WO2020162859A2 - A novel combination containing passiflora, glycine, metylfolate and magnesium threonate and production method thereof - Google Patents

A novel combination containing passiflora, glycine, metylfolate and magnesium threonate and production method thereof Download PDF

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Publication number
WO2020162859A2
WO2020162859A2 PCT/TR2020/050081 TR2020050081W WO2020162859A2 WO 2020162859 A2 WO2020162859 A2 WO 2020162859A2 TR 2020050081 W TR2020050081 W TR 2020050081W WO 2020162859 A2 WO2020162859 A2 WO 2020162859A2
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combination according
ratio
weight
passiflora
magnesium
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PCT/TR2020/050081
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French (fr)
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WO2020162859A3 (en
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Natig YUSUBOV
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Gmg Grand Medical Ilaclari Limited Sirketi
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/84—Valerianaceae (Valerian family), e.g. valerian
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • This invention relates to a dietary supplement developed for being used in the field of pharmaceutical, for the treatment of somatoform disorders such as vegetative-vascular dystonia, for reducing stress in adults, for the treatment of psychological disorders such as depression and anxiety and for the treatment of menopause disorders, premenstrual syndrome and migraine, and containing combination of passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form, glycine, L-methyfolate (folic acid), magnesium L-threonate. Also, the invention discloses the production method of said combination.
  • Vegetative vascular dystonia can be identified as basically functional autonomic disorders due to impaired neurohormonal regulation of the functions. Those disorders are frequently encountered in neuropsychiatric or physical fatigue, infections, intoxications, neurosis-like conditions associated with drug addiction as well as in neurosis, physical inactivity, puberty and endocrine incompatibility during menopause. In fact, vascular dystonia, chronic stress, excessive fattening and infections (especially viral) are a neurosis caused by endocrinological disorders.
  • Vegetative-vascular dystonia is a syndrome. In other words, it is a combination of symptoms, occurred in the body, of changes or pathological processes which are a consequent of chronical stress.
  • the main reason of this syndrome is violation of regulation of vascular tone of autonomic nervous system. Its frequency in adult population is between 60% and 70%, in children and teenagers is between 10% and 15%.
  • neurometabolic stimulants In the state of the art, neurometabolic stimulants, vitamins, minerals, antidepressants, psychotherapy, massage and acupuncture therapy are used to overcome this syndrome.
  • Passiflora is one of the most used plants in depression, panic attack and anxiety disorders and sleep problems in addition to vegetative vascular dystonia. In the state of the art, the use of products containing passiflora is also common since it has lower side effects.
  • Perennial plant passiflora is the main component of Passiflora incarnata. This plant, which has main active ingredients such as flavonoids and alkaloids, is used for complaints such as discomfort, anxiety, insomnia, epilepsy, menstruation and various disorders during menopause and is known to have antitussive, antiasthmatic, aphrodisiac and anti-inflammatory effects (Miroddi M, Calapai G, Navarra M, Minciullo PL, Gangemi S.
  • Passiflora incarnata L. ethnopharmacology, clinical application, safety and evaluation of clinical trials. J Ethnopharmacol 2013;150:791-804. , ESCOP Monographs. 2nd edition. Thieme Press, New York, 2003). Even though Passiflora incarnata extract has been tested in preclinical studies, its mechanism of action is still being discussed. Sedative effects of Passiflora incarnata are shown on rodents (Krenn L. [Passion Flower (Passiflora incarnata L.)--a reliable herbal sedative] Wien Med Klischr 2002;152:404-6.).
  • Brain calm contains inositol, GABA, passiflora (passion flower) and l-glycine. It is a dietary supplement for individuals who desire to their support neurological health.
  • Imipramine is another state of the art active substance used for all types of depression including panic attacks, chronic painful conditions and fear of night, endogenous, organic and psychogenic forms and personality disorders or depression accompanied by chronic alcoholism.
  • Imipramine is a tricyclic antidepressant, wherein it has various pharmacological features such as alpha-adrenolytic, antihistaminic, anticholinergic and 5-FIT-receptor blockade.
  • main therapeutic activity is considered to be the inhibition of re-uptake of noradrenaline and serotonin (5-HT) in neurons.
  • the aim of the invention is to develop a combined production exhibiting a synergistic action, for the treatment of somatoform disorders such as vegetative-vascular dystonia, menopausal disorders, premenstrual syndrome and migraine attacks and for the treatment of psychological disorders such as depression and anxiety, and for reducing stress in adults by providing a combined therapy with the actives of passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form, glycine, L-methyfolate (folic acid), Mg L-threonate.
  • passiflora passiflora incarnata
  • glycine glycine
  • L-methyfolate folic acid
  • Mg L-threonate Mg L-threonate
  • the formulation contains passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form in the ratio of 10% - 30% by weight, glycine in the ratio of 1% - 30% by weight, L-methyfolate (folic acid) in the ratio of 0.008% - 25% by weight, Magnesium L- threonate in the ratio of 2% - 41% by weight.
  • Another aim of the invention is to assist in supporting neurological health of individuals by the developed dietary supplement that is subject of the invention.
