includes any single symptom or effect, combination of the aforementioned symptoms or effects, or commonly accepted signs of physical and mental stress or excitation.
- 'Sedative' action is the process by which the motivation to engage in activities, the length to which and the intensity in which an activity is performed by an individual is reduced. Furthermore, 'sedative' can additionally be defined as reducing excitation, alertness and increasing calmness and/or drowsiness/sleepiness. Therefore, a sedative substance may in a high dose lead to the onset of sleep, while it may reduce e.g. excitement or stress in lower doses.
- 'Anxiolytic' refers to the capacity of a substance to reduce feelings of anxiety. It is understood that improvement of sleep, sedation, and/or anxiolytic action results in improved feelings of well-being, including improved mood.
- Hesperidin' is a flavonoid, specifically a flavanone, which is commonly found in several plants, including citrus fruits (e.g. oranges, grapefruits) and roots from valerian species.
- 'Hesperidin' may originate from any plant and may refer to any of the following: the native glycoside, as well as partially deglycosylated forms, the aglycon form
- Hesperidin further comprises any chemically or enzymatically derived derivative of any of the foregoing molecules.
- Hesperidin after extraction without enantiomeric enrichment is a mixture of an R- and S-enantiomers, the R:S molar ratio of which is between 1 :1 and 1 :5, depending on its source.
- a mixture of R and S-enantiomers which has a molar ratio of 1 :1 is also known as a racemic mixture, It has been reported that the S-isoform is the more active substance for sleep and anxiolytic activity.
- 'Hesperidin' can refer to any enantiomeric mixture.
- hesperidin may refer to racemic hesperidin, preferably to enantiomericlaly enriched hesperidin, more preferably hesperidin which is enantiomerically enriched in (2S)-hesperidin.
- hesperidin has an excess of one enantiomer over the other.
- Enantiomeric enrichment can be achieved amongst other methods known by a person skilled in the art by selection of the botanic source of Hesperidin, and/or
- 'Apigenin' is a flavonoid, specifically a flavone, found in numerous plants in its deglycosylated or glycoside forms. These forms include Apiin, Apigetrin, Vitexin, Isovitexin and Rhoifolin, a related compound, and are found in eg. bamboo leaves, celery, chaste tree, citrus leaves, dandelion root, parsley, passion flowers, pearl millet and more. 6-methylApigenin, is a specific subform of Apigenin, such as found in valerian root.
- Apigenin may in addition be derived by chemical synthesis based on any suitable organic precursor compound.
- One example is the synthesis of Apigenin from naringenin in multistep process using modification steps common to pharmaceutical industries.
- Apigenin refers to any substance described, including precursors and derivatives of Apigenin by means of any modifications, but excluding 6-methylApigenin.
- Hesperidin and Apigenin may be extracted from any source, including, but not limited to those mentioned, with any technique suitable for obtaining food or pharmaceutical grade substances.
- 'Buccal mucosa' refers to the mucous membrane, ie the thin skin layer, lining the inside of the mouth.
- Sublingual' refers to the position under the tongue and sublingual administration implies that the substance that is administered is in close contact with the buccal mucosa under the tongue. It is known that this part of the buccal mucosa is relatively highly permeable to numerous substances, including drugs. Sublingual administration of herbal preparations has the benefit of quick systemic availability and thus fast and high efficacy (e.g. WO2009079601 A1 ). Furthermore, the use of this method of administration bypasses the gastrointestinal system and hepatic metabolization, which is desired in the case of Hesperidin and/or Apigenin to avoid the breakdown of the compound.
- Sublingual administration' is the sublingual delivery of the active substances for example by means of liquid solution or suspension, gels, tablets, lozenges or dissolvable film.
- the invention relates to a composition comprising hesperidin and apigenin, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
- Examples of pharmaceutical carriers are known to the person skilled in the art and include but are not limited to D-mannitol, sorbitol, sucrose, galactose, cellulose, other sugars, other saccharides, other oligosaccharides and/or polysaccharides, gelatin, guar gum, Arabic Gum (acacia gum), agar agar, xanthan gum, locust bean gum, starch, starch fragments, dextrins, British gum and any mixtures thereof.
- the pharmaceutically acceptable carrier is of natural origin
- compositions of the invention further comprising an effective amount of an ingredient selected from the group of Lemon Balm, Mesua
- the invention relates to a composition comprising hesperidin wherein the composition is in a form suitable for sublingual and/or buccal
- composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
- the invention relates to a composition
- a composition comprising hesperidin and apigenin, wherein the composition is in the form of a liquid, solution, (disintegrating) tablet, lozenge, dissolvable film, suspension, (dietary) gel, capsule, chewable or syrup.
