Valerian Compositions for Sleep Management

Abstract

The present invention relates to a valerian composition and / or valerian extract for the prevention, improvement, and maintenance of sleep disorders and / or sleep management, and as such, improves sleep quality, improves sleep time, improves sleep duration, reduces sleep disturbances, and maintains healthy stress levels in subjects in need thereof. A valerian composition comprising a valerian extract and at least one pharma- tically and / or nutraceutical acceptable excipient. The present invention further encompasses the valerian composition, which is further formulated in various forms, such as powders, beadlets, granules, capsules, tablets, oil suspensions, films, or any other suitable oral or topical dosage forms, using pharma-tically and / or nutraceutical acceptable excipients.

Description

[Technical field]

[0001] The present invention relates to a valerian composition and / or valerian extract for the prevention and / or improvement of sleep disorders in a subject in need thereof. More specifically, the present invention describes a valerian composition comprising a valerian extract and at least one pharma- ceutically and / or nutraceutically acceptable excipient. The present invention further relates to a composition, the valerian extract comprising valerenic acid, hydroxyvalerenic acid, and acetoxyvalerenic acid for the prevention and / or improvement of sleep-related disorders. The present invention also relates to a process for the extraction and isolation of the valerian extract from the valerian plant. In addition, the present invention relates to a process for the preparation of the valerian composition comprising a valerian extract and at least one pharma- ceutically and / or nutraceutically acceptable excipient. The present invention also discloses a valerian composition formulated into various forms, such as powders, beadlets, granules, capsules, tablets, oil suspensions, films, or any other suitable oral or topical dosage forms, using pharma- ceutically and / or nutraceutically acceptable excipients. [Background technology]

[0002] Insomnia is one of the most common sleep disorders among adults. Numerous surveys conducted in countries around the world have shown that approximately 30%-40% of adults report problems initiating or maintaining sleep. Although the percentage of adults reporting serious problems is small (10%-15%), the prevalence of severe chronic sleep problems increases to 25% in older adults. Insomnia is also more common in patients with chronic medical problems, being present in up to 69% of patients enrolled in primary care clinics.

[0003] Approximately 40% of adults with insomnia use either over-the-counter drugs or alcohol to help induce sleep, and approximately 25% have used prescription drugs at least once. There is limited evidence supporting the effectiveness of many commonly used medications for insomnia, including antihistamines, chloral hydrate, barbiturates, tryptophan, and melatonin. Benzodiazepines are known to be effective for insomnia, but the clinical benefits are small (<1 hour sleep extension) and similar to those seen with exercise therapy alone. Furthermore, chronic benzodiazepine therapy for sleep is associated with several negative side effects, including cognitive impairment and increased risk of motor vehicle accidents, falls, and fractures.

[0004] An extract of the root of valerian (Valeriana officinalis), a flowering plant native to temperate regions of America, Europe, and Asia. The active compounds present in valerian include flavonones, alkaloids, and sesquiterpenes. These extracts contain, in unknown proportions, a number of chemicals with CNS activity, including sesquiterpenes, valepotriates, valerenic acid, and various other alkaloids. The ingredients of a particular valerian preparation will also depend on the actual valerian species used and the method of extraction.

[0005] US Patent No. 6,383,526 relates to a process for isolating pharma- ceutical active extracts from plant roots. More specifically, the present invention relates to a process for maximizing the yield of valerenic acid and other valerenic acids and their derivatives, while simultaneously minimizing the yield of valepotriates and valepotriate degradation products or derivatives in the extract of the roots of the plant Valeriana officinalis L.

[0006] US Patent Application Publication No. 2004 / 0241255 relates to pharmaceutical compositions and methods for treating human patients suffering from sleep apnea or hypopnea. Patients who suffer from hypopnea (very shallow breathing) or apnea (near-periodic cessation of breathing) during sleep tend to experience sleep deprivation upon waking, which can result in decreased alertness and increased sleepiness.