  • Fig. 1 The graphic showing the effect of imipramine (15 mg / kg) and the present invention combination (passiflora 125, passiflora 250, passiflora 500 and passiflora 1000 mg / kg) on immobility time in forced swimming test
  • This invention describes a combination containing passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form in the ratio of 10% - 30% by weight, glycine in the ratio of l%-30% by weight, L-methyfolate (folic acid) in the ratio of 0.008%-25% by weight, magnesium L-threonate in the ratio of 2%-41% by weight, for the treatment of somatoform disorders such as vegetative-vascular dystonia, for reducing stress in adults, for the treatment of psychological disorders such as depression and anxiety and for the treatment of menopause disorders, premenstrual syndrome and migraine.
  • passiflora passiflora incarnata
  • glycine in the ratio of l%-30% by weight
  • L-methyfolate folic acid
  • magnesium L-threonate in the ratio of 2%-41% by weight
  • the present invention supplement production provides sedative and hypnotic effect by the Passiflora extract contained therein.
  • Passiflora enables reduction of reflex stimulability in central nervous system and strengthening of inhibition effects on neurons of cortex and subcortical structures in cerebrum by means of bromobutyric acid ethyl ester contained therein.
  • Passiflora is an anxiolytic used also in sleep problems.
  • L-Glycine another substance of the product, decreases emotional stresses, increases mental efficiency, enhances nervous system metabolism, also has anti-stress and sedative effects.
  • Glycine is a natural metabolite in central nervous system and decreases emotional stress as being a type of neurotransmitter inhibitor action and regulator of metabolic processes. It increases mental efficiency, exhibits neuroprotective effect. Glycine has anti-stress property and sedative effect. Furthermore it enhances metabolism of brain, normalizes sleep and decreases toxic effects of alcohol.
  • L-methyfolate another substance of the product, supports adequate synthesis of biochemical compounds such as serotonin, norepinephrine and dopamine required for reducing depression.
  • L-methyfolate is primary biological active isomer of folate and its primary active folate form in the circulation. Also, it is the form conveyed to peripheral tissues along the membranes, especially to brain against blood brain barrier.
  • Magnesium plays a critical role in depression, anxiety, bipolar disorder, schizophrenia and some neurological disorders such as L-methyfolate associated with brain, and is known to be effective in the treatment of depression, dementia and schizophrenia. Additionally, it increases the effects of serotonin and norepinephrine retake inhibitors (SNRi) and selective serotonin retake inhibitors (SSRI).
  • SNRi serotonin and norepinephrine retake inhibitors
  • SSRI selective serotonin retake inhibitors
  • Magnesium l-threonate is specially developed for passing protective filter of brain, blood brain barrier and for increasing elementary magnesium concentration in brain. Magnesium increases synaptic connections between neurons and thus intensifies by improving short term memory, long term memory and multiple learning types. Moreover, enhances the sleep and decreases anxiety.
  • the present invention combined production is a combination exhibiting synergistic action, for the treatment of somatoform disorders such as vegetative-vascular dystonia, menopausal disorders, premenstrual syndrome and migraine attacks, for the treatment of psychological disorders such as depression and anxiety, and for reducing stress in adults by providing a combined therapy with the actives of passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form, glycine, L-methyfolate Mg L-threonate.
  • passiflora passiflora incarnata
  • glycine L-methyfolate Mg L-threonate
  • the combination containing passiflora (passiflora incarnata), glycine, L-methyfolate, Magnesium L-threonate provided a better treatment than cumulative effects of actives during treatment.
  • the present invention formulation may be in different dosage forms according to excipients to be used.
  • the present invention combination may be in capsule, tablet etc. solid dosage forms as well as liquid forms such as oral suspension, syrup, solution.
  • the present invention combination product comprises at least one excipient.
  • the state of the art preservatives, acidity regulating agents, colorants, sweeteners, solvents, thickeners, plasticizers, anti-caking agents can be used as excipient.
  • the preservative agent used in the invention is used for the aim of lengthening the expiry date of the product, preventing microbial reproduction, wherein at least one preservative among sodium benzoate, potassium sorbate, methyl ethyl propyl paraben or salts can be selected.
  • the present invention formulation comprises preservative in the ratio of 0.02%- 1.4% by weight.
  • the sweetener agent used in the invention is used with the intent of being easily accepted by patients by masking the taste of the drug, wherein at least one sweetener among sugar, sodium saccharine, aspartam, sorbitol, xylitol, menthol, glycerin or sweetener having aroma such as lemon, orange can be selected.
  • the present invention formulation comprises sweetener in the ratio of 0.01%- 0.4% by weight.
  • the colorant agent used in the invention is generally used for the discrimination of the drug, and is selected from natural and synthetic colorants.
  • the present invention formulation comprises colorant in the ratio of 0.001%- 0.03% by weight.
  • the solvents used in the invention is used for the better dissolution of the components, wherein at least one solvent among propylene glycol, glycerin, ethanol, distilled water, oleic acid ethyl esters, mono and di glycerin palmitates is selected.
  • the present invention formulation comprises solvent in the ratio of 60%- 85% by weight.