- the invention relates to a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal
- composition is in the form of a liquid, solution
- 'Tablets' are entities of compressed materials, including inert filler substances, disintegrants, binding agents, lubricants, glidants, antiadherents, flavors, coloring agents etc. Tablets generally contain one or more active substances.
- 'Disintegrating tablets' are tablets for which a composition is chosen that disintegrates quickly when in contact with saliva in the mouth. These tablets may contain similar substances as tablets, however, optimized for specific disintegration times e.g. by using specific compression of the substances, by adding specific disintegrants etc.
- Capsules' consist of a thin layer outer wall, made of gelatin, agar or other substances that are soluble in stomach and/or intestinal fluids.
- the active ingredients can be filled into capsules as a dry powder similar as described under for tablets, or as a fluid, consisting of aqueous solutions, oil solutions etc. that contain the active substances.
- 'Syrups' are sweetened, flavored, viscous fluids, that contain a set amount of active substances, which can be taken in small amounts, or diluted in food or drinks.
- Several viscosities of syrups may be achieved by using any edible viscosity increasing agent, such as sugars, sugar alcohols, gelling agents and others.
- Dietary gels' are highly viscous aqueous solutions of active substances, that may contain flavoring and coloring agents and a gelling agent such as gelatin, agar, acacia gum and others, that consequently present themselves as a slowly flowing substance or a semi-solid.
- Lozenges are bodies of solid candy materials that contain active substances. Lozenges are designed to dissolve and slowly release the active ingredients at the site of placement, resulting in local effects and/or uptake of the active substances. Lozenges often contain flavorings and/or sweeteners to make them more palatable.
- lozenges are designed as formulations that completely dissolve in a specific lapse of time, which results in prolonged contact of the active substances with the buccal mucosa.
- Different ingredients and formulations may be used to achieve the intended dissolution times:
- the nutritional supplement may be consumed in any form.
- the dosage form of the nutritional supplement may be provided as, e.g., a powder beverage mix, beverage syrup, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid capsule, a tablet, a caplet, a lozenge, a chewable tablet, dissolvable film, a dietary gel, or syrup.
- the invention relates to a composition comprising hesperidin and apigenin, wherein the composition is a food or a beverage or a supplement composition for a food or a beverage, for example a chewing gum.
- the invention also relates to the use a composition comprising hesperidin and apigenin, preferably of the composition comprising hesperidin and apigenin, wherein the composition is a food or a beverage or a supplement composition for a food or a beverage, for example a chewing gum for promotion of sleep, for reduction of stress, for relieving anxiety, for improving the mood and/or for increasing relaxation in animals, preferably mammals, for example humans.
- the invention relates to a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal
- composition is a food or a beverage or a supplement composition for a food or a beverage, for example a chewing gum.
- the invention also relates to the use of a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration, preferably to the use of a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration wherein the
- composition is a food or a beverage or a supplement composition for a food or a beverage, for example a chewing gum for promotion of sleep, for reduction of stress, for relieving anxiety, for improving the mood and/or for increasing relaxation in animals, preferably mammals, for example humans.
- Hesperidin as a sedative or anxiolytic is absent or severely reduced when taken orally.
- the invention provides specific active formulations of Hesperidin with other substances, including Apigenin are created.
- the components of the present invention will act in concert through distinct mechanisms each having synergistic or additive effects to promote sleep, a feeling of relaxation and/or a feeling of a reduction in stress.
- the invention in another aspect, relates to a composition comprising hesperidin and apigenin, for use as a medicament.
- the invention relates to the composition comprising hesperidin and apigenin for use in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increasing relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic.
- the invention relates to the composition comprising hesperidin and apigenin wherein the composition is in a form suitable for sublingual and/or bucal administration for use in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increasing relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic, wherein the composition is administered sublingually and/or buccally.
- the invention also relates to the use of the composition comprising hesperidin and apigenin for the manufacture of a medicament for use in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic, and in particular to the use of the composition comprising hesperidin and apigenin for the manufacture of a medicament for use in in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic, wherein the composition is administered sublingually and/or buccally.