[0007] Therefore, there is a need for an effective and convenient solution for sleep-related disorders. Considering the high prevalence, accurate methodological clinical trials of natural sleep aids such as valerian are required. The use of valerian extracts can be an important treatment option since it is a component available in nature, relatively inexpensive and without side effects. In order to successfully industrialize these products, optimization of the extraction, preparation of active and compound-rich products, and standardization should be further investigated. Therefore, it is important to understand the sleep-promoting effects of valerian compositions and / or valerian extracts with the help of appropriate animal models. Summary of the Invention

[0008] Objective of the invention A primary object of the present invention is to provide a valerian composition comprising a valerian extract.

[0009] It is a further object of the present invention to provide a valerian composition and / or valerian extract comprising valerenic acid, hydroxyvalerenic acid, and acetoxyvalerenic acid in effective ratios.

[0010] Another object of the present invention is to provide a valerian composition comprising a valerian extract for intended use in the prevention and / or amelioration of sleep disorders in a subject in need thereof.

[0011] It is a further object of the present invention to provide a valerian composition comprising a valerian extract for improving sleep quality, improving sleep time, improving sleep duration, reducing sleep disturbances, and maintaining healthy stress levels.

[0012] Another object of the present invention is to provide a process for extracting valerian extract components from the valerian plant.

[0013] A further object of the present invention is to provide a process for the preparation of a valerian composition containing one or more pharma- ceutical and / or nutraceutical acceptable excipients.

[0014] It is a further object of the present invention to provide a valerian composition having at least one pharma- ceutical and / or nutraceutical acceptable excipient, the composition being formulated in various forms, e.g., orally administrable solid, semi-solid, liquid forms, selected from, but not limited to, powders, granules, pellets, beadlets, caplets, tablets, capsules, softgel capsules, liquids, emulsions, suspensions, oily suspensions, dispersions, and the like formulations. [Brief description of the drawings]

[0015] [Figure 1] Effects of melatonin and valerian extract (VA) on brain electrical activity. [Diagram 2] Effects of melatonin and valerian extract (VA) on sleep duration (A) and sleep onset latency (B) after pentobarbital administration. [Diagram 3] Effects of melatonin and valerian extract (VA) on serum serotonin, dopamine, and melatonin. [Figure 4] Effects of melatonin and valerian extract (VA) on brain tissue MDA (A), SOD (B), CAT (C), and GPx. [Diagram 5]Effects of melatonin and valerian extract (VA) on brain tissue GABAergic receptors GABAAR2 (A), GABABR1 (B), GABABR2 (C), and serotonergic 5-HT1A (D). [Figure 6] Effects of melatonin and valerian extract (VA) on brain GluA1 (A), GluN2A (B), and GluN1 (C). [Figure 7] Effects of melatonin and valerian extract (VA) on brain Bax (A), Bcl-2 (B), and caspase-3 (C). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Valerian (Valeriana officinalis) is a medicinal plant native to Europe, Asia, and widely introduced into North America. Various parts of the plant, including flowers, fruits, and leaves, are consumed for medical reasons. However, it is the root of valerian that is considered the most psychoactive, and its extracts are used as hypnotics and anxiolytics. The active compounds present in valerian include flavonones, alkaloids, and sesquiterpenes. These extracts contain, in unknown proportions, a number of chemicals with CNS activity, including sesquiterpenes, valepotriates, valerenic acid, and various other alkaloids. Valerenic acid is a monocarboxylic acid that is 2-methylprop-2-enoic acid substituted at the 3-position by a 3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl group. Bicyclic sesquiterpenoids are constituents of the essential oil of the valerian plant.

[0017] The present invention is primarily intended to provide a valerian composition comprising a valerian extract.

[0018] The invention described herein also relates to a valerian composition comprising a valerian extract for use in the prevention and improvement of sleep disorders.

[0019] It is recognized that the term "valerian extract" may be interpreted within the scope to include valerenic acid, either alone or in combination with hydroxyvalerenic acid and / or acetoxyvalerenic acid.