  • At least one acidity regulating agent used in the invention is selected among citric acid, citric acid anhydrate, citric acid monohydrate etc.
  • the present invention formulation comprises acidity regulating agent in the ratio of 0.01%- 0.8% by weight.
  • the thickening agents used in the invention at least one thickening agent is selected among cellulose microcrystalline, agar agar, propylene glycol, sorbitol, mannitol, polysorbate, pectin, hydroxypropyl cellulose, ethyl methyl cellulose.
  • the present invention formulation comprises thickening agent in the ratio of 8%- 20% by weight.
  • the plasticizer used in the invention at least one plasticizer is selected among magnesium stearate, calcium stearate, calcium phosphate, glyceryl monostearate, leucine.
  • the present invention formulation comprises plasticizer in the ratio of 0.3%- 1% by weight.
  • the anti-caking agents used in the invention at least one anti-caking agent is selected among silicon dioxide, magnesium trisilicate, colloidal silicon dioxide, magnesium oxide, talc.
  • the present invention formulation comprises anti-caking agent in the ratio of 0.1%- 0.9% by weight.
  • Another property of the production method is weighing all the components one by one under laminar flow system.
  • the inventor has carried a study by realizing forced swimming test in mice for evaluating anti depression effect and synergistic effect of the present invention combination.
  • a solution formed formulation containing Passiflora incarnata, L-glycine, Magnesium L-threonate and L- methyl folate is used in this study.
  • mice are divided into 6 equal group in experimental design: control group (1); the animals are fed by usual mouse feed and given tap water, group (2); is given the present invention combination containing 125 mg passiflora, 12.5 mg L-glycine, 18.75mg MG L-threonate, 0.0625 mg L-methyl folate with drinking water daily, group (3); the present invention combination containing 250 mg passiflora, 25 mg L-glycine, 37.5 mg MG L-threonate, 0.125 mg L-methyl folate is given with drinking water daily, group (4); the present invention combination containing 500 mg passiflora, 50 mg L-glycine, 75 mg MG L-threonate, 0.25 mg L-methyl folate is given with drinking water daily, group (5); the present invention combination containing 1000 mg passiflora, 100 mg L-glycine, 150 mg MG L-threonate, 0.5 mg L-methyl folate is given with drinking water daily, group (6); is given 15 mg / kg / day dosage imipramine
  • Figure 1 shows immobility times of the mice in FST. A substantial decrease in immobility time of the animals treated with 15 mg / kg imipramine (the present invention combination (p ⁇ 0.01) containing p ⁇ 0.001), 1000 mg / kg passiflora and the present invention combination (p ⁇ 0.05) containing 500 mg / kg passiflora) is stated.
  • Figure 2 shows swimming time of the mice in FST. In comparison to the control group, a substantial increase in swimming time of the mice treated with 15 mg / kg imipramine (the present invention combination 1000 mg / kg (p ⁇ 0.05) containing p ⁇ 0.001) and passiflora) is recorded.
  • Figure 3 shows climbing time of the mice in FST.
  • the forced swimming test is one the most commonly used animal models for researching anti depression like effects of conventional drugs and herbal substances on mice and rats. This model is sensible to effects of drugs and plant extracts. Decrease of immobility time in FST is considered to be the indicative of an anti-depression like effect, whereas it is suggested that the increase in noradrenergic activity lead the animal to climbing behavior and the increase in serotonergic activity can be associated with swimming behavior. Imipramine has shortened immobility time of the animals in our study as in other studies. The imipramine that is a tricyclic anti-depressant has increased both climbing and swimming behavior thanks to its effects on noradrenergic and serotonergic ways.
  • the present invention combination containing passiflora is found to shorten immobility time of the mice depending on the dosage and this exhibits antidepressant-like effect. It is seen that the present invention combination containing passiflora increases both swimming and climbing behavior and its effect on the climbing behavior can be dependent on a significant noradrenergic effect.
  • incarnata plant is known to have an effect on GABAergic system that can contribute to antidepressant activity.
  • Some studies have shown that the P. incarnata plant, when used alone, does not have a significant affect on swimming behavior (Jafarpoor N, Abbasi-Maleki S, Asadi-Samani M, Khayatnouri M. Evaluation of antidepressant- like effect of hydroalcoholic extract of Passiflora incarnata in animal models of depression in male mice. J HerbMed Pharmacol 2014;3:41-5.).
  • Fig. 1 is the graphic showing the effect of imipramine (15 mg / kg) and the present invention combination containing passiflora (125, 250, 500 and 1000 mg / kg) on immobility time in forced swimming test.
  • IM imipramine treatment group
  • P125 the present invention combination containing 125 mg / kg passiflora treatment group
  • P250 the present invention combination containing 250 mg / kg passiflora treatment group
  • P500 the present invention combination containing 500 mg / kg passiflora treatment group
  • P1000 the present invention combination containing 1000 mg / kg passiflora treatment group, * p ⁇ 0.05, control group against significant change; ** p ⁇ 0.01, significant change according to control group; *** p ⁇ 0.001, significant change according to control group;
  • Fig. 3 is the graphic showing the effect of imipramine (15 mg / kg) and the present invention combination containing passiflora (125, 250, 500 and 1000 mg / kg) on climbing time in forced swimming test.