- the invention in another aspect, relates to a method for the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, for sedation, for tranquilization and/or in the treatment of anxiety disorders in animals, preferably mammals and including humans, comprising the step of administering an effective amount of the composition comprising hesperidin and apigenin to an animal which is in need thereof and in particular to a method for the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, for sedation, for tranquilization and/or in the treatment of anxiety disorders in animals, preferably mammals and including humans, comprising the step of administering an effective amount of the composition comprising hesperidin and apigenin to an animal which is in need thereof, wherein the composition is administered sublingually and/or buccally.
- the optimal dose of hesperidin and/or apigenin for humans, preferably human adults can be derived using the FDA recommendation for translating to the human equivalent dose (HED) from animal studies. This recommendation translates the dosages used for animal studies to dosages per day for the general population (i.e. average human adults).
- HED human equivalent dose
- the hesperidin is administered (to a human adult) once daily in an amount of approximately 500-1000 mg and if present in the composition of the invention, apigenin is preferably administered (to a human adult) in an amount of about 250 to about 500mg, preferably before sleeping.
- the invention relates to a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal
- the invention relates to a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration for use in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increasing relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic and in particular to a composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration for use in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic, wherein the composition is administered sublingually and/or buccally.
- the invention relates to the use of a composition comprising hesperidin, for the manufacture of a medicament suitable for sublingual and/or buccal administration for use in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic and in particular to the use of a composition comprising hesperidin, for the manufacture of a medicament suitable for sublingual and/or buccal administration for use in the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, as a sedative, as a tranquilizer and/or as an anxiolytic wherein the composition is administered sublingually and/or buccally.
- the invention relates to a method for the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, for sedation, for tranquilization and/or in the treatment of anxiety disorders in animals, preferably mammals, more preferably humans, comprising the step of administering an effective amount of the composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration to an animal which is in need thereof and in particular to a method for the treatment of sleeping disorders, for promoting sleep, for reducing stress, for increased relaxation, for sedation, for tranquilization and/or in the treatment of anxiety disorders in animals, preferably mammals, more preferably humans, comprising the step of administering an effective amount of the composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal administration to an animal which is in need thereof wherein the composition is administered sublingually and/or buccally
- the composition comprises Hesperidin
- a serving size of the supplemental composition includes from about 10 mg to about 1 .000 mg of Hesperidin and may contain a serving of Apigenin of about 5 mg to about 500 mg.
- the preferred dosage of Hesperidin in the present invention comprises between about 100 mg to about 1000 mg per serving.
- the preferred dosage of Apigenin in the present invention comprises of between about 50 mg to about 500 mg per serving.
- the composition comprises Hesperidin and at least one form of Apigenin as defined.
- Hesperidin:Apigenin may be between 1 :1 and 20:1 with a preferred weight ratio of approximately 2:1 .
- hesperidin is present in the composition in an amount of from about 100mg to about 1000, for example from about 100 to about 500mg and wherein apigenin is present in an amount of from about 5mg to about 500mg, for example from about 50mg to about 250mg, for example from about 100mg to about 500mg.
- the composition comprises Hesperidin with at least 60% of the S-Hesperidin isomer or an R:S ratio of 1 :1 up to 1 :40, with a more preferred ratio of 1 :2— 1 :25.
- the weight ratio of hesperidin to apigenin in the composition of the invention comprising hesperidin and apeginin is preferably in the range from 1 :1 to 20:1 .
- hesperidin is present in the composition in an amount of from about 50 mg to about 1000mg, for example from about 100mg to about 600mg..
- any of the aforementioned compositions is contained in a tablet, liquid, capsule or syrup.
- any of the aforementioned compositions is incorporated in a food, including juices, dairy products and beverages.
- Hesperidin As a sedative or anxiolytic is absent or severely reduced when taken orally. To overcome this shortcoming of Hesperidin specific administration forms of Hesperidin and/or Apigenin are created.
- Hesperidin and/or Apigenin is formulated in a carrier for buccal and/or sublingual administration.
- the invention relates to the composition comprising hesperidin and/or apigenin, wherein the composition is in a form suitable for oral administration, for example in a form suitable for sublingual and/or buccal
- the invention relates to the composition comprising hesperidin, wherein the composition is in a form suitable for sublingual and/or buccal
- Carriers for buccal and/or sublingual administration may consist of a soluble film, lozenge, tablet gel, or syrup.
- the uptake of Hesperidin and/or Apigenin may be increased by means of incorporating the substance into structures, such as liposomes, adding small quantities of ethyl alcohol, glycol, menthol or xylitol, or any other state of the art technique and/or technology.
- Hesperidin and /or Apigenin is formulated in a chewing gum.