[0020] According to one embodiment, the valerian extract comprises at least 1% w / w of the valerian extract, at least 2% w / w of the valerian extract, at least 3% w / w of the valerian extract, at least 4% w / w of the valerian extract, at least 5% w / w of the valerian extract, at least 6% w / w of the valerian extract, at least 7% w / w of the valerian extract, at least 8% w / w of the valerian extract, at least 9% w / w of the valerian extract, at least 10% w / w of the valerian extract, at least 11% w / w of the valerian extract. In one embodiment, the valerian extract comprises at least 12% w / w of the valerian extract, at least 13% w / w of the valerian extract, at least 14% w / w of the valerian extract, at least 15% w / w of the valerian extract, at least 16% w / w of the valerian extract, at least 17% w / w of the valerian extract, at least 18% w / w of the valerian extract, at least 19% w / w of the valerian extract, or at least 20% w / w of the valerian extract. According to another embodiment, the valerian extract comprises total valerenic acid in an amount within the % w / w amounts set forth in this paragraph.

[0021] According to further embodiments, the valerian extract comprises at least 0.20% w / w of valerian extract, at least 0.25% w / w of valerian extract, at least 0.33% w / w of valerian extract, at least 0.4% w / w of valerian extract, at least 0.45% w / w of valerian extract, at least 0.5% w / w of valerian extract, at least 0.55% w / w of valerian extract, at least 0.6% w / w of valerian extract, at least 0.7% w / w of valerian extract, at least 0.8% w / w of valerian extract, at least 0.9% w / w of valerian extract, at least 0.10% w / w of valerian extract, at least 0.15% w / w of valerian extract, at least 0.16% w / w of valerian extract, at least 0.18% w / w of valerian extract, at least 0.19% w / w of valerian extract, at least 0.20% w / w of valerian extract, at least 0.25% w / w of valerian extract, at least 0.26% w / w of valerian extract, at least 0.27% w / w of valerian extract, at least 0.28% w / w of valerian extract, at least 0.29% w / w of valerian extract, at least 0.30% w / w of valerian extract, at least 0.31% w / w of valerian extract, at least 0.32% w / w of valerian extract, at least 0.33% w / w of valerian extract, at least 0.34% w / w of valerian extract, at least 0.35% w / w of valerian extract, at 65% w / w of hydroxyvalerenic acid, at least 0.7% w / w of the valerian extract, at least 0.8% w / w of the valerian extract, at least 0.9% w / w of the valerian extract, at least 1.0% w / w of the valerian extract, at least 1.2% w / w of the valerian extract, at least 1.4% w / w of the valerian extract, at least 1.6% w / w of the valerian extract, at least 1.8% w / w of the valerian extract, or at least 2% w / w of the valerian extract. According to another embodiment, the hydroxyvalerenic acid is present in an amount within the % w / w amounts set forth in this paragraph.

[0022] According to further embodiments, the valerian extract comprises at least 0.5% w / w of the valerian extract, at least 1.0% w / w of the valerian extract, at least 1.5% w / w of the valerian extract, at least 1.59% w / w of the valerian extract, at least 1.75% w / w of the valerian extract, at least 2.0% w / w of the valerian extract, at least 2.5% w / w of the valerian extract, at least 3.0% w / w of the valerian extract, at least 3.21% w / w of the valerian extract, at least 3.5% w / w of the valerian extract, at least 4.0% w / w of the valerian extract, at least 4.5% w / w of the valerian extract, or at least 5.0% w / w of the valerian extract. According to another embodiment, the acetoxyvalerenic acid is present in an amount within the range of % w / w amounts described in this paragraph.

[0023] According to another embodiment, the valerian extract comprises valerenic acid in an amount of 2% w / w of the valerian extract, 3% w / w of the valerian extract, 4% w / w of the valerian extract, 5% w / w of the valerian extract, 6% w / w of the valerian extract, 7% w / w of the valerian extract, 8% w / w of the valerian extract, 9% w / w of the valerian extract, 10% w / w of the valerian extract, 11% w / w of the valerian extract, 12% w / w of the valerian extract, 13% w / w of the valerian extract, 14% w / w of the valerian extract, or 15% w / w of the valerian extract.

[0024] According to yet another embodiment, valerenic acid is included in an amount within the % w / w amounts described in this paragraph.