  • IM imipramine treatment group
  • P125 the present invention combination containing 125 mg / kg passiflora treatment group
  • P250 the present invention combination containing 250 mg / kg passiflora treatment group
  • P500 the present invention combination containing 500 mg / kg passiflora treatment group
  • P1000 the present invention combination containing 1000 mg / kg passiflora treatment group, * p ⁇ 0.05, control group against significant change; ** p ⁇ 0.01, significant change according to control group; *** p ⁇ 0.001, significant change according to control group;
  • the present formulation can additionally contain Hypericum perforatum in the ratio between 10-42% by weight from Hpericaceae family. Furthermore, it can contain Valeriana officinalis in the ratio between 13-65% by weight from Valerian family.
  • Another characterization of the invention is that it contains Crocus Sativus in the ratio between 15-56% by weight selected from Iridaceae family.

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Abstract

This invention relates a supplemental product developed for the treatment of somatoform disorders such as vegetative-vascular dystonia, for reducing stress in adults, for the treatment of pyschological disorders such as depression and anxiety and for the treatment of menopause disorders, premenstrual syndrome and migraine, wherein it discloses a combination and production method thereof, containing passiflora (passiflora incarnata) in the ratio of 10% - 30% by weight, glycine in the ratio of 1%-30% by weight, L-methyfolate (folic acid) in the ratio of 0.008%-25% by weight, magnesium L-threonate in the ratio of 2%-41% by weight.

Description

A NOVEL COMBINATION CONTAINING PASSIFLORA, GLYCINE, METYLFOLATE AND MAGNESIUM THREONATE AND PRODUCTION METHOD THEREOF
Technical Field
This invention relates to a dietary supplement developed for being used in the field of pharmaceutical, for the treatment of somatoform disorders such as vegetative-vascular dystonia, for reducing stress in adults, for the treatment of psychological disorders such as depression and anxiety and for the treatment of menopause disorders, premenstrual syndrome and migraine, and containing combination of passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form, glycine, L-methyfolate (folic acid), magnesium L-threonate. Also, the invention discloses the production method of said combination.
State of the Art
Vegetative vascular dystonia, better described as vegetative vascular dysfunction can be identified as basically functional autonomic disorders due to impaired neurohormonal regulation of the functions. Those disorders are frequently encountered in neuropsychiatric or physical fatigue, infections, intoxications, neurosis-like conditions associated with drug addiction as well as in neurosis, physical inactivity, puberty and endocrine incompatibility during menopause. In fact, vascular dystonia, chronic stress, excessive fattening and infections (especially viral) are a neurosis caused by endocrinological disorders.
Vegetative-vascular dystonia is a syndrome. In other words, it is a combination of symptoms, occurred in the body, of changes or pathological processes which are a consequent of chronical stress. The main reason of this syndrome is violation of regulation of vascular tone of autonomic nervous system. Its frequency in adult population is between 60% and 70%, in children and teenagers is between 10% and 15%.
In the state of the art, neurometabolic stimulants, vitamins, minerals, antidepressants, psychotherapy, massage and acupuncture therapy are used to overcome this syndrome.
Passiflora is one of the most used plants in depression, panic attack and anxiety disorders and sleep problems in addition to vegetative vascular dystonia. In the state of the art, the use of products containing passiflora is also common since it has lower side effects. Perennial plant passiflora is the main component of Passiflora incarnata. This plant, which has main active ingredients such as flavonoids and alkaloids, is used for complaints such as discomfort, anxiety, insomnia, epilepsy, menstruation and various disorders during menopause and is known to have antitussive, antiasthmatic, aphrodisiac and anti-inflammatory effects (Miroddi M, Calapai G, Navarra M, Minciullo PL, Gangemi S. Passiflora incarnata L.: ethnopharmacology, clinical application, safety and evaluation of clinical trials. J Ethnopharmacol 2013;150:791-804. , ESCOP Monographs. 2nd edition. Thieme Press, New York, 2003). Even though Passiflora incarnata extract has been tested in preclinical studies, its mechanism of action is still being discussed. Sedative effects of Passiflora incarnata are shown on rodents (Krenn L. [Passion Flower (Passiflora incarnata L.)--a reliable herbal sedative] Wien Med Wochenschr 2002;152:404-6.). Furthermore, anxiolytic effects of Passiflora incarnata has been detected (Grundmann O, Wahling C, Staiger C, Butterweck V. Anxiolytic effects of a passion flower (Passiflora incarnata L.) extract in the elevated plus maze in mice. Pharmazie 2009;64:63-4.- de Castro PC, Floshino A, da Silva JC, Mendes FR. Possible anxiolytic effect of two extracts of Passiflora quadrangularis L. in experimental models. Phytother Res 2007;21:481-4.)
In the state of the art, the preparation called as Brain calm contains inositol, GABA, passiflora (passion flower) and l-glycine. It is a dietary supplement for individuals who desire to their support neurological health.