- the serving of the buccal and/or sublingual composition includes 50-1000, for example 100-600 mg of Hesperidin.
- the serving of the buccal and/or sublingual composition includes 50-300 mg of Hesperidin and 25-150 mg of Apigenin.
- FIG. 1 Sleeping time 1 hour after administration of vehicle (VEH), Hesperidin (HN) or HN + Apigenin (AP): * P ⁇ 0.05, significantly different from vehicle; Number of mice tested is indicated between parentheses.
- Figure 2 Sodium thiopental-induced sleeping time assay-Time of loss of righting reflex. Sleeping time 4 hours after administration of vehicle (VEH), Hesperidin (HN) or HN + Apigenin (AP) Number of mice tested is indicated between parentheses.
- Figure 3 shows the sodium thiopental-induced sleeping time assay - Time of loss of righting reflex.
- Mean ⁇ S.E.M. standard error of the mean of sleeping time of mice given a sub-hypnotic dose of sodium thiopental (35 mg/kg), 1 h after the oral administration of vehicle (VEH) or the drugs.
- AP 25, 50 and 100 mg/kg
- HN + AP 100 mg/kg + 50 mg/kg or 100 mg/kg + 25 mg/kg
- *** P ⁇ 0.001 significantly different from vehicle, Dunn's multiple comparison test after Kruskal - Wallis nonparametric ANOVA. Number of mice per group is indicated between parentheses.
- Figure 4 shows the sodium thiopental-induced sleeping time assay - Number of mice that lose righting reflex after a sub-hypnotic dose of sodium thiopental (35 mg/kg), 1 h after the oral administration of vehicle (VEH) or the drugs. ** P ⁇ 0.01 , significantly different from vehicle, Chi-square test.
- Figure 5 shows the sodium thiopental-induced sleeping time assay - Percentage of mice that lose the righting reflex after a sub-hypnotic dose of sodium thiopental (35 mg/kg), 1 h after the oral administration of vehicle (VEH) or the drugs.
- the objective was to assess the efficacy of Hesperidin with or without Apigenin when administered orally to mice.
- HESPERIDIN Hesperidin
- APIGENIN Apigenin
- mice were fasted for 18 h before performing the tests and the study drugs were administered by oral gavage 1 h or 4 h prior to the assays.
- a sub-hypnotic dose of sodium thiopental (35 mg/kg) was i.p. injected to mice 60 min or 4 h after the oral administration of vehicle or the drug. Sleeping time was determined as the interval between the loss and the recovery of the righting reflex. Furthermore, the number of rearings were assessed in a holeboard assay and locomotor activity was assessed in a Plexiglas cage according to scientifically accepted procedures.
- HESPERIDIN (100 and 300 mg/kg) alone exerted no effects on the sleeping time in mice, measured at 1 h or 4 h after its administration.
- HESPERIDIN + APIGENIN (100 + 50 mg/kg) showed an increment of the sleeping time that was significantly different from control mice 1 h after oral administration.
- mice Male male Swiss mice weighing 25-30 g (two month old) were used, obtained from the Central Animal House of the School of Pharmacy and Biochemistry, University of wholesome Aires. For the assays mice were housed in groups of five in a controlled environment (20-23 Q C), with free access to food and water and maintained on a 12h/12h day/night cycle, light on at 06:00 AM. Housing, handling, and experimental procedures complied with the recommendations set forth by the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication No. 85-23, revised 1985) and CICUAL (Institutional Committee for the Care and Use of Laboratory Animals, University of wholesome Aires, Argentina). All efforts were taken in order to minimize animal suffering. The number of animals used was the minimum number consistent with obtaining significant data. The animals were randomly assigned to any treatment groups and were used only once. The tests were evaluated by
- Hesperidin (HN, Zoster) and Apigenin (AP, Zoster) were suspended in 0.5 % sodium carboxy methyl cellulose (SIGMA) and orally administrated to mice.
- the volume of the administrations was 0.20 ml/30 g body weight.
- a control group receiving only vehicle was tested in parallel, which rendered 41 mice in the control group.
- the doses of AP were 25 mg/kg, 50 mg/kg and 100 mg/kg (16 mice in each group).
- the doses of the combination of (HN+AP) were 100 mg/kg and 50 mg/kg (17 mice) or 100 mg/kg and 25 mg/kg (10 mice), respectively. HN and AP were administered together.
- mice were fasted for 18 h before performing the tests and HP/AN were administered by oral gavage 1 h prior the assays.