[0025] According to an embodiment of the present invention, the "valerian composition" of the present invention is composed of a valerian extract as defined above and one or more pharma- ceutically and / or nutraceutical acceptable excipients.

[0026] In some embodiments of the present invention, a process is provided for preparing the valerian extract of the present invention from plant parts of "Valeriana officinalis," the process comprising: a) obtaining plant material from one or more parts of a valerian plant; b) obtaining an extract from the plant material by soaking in a suitable aqueous or organic solvent, or a combination thereof, for a suitable period of time; c) agitating the soaked plant material for a predetermined period of time; d) Adding a suitable aqueous or organic solvent, or a combination thereof, allowing to settle at room temperature and filtering / decanting to remove the extractable materials. Includes.

[0027] According to a further embodiment, the suitable aqueous solvent may be selected from water and the organic solvent may be selected from methanol, ethanol, propanol, acetone, ethyl acetate, chloroform, either alone or in combination.

[0028] More preferably, the valerian composition is formulated using excipients selected from, but not limited to, the group of solvents, anti-caking agents, carriers / diluents, bioavailability enhancers, solubilizers, disintegrants, emulsifiers, binders, fillers, pH adjusters and coating agents or combinations thereof.

[0029] According to further embodiments, the compositions described herein may be available in orally administrable solid, semi-solid, liquid forms selected from, but not limited to, formulations such as powders, granules, pellets, beadlets, caplets, tablets, capsules, softgel capsules, liquids, emulsions, suspensions, oil suspensions, dispersions, and the like.

[0030] The valerian compositions described herein are comprised of valerian extract and at least one excipient, such as a pharma- ceutically and / or nutraceutical acceptable excipient, and may be formulated as granules, powders, and / or beadlets.

[0031] In some embodiments, the process for preparing a valerian composition in powder form comprises: (i) adding a suitable solvent and valerian extract into a container under stirring to obtain a homogenous dispersion; (ii) adding a suitable solvent and carrier under stirring to obtain a clear solution in a separate vessel; (iii) adding the dispersion obtained in step (i) under stirring into the solution of step (ii) under stirring for the required period of time; (iv) spraying and drying the dispersion obtained from step (iii); and (v) adding an anti-caking agent to the dry powder obtained in step (iv) to obtain a valerian composition in powder form. Includes.

[0032] In another embodiment, suitable solvents used in the preparation of the valerian composition are selected from the group including, but not limited to, water, methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, methylene dichloride, and / or combinations thereof.

[0033] In another embodiment, the carrier used in the preparation of the valerian composition is selected from the group including, but not limited to, hydroxypropylmethylcellulose and cellulose derivatives, microcrystalline cellulose, polyacrylates, polyethylene glycol, povidone, starch and starch derivatives, chitosan, gums, polyvinyl alcohol, dextran, polylactic-co-glycolic acid, polyethylene glycol, maltodextrin, and / or combinations thereof.

[0034] In another embodiment, the anti-caking agent in the preparation of the valerian composition is selected from, but is not limited to, silicon dioxide, dicalcium phosphate, talc, magnesium stearate, stearic acid, mannitol, and / or combinations thereof.

[0035] In some embodiments, the process for the preparation of a valerian composition in the form of a beadlet comprises: (i) adding a suitable solvent, bioenhancer and valerian extract in a clean container under stirring to obtain a homogenous dispersion; (ii) adding a suitable solvent and binder in a separate clean container under stirring to obtain a homogenous solution; (iii) adding the solution resulting from step (ii) to step (i) under stirring to form a homogenous dispersion; (iv) The carrier / diluent and anti-caking agent were accurately weighed and loaded into a RMG (rapid mixer granulator) vessel and dry mixed at appropriate impeller speed to form a homogenous blend; (v) The dispersion prepared in step (iii) was gradually added to the dry blend in RMG to obtain wet mass / wet granules. (vi) The wet mass was then passed through an extruder to obtain an extrudate. (vii) The extrudate was loaded onto a pitch spheronizer plate to obtain spherical beadlets / pellets. (viii) The spherical beadlets were loaded into a tray dryer for drying to obtain the desired %LOD. (ix) The dried beadlets were sieved to obtain the desired particle size distribution. Includes.