The invention subjected to American Patent Registration titled "Method for reducing daily stress and anxiety in adults" with the publication no US6080410(A) which is another passiflora combination encountered in the state of the art discloses a dietary supplement composition that serves as a general relaxant for reducing daily stress and anxiety in adults and comprises Kava root extract and at least one additional relaxing herb selected from the group consisting of Passion Flower, Chamomile Flower, Flops, and Schizandra Fruit.
Imipramine is another state of the art active substance used for all types of depression including panic attacks, chronic painful conditions and fear of night, endogenous, organic and psychogenic forms and personality disorders or depression accompanied by chronic alcoholism. Imipramine is a tricyclic antidepressant, wherein it has various pharmacological features such as alpha-adrenolytic, antihistaminic, anticholinergic and 5-FIT-receptor blockade. However, main therapeutic activity is considered to be the inhibition of re-uptake of noradrenaline and serotonin (5-HT) in neurons.
The inventor has aimed to develop a dietary supplement containing a novel combination and production method thereof, unlike the state of the art.
Description of the Invention
The aim of the invention is to develop a combined production exhibiting a synergistic action, for the treatment of somatoform disorders such as vegetative-vascular dystonia, menopausal disorders, premenstrual syndrome and migraine attacks and for the treatment of psychological disorders such as depression and anxiety, and for reducing stress in adults by providing a combined therapy with the actives of passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form, glycine, L-methyfolate (folic acid), Mg L-threonate. The formulation contains passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form in the ratio of 10% - 30% by weight, glycine in the ratio of 1% - 30% by weight, L-methyfolate (folic acid) in the ratio of 0.008% - 25% by weight, Magnesium L- threonate in the ratio of 2% - 41% by weight.
Another aim of the invention is to assist in supporting neurological health of individuals by the developed dietary supplement that is subject of the invention.
Description of the Figures
Fig. 1: The graphic showing the effect of imipramine (15 mg / kg) and the present invention combination (passiflora 125, passiflora 250, passiflora 500 and passiflora 1000 mg / kg) on immobility time in forced swimming test
Fig. 2: The graphic showing the effect of imipramine (15 mg / kg) and the present invention combination (passiflora 125, passiflora 250, passiflora 500 and passiflora 1000 mg / kg) on swimming time in forced swimming test
Fig. 3: The graphic showing the effect of imipramine (15 mg / kg) and the present invention combination (passiflora 125, passiflora 250, passiflora 500 and passiflora 1000 mg / kg) on climbing time in forced swimming test Detailed Description of the Invention
This invention describes a combination containing passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form in the ratio of 10% - 30% by weight, glycine in the ratio of l%-30% by weight, L-methyfolate (folic acid) in the ratio of 0.008%-25% by weight, magnesium L-threonate in the ratio of 2%-41% by weight, for the treatment of somatoform disorders such as vegetative-vascular dystonia, for reducing stress in adults, for the treatment of psychological disorders such as depression and anxiety and for the treatment of menopause disorders, premenstrual syndrome and migraine.
The present invention supplement production provides sedative and hypnotic effect by the Passiflora extract contained therein. Passiflora enables reduction of reflex stimulability in central nervous system and strengthening of inhibition effects on neurons of cortex and subcortical structures in cerebrum by means of bromobutyric acid ethyl ester contained therein. Passiflora is an anxiolytic used also in sleep problems.
L-Glycine, another substance of the product, decreases emotional stresses, increases mental efficiency, enhances nervous system metabolism, also has anti-stress and sedative effects. Glycine is a natural metabolite in central nervous system and decreases emotional stress as being a type of neurotransmitter inhibitor action and regulator of metabolic processes. It increases mental efficiency, exhibits neuroprotective effect. Glycine has anti-stress property and sedative effect. Furthermore it enhances metabolism of brain, normalizes sleep and decreases toxic effects of alcohol.
L-methyfolate, another substance of the product, supports adequate synthesis of biochemical compounds such as serotonin, norepinephrine and dopamine required for reducing depression. L-methyfolate is primary biological active isomer of folate and its primary active folate form in the circulation. Also, it is the form conveyed to peripheral tissues along the membranes, especially to brain against blood brain barrier.
Magnesium, among the other preparation substances, plays a critical role in depression, anxiety, bipolar disorder, schizophrenia and some neurological disorders such as L-methyfolate associated with brain, and is known to be effective in the treatment of depression, dementia and schizophrenia. Additionally, it increases the effects of serotonin and norepinephrine retake inhibitors (SNRi) and selective serotonin retake inhibitors (SSRI). Magnesium l-threonate is specially developed for passing protective filter of brain, blood brain barrier and for increasing elementary magnesium concentration in brain. Magnesium increases synaptic connections between neurons and thus intensifies by improving short term memory, long term memory and multiple learning types. Moreover, enhances the sleep and decreases anxiety.
The present invention combined production is a combination exhibiting synergistic action, for the treatment of somatoform disorders such as vegetative-vascular dystonia, menopausal disorders, premenstrual syndrome and migraine attacks, for the treatment of psychological disorders such as depression and anxiety, and for reducing stress in adults by providing a combined therapy with the actives of passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form, glycine, L-methyfolate Mg L-threonate.