- a sub-hypnotic dose of sodium thiopental (35 mg/kg) was intra-peritoneally injected to mice 1 h after the oral administration of vehicle or the drugs. Sleeping time was determined as the interval between the loss and the recovery of the righting reflex.
- the oral administration of AP at 25 mg/kg, 50 mg/kg or 100 mg/kg exerted no effects on the sodium thiopental induced sleeping time of mice, 1 h after administration.
- the co-administration of AP + HN (25 mg/kg and 100 mg/kg, respectively) did not show any effect on mice on this assay.
- AP + HN (50 mg/kg and 100 mg/kg, respectively) showed an increment of the sleeping time of mice that was significantly different from control mice 1 h after oral administration.
- the results were conclusive.
- the data were analyzed by a nonparametric analysis of variance (Dunn's multiple comparison test was used after Kruskal-Wallis test) or by comparing the number of mice that lose the righting reflex (success) vs.
- An intrabuccally rapidly disintegrating tablet can be produced using the known principles described in e.g. "Pharmaceutics, the science of dosage form design", M.E. Aulton, Churchill Livingstone, 2002. by growing a powder material into a granulated material with a fixed particle diameter, suitable for tableting in e.g. a rotary press.
- the powder material D-mannitol, sorbitol or sucrose to which may be added a disintegrant according to the state of the art (e.g. starch, cellulose).
- the powder material is sprayed with purified water in a granulation dryer, to obtain a final particle diameter of around 30 ⁇ ; Subsequently, 400g of enantiomerically enriched hesperidin (70wt% S- enantiomer) is then mixed with 1590g of the powder material. 10g of magnesium stearate is added after the granulation/mixing processes and they are compressed and tabeletted with a rotary tabletting machine (e.g. Kikusui Co., Ltd, clean press collect type 12). Each tablet will have a weight of 200 mg and is compressed with forces of 250-450 kg to produce up to 10 different tablet densities that are tested for their disintegration time.
- a rotary tabletting machine e.g. Kikusui Co., Ltd, clean press collect type 12
- composition per tablet is hence 159 mg powder material, 40 mg of Hesperidin and 0.1 mg of magnesium stearate.
- a composition and mechanical compression is chosen such that resulting tablets shall have a hardness of ⁇ 5 kgf and a disintegration time of -16 seconds in the buccal environment.
- a typical daily dose of Hesperidine will be achieved by administering 4-12 tablets (160 - 480mg) on 2-4 time points per day.
- sucrose (6 parts), corn syrup (3 parts) and water (2 parts) are mixed and heated to 150 ° C.
- Flavoring eg orange extract (1/8 part) is added and while cooling starts, Hesperidin and Apigenin in a ratio of 2:1 is added.
- Each lozenge is formed by dividing the mixture into molds to contain a total weight of 2.5-3 grams, in which 250 mg Hesperidin and 125 mg of Apigenin is distributed.
- Each lozenge thereby contains 1551 mg sucrose, 775mg corn syrup, up to 517mg water, and 32mg flavoring.
- lozenges After cooling, lozenges have to be stored separately in blister packaging to avoid melting due to their hygroscopic properties.