[0036] In another embodiment, the bioavailability enhancer used in the preparation of the valerian composition is selected from the group including, but not limited to, d-limonene, monoglycerides, and phospholipids such as lecithin / phosphatidylcholine, vegetable oils and plant extracts, combinations thereof, etc.

[0037] In another embodiment, the solubilizer in the preparation of the valerian composition is selected from the group including, but not limited to, MCT oil, polysorbate, propylene glycol, alginic acid, sugar alcohol, sugar ester, phospholipid, Vitamin E TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), beta cyclodextrin, and / or combinations thereof.

[0038] In another embodiment, the disintegrant in the preparation of the valerian composition is selected from the group including, but not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, magnesium aluminum silicate, and / or combinations thereof.

[0039] In another embodiment, the emulsifier in the preparation of the valerian composition is selected from the group including, but not limited to, steric acid, phosphatidylcholine, polysorbate, sugar alcohols, glycerol & derivatives and / or combinations thereof.

[0040] In another embodiment, the binder in the preparation of the valerian composition is selected from the group including, but not limited to, hydroxypropyl cellulose, gum, xanthan gum, pregelatinized starch, and / or combinations thereof.

[0041] In another embodiment, the filler in the preparation of the valerian composition is selected from the group including, but not limited to, microcrystalline cellulose, corn starch, lactose, maltose, and / or combinations thereof.

[0042] In another embodiment, the pH adjusting agent in the preparation of the valerian composition is selected from the group including, but not limited to, sodium bicarbonate, citric acid, trisodium citrate, lactic acid, L-arginine, calcium carbonate, magnesium carbonate, and / or combinations thereof.

[0043] In another embodiment, the coating agent in the preparation of the valerian composition is selected from the group including, but not limited to, stearic acid, glycerol distearate, shellac, zein, acrylate polymers, cellulose polymers, and / or combinations thereof.

[0044] Preparation of powder formulations Example 1:

[0045] [Table 1] *Valerenic acid in the amount of 5.55% w / w of the valerian extract, hydroxyvalerenic acid in the amount of 0.64% w / w of the valerian extract, and acetoxyvalerenic acid in the amount of 2.96% w / w of the valerian extract.

[0046] Valerian extract (0.262 kg) was weighed and added to water under stirring to prepare a homogenous dispersion. Hydroxypropyl methylcellulose (0.733 kg) was added to purified water in a separate container under stirring to prepare a homogenous solution. Hydroxypropyl methylcellulose solution was added into the valerian extract dispersion under stirring for the required period of time. In the next step, the dispersion was spray dried to obtain a free-flowing powder. Anti-caking agent (0.005 kg) was added to the spray dried powder.

[0047] Example 2:

[0048] [Table 2] *Valerenic acid in the amount of 5.55% w / w of the valerian extract, hydroxyvalerenic acid in the amount of 0.64% w / w of the valerian extract, and acetoxyvalerenic acid in the amount of 2.96% w / w of the valerian extract.

[0049] The process for the preparation of the valerian composition is defined step by step as follows:

[0050] Hydroxypropyl methylcellulose (0.733 kg) and valerian extract (0.262 kg) were accurately weighed and added to purified water under stirring to prepare a homogenous dispersion. The dispersion was spray dried to obtain a free-flowing powder. Anticaking agent (0.005 kg) was added to the spray dried powder.

[0051] Preparation of beadlet formulations Example 3:

[0052] [Table 3] *Valerenic acid in the amount of 5.73% w / w of the valerian extract, hydroxyvalerenic acid in the amount of 0.44% w / w of the valerian extract, and acetoxyvalerenic acid in the amount of 2.8% w / w of the valerian extract.