By means of the synergistic effect provided by the present invention, the combination containing passiflora (passiflora incarnata), glycine, L-methyfolate, Magnesium L-threonate provided a better treatment than cumulative effects of actives during treatment.
The present invention formulation may be in different dosage forms according to excipients to be used. The present invention combination may be in capsule, tablet etc. solid dosage forms as well as liquid forms such as oral suspension, syrup, solution.
The present invention combination product comprises at least one excipient. The state of the art preservatives, acidity regulating agents, colorants, sweeteners, solvents, thickeners, plasticizers, anti-caking agents can be used as excipient.
The preservative agent used in the invention is used for the aim of lengthening the expiry date of the product, preventing microbial reproduction, wherein at least one preservative among sodium benzoate, potassium sorbate, methyl ethyl propyl paraben or salts can be selected. The present invention formulation comprises preservative in the ratio of 0.02%- 1.4% by weight.
The sweetener agent used in the invention is used with the intent of being easily accepted by patients by masking the taste of the drug, wherein at least one sweetener among sugar, sodium saccharine, aspartam, sorbitol, xylitol, menthol, glycerin or sweetener having aroma such as lemon, orange can be selected. The present invention formulation comprises sweetener in the ratio of 0.01%- 0.4% by weight. The colorant agent used in the invention is generally used for the discrimination of the drug, and is selected from natural and synthetic colorants. The present invention formulation comprises colorant in the ratio of 0.001%- 0.03% by weight.
The solvents used in the invention is used for the better dissolution of the components, wherein at least one solvent among propylene glycol, glycerin, ethanol, distilled water, oleic acid ethyl esters, mono and di glycerin palmitates is selected. The present invention formulation comprises solvent in the ratio of 60%- 85% by weight.
At least one acidity regulating agent used in the invention is selected among citric acid, citric acid anhydrate, citric acid monohydrate etc. The present invention formulation comprises acidity regulating agent in the ratio of 0.01%- 0.8% by weight. The thickening agents used in the invention; at least one thickening agent is selected among cellulose microcrystalline, agar agar, propylene glycol, sorbitol, mannitol, polysorbate, pectin, hydroxypropyl cellulose, ethyl methyl cellulose. The present invention formulation comprises thickening agent in the ratio of 8%- 20% by weight.
The plasticizer used in the invention; at least one plasticizer is selected among magnesium stearate, calcium stearate, calcium phosphate, glyceryl monostearate, leucine. The present invention formulation comprises plasticizer in the ratio of 0.3%- 1% by weight.
The anti-caking agents used in the invention; at least one anti-caking agent is selected among silicon dioxide, magnesium trisilicate, colloidal silicon dioxide, magnesium oxide, talc. The present invention formulation comprises anti-caking agent in the ratio of 0.1%- 0.9% by weight.
In exemplary embodiments of the invention the product in oral suspension form and in capsule dosage form is developed by using the following ratios.
Table 1: Example formulation for oral suspension form
Figure imgf000007_0001
Figure imgf000008_0001
Table 2: Example formulation for capsule form
Figure imgf000008_0002
For preparing liquid forms such as oral suspension, syrup and solution, the inventor implemented the following process steps in production method. · Distillation of passiflora active and taking the 22% of distillate by volume into tank,
• Addition of L-glycine, L-methyfolate, Magnesium threonate actives, respectively,
• Mixing,
• Addition of the remaining distillate (distilled passiflora 78% by volume),
• Addition of excipients and mixing,
· Mixing for 20 min. and storing in the flasks.
Another property of the production method is weighing all the components one by one under laminar flow system.
For preparing solid forms such as capsule and tablet, the inventor implemented the following process steps in production method. • Weighing active substances (passiflora, L-glycine, L-methyfolate, Magnesium threonate),
• Weighing excipients,
• Sifting
• Stirring,
• Pressing into tablet or filling into capsule
The inventor has carried a study by realizing forced swimming test in mice for evaluating anti depression effect and synergistic effect of the present invention combination. A solution formed formulation containing Passiflora incarnata, L-glycine, Magnesium L-threonate and L- methyl folate is used in this study.
42 Balb-c mice in 35 - 40 gr. weights are provided for the study. Average body weights of the mice are determined as 36,6 ± 2,1 gr. and the mice are separated into six groups (n = 7 mice in each group). The animals are treated humanely in accordance with NIH Guide for the Care and Use of Laboratory Animals and kept at room temperature (21 ° C ± 2 ° C), at relative humidity of 52 % ± 3% for 12 hours in day/night cycle. Mice are divided into 6 equal group in experimental design: control group (1); the animals are fed by usual mouse feed and given tap water, group (2); is given the present invention combination containing 125 mg passiflora, 12.5 mg L-glycine, 18.75mg MG L-threonate, 0.0625 mg L-methyl folate with drinking water daily, group (3); the present invention combination containing 250 mg passiflora, 25 mg L-glycine, 37.5 mg MG L-threonate, 0.125 mg L-methyl folate is given with drinking water daily, group (4); the present invention combination containing 500 mg passiflora, 50 mg L-glycine, 75 mg MG L-threonate, 0.25 mg L-methyl folate is given with drinking water daily, group (5); the present invention combination containing 1000 mg passiflora, 100 mg L-glycine, 150 mg MG L-threonate, 0.5 mg L-methyl folate is given with drinking water daily, group (6); is given 15 mg / kg / day dosage imipramine with drinking water. Forced swimming test (FST) is conducted after 7 days treatment.