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Abstract
L'invention concerne une composition qui comprend de l'hespéridine et de l'apigénine. La présente invention concerne en outre une composition qui comprend de l'hespéridine, la composition se trouvant sous une forme adaptée à une administration sublinguale et/ou buccale. Les compositions peuvent être un aliment ou une boisson ou une composition de supplément pour aliment ou boisson, par exemple un chewing-gum. Les compositions peuvent en outre être utilisées comme un médicament. Les compositions peuvent être utilisées pour promouvoir le sommeil, pour réduire le stress, pour augmenter la relaxation, pour la sédation, pour la tranquillisation et/ou dans le traitement de troubles de l'anxiété, pour soulager l'anxiété, pour améliorer l'humeur et/ou augmenter la relaxation chez les animaux, de préférence les mammifères, par exemple les humains.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108250172A (zh) * | 2017-11-22 | 2018-07-06 | 中国科学院西北高原生物研究所 | 一种具有抗焦虑功效的化合物及其制备方法 |
JP2021520855A (ja) * | 2018-05-04 | 2021-08-26 | ノアス カンパニー リミテッドNoahs Co.,Ltd. | シトラス果皮抽出物を含むカフェインによる睡眠障害改善用組成物 |
IT202000004747A1 (it) * | 2020-03-06 | 2021-09-06 | A M Italy S R L | Composizione per l’uso nella terapia, in particolare per la cura dell’ansia |
CN114522116A (zh) * | 2022-01-21 | 2022-05-24 | 湖北中医药大学 | 一种橙皮苷脂质体凝胶剂及其制备方法和用途 |
US11642360B2 (en) * | 2019-09-03 | 2023-05-09 | BioRelief, LLC | Compositions for improving joint health |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003061678A1 (fr) | 2002-01-25 | 2003-07-31 | Universtiy Of Strathclyde | Substances et traitements sedatifs |
US20090061029A1 (en) * | 2007-08-28 | 2009-03-05 | Kaira Rouda | Nighttime water |
WO2009079601A1 (fr) | 2007-12-17 | 2009-06-25 | Bret Nelson | Méthodes et systèmes destinés à l'administration sublinguale de guarana |
EP2522346A1 (fr) * | 2011-05-07 | 2012-11-14 | Dr. Loges + Co. GmbH | Combinaisons de substances actives d'hespéridine destinées au traitement de troubles du sommeil |
-
2013
- 2013-06-11 WO PCT/EP2013/062046 patent/WO2013186220A1/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003061678A1 (fr) | 2002-01-25 | 2003-07-31 | Universtiy Of Strathclyde | Substances et traitements sedatifs |
US20090061029A1 (en) * | 2007-08-28 | 2009-03-05 | Kaira Rouda | Nighttime water |
WO2009079601A1 (fr) | 2007-12-17 | 2009-06-25 | Bret Nelson | Méthodes et systèmes destinés à l'administration sublinguale de guarana |
EP2522346A1 (fr) * | 2011-05-07 | 2012-11-14 | Dr. Loges + Co. GmbH | Combinaisons de substances actives d'hespéridine destinées au traitement de troubles du sommeil |
Non-Patent Citations (7)
Title |
---|
FERNANDEZ, EUR. J. PHARM., vol. 539, no. 3, 2006 |
GUZMAN-GUTIERREZ S L ET AL: "Pharmacological Exploration of the Sedative Mechanism of Hesperidin Identified as the Active Principle of Citrus sinensis Flowers", PLANTA MEDICA, THIEME VERLAG, DE, vol. 75, 1 January 2009 (2009-01-01), pages 295 - 301, XP002680958, ISSN: 0032-0943, [retrieved on 20090213], DOI: 10.1055/S-0029-1185306 * |
KIM, ARCH PHARM RES, vol. 35, no. 2, 2012 |
LOSCALZO L M ET AL: "Opioid receptors are involved in the sedative and antinociceptive effects of hesperidin as well as in its potentiation with benzodiazepines", EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER SCIENCE, NL, vol. 580, no. 3, 12 February 2008 (2008-02-12), pages 306 - 313, XP026864963, ISSN: 0014-2999, [retrieved on 20071113] * |
M.E. AULTON: "Pharmaceutics, the science of dosage form design", 2002, CHURCHILL LIVINGSTONE |
MARDER, PHARM, BIOCHEM BEHAV, vol. 75, no. 3, 2003 |
MARIEL MARDER ET AL: "6-Methylapigenin and hesperidin: new valeriana flavonoids with activity on the CNS", PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, vol. 75, no. 3, 1 June 2003 (2003-06-01), pages 537 - 545, XP055033952, ISSN: 0091-3057, DOI: 10.1016/S0091-3057(03)00121-7 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108250172A (zh) * | 2017-11-22 | 2018-07-06 | 中国科学院西北高原生物研究所 | 一种具有抗焦虑功效的化合物及其制备方法 |
JP2021520855A (ja) * | 2018-05-04 | 2021-08-26 | ノアス カンパニー リミテッドNoahs Co.,Ltd. | シトラス果皮抽出物を含むカフェインによる睡眠障害改善用組成物 |
US11642360B2 (en) * | 2019-09-03 | 2023-05-09 | BioRelief, LLC | Compositions for improving joint health |
IT202000004747A1 (it) * | 2020-03-06 | 2021-09-06 | A M Italy S R L | Composizione per l’uso nella terapia, in particolare per la cura dell’ansia |
CN114522116A (zh) * | 2022-01-21 | 2022-05-24 | 湖北中医药大学 | 一种橙皮苷脂质体凝胶剂及其制备方法和用途 |
CN114522116B (zh) * | 2022-01-21 | 2023-12-01 | 湖北中医药大学 | 一种橙皮苷脂质体凝胶剂及其制备方法和用途 |
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