In the forced swimming test (FST), the animals are forced to swim in a cylindrical tank that is
15 cm in depth, 18 cm in diameter and 40 cm in height. In 5 minutes test, swimming, climbing and immobility times of animals are recorded by a chronometer. After each animal completed the test, the water inside the tank is changed for the mice not to be affected from each other. The animals are considered to be immobile when they stay still and they only performed required movements to stay on the water.
Figure 1 shows immobility times of the mice in FST. A substantial decrease in immobility time of the animals treated with 15 mg / kg imipramine (the present invention combination (p <0.01) containing p <0.001), 1000 mg / kg passiflora and the present invention combination (p <0.05) containing 500 mg / kg passiflora) is stated. Figure 2 shows swimming time of the mice in FST. In comparison to the control group, a substantial increase in swimming time of the mice treated with 15 mg / kg imipramine (the present invention combination 1000 mg / kg (p <0.05) containing p <0.001) and passiflora) is recorded. Figure 3 shows climbing time of the mice in FST. When compared to the control group, a substantial increase in climbing time of the animals treated with 15 mg / kg imipramine (the present invention combination (p <0.01) containing p <0.001), 1000 mg / kg passiflora and the present invention combination (p <0.05) containing 500 mg / kg passiflora) is recorded.
The forced swimming test is one the most commonly used animal models for researching anti depression like effects of conventional drugs and herbal substances on mice and rats. This model is sensible to effects of drugs and plant extracts. Decrease of immobility time in FST is considered to be the indicative of an anti-depression like effect, whereas it is suggested that the increase in noradrenergic activity lead the animal to climbing behavior and the increase in serotonergic activity can be associated with swimming behavior. Imipramine has shortened immobility time of the animals in our study as in other studies. The imipramine that is a tricyclic anti-depressant has increased both climbing and swimming behavior thanks to its effects on noradrenergic and serotonergic ways. The present invention combination containing passiflora is found to shorten immobility time of the mice depending on the dosage and this exhibits antidepressant-like effect. It is seen that the present invention combination containing passiflora increases both swimming and climbing behavior and its effect on the climbing behavior can be dependent on a significant noradrenergic effect. The present invention combination containing passiflora, the main component of Passiflora incarnata plant extract, these alkaloids that are non-recyclable monoamine oxidase-A (MAO-A) and known to have antidepressant properties (known to contain alkaloids such as almalin, harmin and harmalol) have played a significant role in antidepressant-like activities. Beside MAO-A inhibition, the extract of P. incarnata plant is known to have an effect on GABAergic system that can contribute to antidepressant activity. Some studies have shown that the P. incarnata plant, when used alone, does not have a significant affect on swimming behavior (Jafarpoor N, Abbasi-Maleki S, Asadi-Samani M, Khayatnouri M. Evaluation of antidepressant- like effect of hydroalcoholic extract of Passiflora incarnata in animal models of depression in male mice. J HerbMed Pharmacol 2014;3:41-5.). That difference shows that it contributes to antidepressant-like effect by strengthening serotonergic mechanisms of glycine, L-methyfolate (folic acid) and Magnesium L-threonate that are the other components in the present invention combination containing passiflora. Hence, this proves the synergistic energy. Also, it has been concluded that the present invention combination containing passiflora exhibited antidepressant-like effects comparable to imipramine in experimental animal models.
Fig. 1: is the graphic showing the effect of imipramine (15 mg / kg) and the present invention combination containing passiflora (125, 250, 500 and 1000 mg / kg) on immobility time in forced swimming test. IM : imipramine treatment group P125: the present invention combination containing 125 mg / kg passiflora treatment group, P250: the present invention combination containing 250 mg / kg passiflora treatment group, P500: the present invention combination containing 500 mg / kg passiflora treatment group, P1000: the present invention combination containing 1000 mg / kg passiflora treatment group, * p <0.05, control group against significant change; ** p <0.01, significant change according to control group; *** p <0.001, significant change according to control group;
Fig. 2: is the graphic showing the effect of imipramine (15 mg / kg) and the present invention combination containing passiflora (125, 250, 500 and 1000 mg / kg) on swimming time in forced swimming test. IM : imipramine treatment group P125: the present invention combination containing 125 mg / kg passiflora treatment group, P250: the present invention combination containing 250 mg / kg passiflora treatment group, P500: the present invention combination containing 500 mg / kg passiflora treatment group, P1000: the present invention combination containing 1000 mg / kg passiflora treatment group, * p <0.05, control group against significant change; *** p <0.001, significant change according to control group;
Fig. 3: is the graphic showing the effect of imipramine (15 mg / kg) and the present invention combination containing passiflora (125, 250, 500 and 1000 mg / kg) on climbing time in forced swimming test. IM: imipramine treatment group P125: the present invention combination containing 125 mg / kg passiflora treatment group, P250: the present invention combination containing 250 mg / kg passiflora treatment group, P500: the present invention combination containing 500 mg / kg passiflora treatment group, P1000: the present invention combination containing 1000 mg / kg passiflora treatment group, * p <0.05, control group against significant change; ** p <0.01, significant change according to control group; *** p <0.001, significant change according to control group;
Another characterization of the dietary supplement containing the present invention combination is that it is in combination with at least one active selected from Hypericaceae, Valerian, Iridaceae family. The present formulation can additionally contain Hypericum perforatum in the ratio between 10-42% by weight from Hpericaceae family. Furthermore, it can contain Valeriana officinalis in the ratio between 13-65% by weight from Valerian family. Another characterization of the invention is that it contains Crocus Sativus in the ratio between 15-56% by weight selected from Iridaceae family.

Claims

1. A combination for the treatment of somatoform disorders such as vegetative-vascular dystonia, for reducing stress in adults, for the treatment of psychological disorders such as depression and anxiety, for the treatment of menopause disorders, premenstrual syndrome and migraine characterized in that it contains passiflora (passiflora incarnata) or its pharmaceutically acceptable derivative or form in the ratio of 10% - 30% by weight, glycine in the ratio of l%-30% by weight, L-methyfolate (folic acid) in the ratio of 0.008%-25% by weight, magnesium L-threonate in the ratio of 2%- 41% by weight.
2. A combination according to Claim 1, characterized in that it contains at least one excipient.
3. A combination according to Claim 2, characterized in that it contains at least one excipient selected among preservatives, acidity regulating agents, colorants, sweeteners, solvents, thickeners, plasticizers, anti-caking agents.
4. A combination according to Claim 3, characterized in that it contains at least one preservative selected among sodium benzoate, potassium sorbate, methyl ethyl propyl paraben or salts.
5. A combination according to Claim 4, characterized in that it contains preservative in a ratio between 0.02% - 1.4% by weight.
6. A combination according to Claim 3, characterized in that it comprises at least one solvent selected among propylene glycol, glycerin, ethanol, distilled water, oleic acid ethyl esters, mono and di glycerin palmitates.
7. A combination according to Claim 6, characterized in that it contains solvent in a ratio between 60%- 85% by weight.
8. A combination according to Claim 3, characterized in that it comprises at least one acidity regulating agent selected among citric acid, citric acid anhydrate, citric acid monohydrate.
9. A combination according to Claim 8, characterized in that it comprises acidity regulating agent in a ratio between 0.01%- 0.8% by weight.
10. A combination according to Claim 3, characterized in that it comprises at least one thickening agent selected among cellulose microcrystalline, agar agar, propylene glycol, sorbitol, mannitol, polysorbate, pectin, hydroxypropyl cellulose, ethyl methyl cellulose.
11. A combination according to Claim 10, characterized in that it comprises thickening agent in a ratio between 8%- 20% by weight.
12. A combination according to Claim 3, characterized in that it comprises at least one plasticizer selected among magnesium stearate, calcium stearate, calcium phosphate, glyceryl monostearate, leucine.
13. A combination according to Claim 12, characterized in that it comprises plasticizer in a ratio between 0.3% - 1% by weight.
14. A combination according to Claim 3, characterized in that it comprises at least one anti-caking agent selected among silicon dioxide, magnesium trisilicate, colloidal silicon dioxide, magnesium oxide, talc.
15. A combination according to Claim 14, characterized in that it comprises anti-caking agent in a ratio between 0.1%- 0.9% by weight.
16. A combination according to Claim 2, characterized in that it is in solid or liquid form.
17. A combination according to Claim 16, characterized in that it is in a liquid form selected among oral suspension, syrup and solution.
18. A production method of a combination according to Claim 17, characterized in that it comprises the following process steps of;
• distilling passiflora and taking the 22% of distillate by volume into tank,
• adding L-glycine, L-methyfolate, Magnesium threonate, respectively,
• mixing,
• adding the remaining distillate (distilled passiflora 78% by volume),
• adding excipients and mixing,
• mixing for 20 minutes and storing in the flasks.
19. A combination according to Claim 16, characterized in that it is in a solid form selected among tablet and capsule.
20. A production method of a combination according to Claim 19, characterized in that it comprises the process steps of;
• Weighing active substances,
• Weighing excipients,
• Sifting,
• Stirring.
21. A combination according to Claim 1, characterized in that it is in combination with at least one active selected from Hypericaceae, Valerian, Iridaceae families.
22. A combination according to Claim 21, characterized in that it comprises Hypericum perforatum in a ratio between 10%- 42% by weight.
23. A combination according to Claim 21, characterized in that it comprises Valeriana officinalis in a ratio between 13%- 65% by weight.
24. A combination according to Claim 21, characterized in that it comprises Crocus Sativus in a ratio between 15%- 56% by weight.
PCT/TR2020/050081 2019-02-08 2020-02-07 A novel combination containing passiflora, glycine, metylfolate and magnesium threonate and production method thereof WO2020162859A2 (en)

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