[0053] The process for the preparation of a step-by-step valerian composition is as follows: Phosphatidylcholine (0.010 Kg), and valerian extract (0.268 Kg) were weighed and added to purified water under stirring to prepare a homogenous dispersion. Hydroxypropyl methylcellulose (0.020 Kg) was weighed and added to purified water in a separate vessel under stirring to prepare a solution. The resulting hydroxypropyl methylcellulose solution was added to the valerian extract dispersion to form a homogenous dispersion. Microcrystalline cellulose (0.727 Kg) and colloidal silicon dioxide (0.010 Kg) were accurately weighed and loaded into the RMG vessel and dry mixed at appropriate impeller speed to form a homogenous blend. The resulting valerian extract dispersion was gradually added to the dry blend in the RMG to obtain wet mass / wet granules. The wet mass was then passed through an extruder to obtain the extrudate. The extrudate was loaded into a pitch spheronizer plate to obtain spherical beadlets / pellets. The spherical beadlets were loaded into a tray dryer for drying. The dried beadlets were sieved to obtain the desired particle size distribution.

[0054] Example 4:

[0055] [Table 4] *Valerenic acid in the amount of 5.73% w / w of the valerian extract, hydroxyvalerenic acid in the amount of 0.44% w / w of the valerian extract, and acetoxyvalerenic acid in the amount of 2.8% w / w of the valerian extract.

[0056] Phosphatidylcholine (0.010 Kg), and valerian extract (0.268 Kg) were weighed and added to purified water under stirring to prepare a homogenous dispersion. Xanthan gum (0.010 Kg) was weighed and added to purified water in a separate vessel under stirring to prepare a solution. The resulting xanthan gum solution was added into the valerian extract dispersion to form a homogenous dispersion. Microcrystalline cellulose (0.727 Kg) and colloidal silicon dioxide (0.010 Kg) were accurately weighed and loaded into the RMG vessel and dry mixed at appropriate impeller speed to form a homogenous blend. The resulting valerian extract dispersion was gradually added to the dry blend in the RMG to obtain wet mass / wet granules. The wet mass was then passed through an extruder to obtain the extrudate. The extrudate was loaded into a pitch spheronizer plate to obtain spherical beadlets / pellets. The spherical beadlets were loaded into a tray dryer for drying. The dried beadlets were sieved to obtain the desired particle size distribution.

[0057] According to a further embodiment of the present invention, there is provided a valerian composition comprising a valerian extract for improving and maintaining sleep quality, improving sleep time, improving sleep duration, reducing sleep disturbances, and maintaining healthy stress levels.

[0058] The present study was proposed to evaluate the efficacy and use of a valerian composition consisting of a valerian extract as defined in the present invention for the prevention and treatment of sleep disorders.

[0059] Research Objective The primary objective of the study was to investigate the effects of a valerian composition consisting of valerian extract compared to melatonin on sleep and related behaviors in a rodent model.

[0060] material and method Experimental animals: A study was designed to investigate the effects of valerian extract and melatonin on sleep and related behaviors in a rodent model. Five male BALB / c mice (age: 8 weeks, weight: 20±3 g) in each treatment group were housed in a controlled environment with a 12:12 h light / dark cycle at 22°C and provided with mouse chow and water ad libitum. All experiments were performed under the National Institutes of Health guidelines for the care and use of laboratory animals and with the approval of the ethics committee.

[0061] The animals were further randomly assigned to 5 groups defined as follows: Group 1 (Control) - Animals in this group were treated with saline only. Group 2 (C) - Animals in this group received caffeine (7.5 mg / kg) followed by saline. Group 3 (CM) - animals in this group received melatonin (2 mg / kg) followed by caffeine (CM) Group 4 (CVA1) - Animals in this group received caffeine followed by a valerian composition (100 mg / kg) consisting of valerian extract. Group 5 (CVAII) - Animals in this group received caffeine followed by a valerian composition (300 mg / kg) consisting of valerian extract.

[0062] Groups for sleep parameters (sleep duration and sleep onset latency) 1) Control: Saline followed by saline 2) P: Pentobarbital followed by saline 3) PM: Pentobarbital followed by melatonin at a dose of 2 mg / kg. 4) PVA I: A valerian composition consisting of pentobarbital followed by a dose of 100 mg / kg of valerian extract. 5) PVA II: A valerian composition consisting of valerian extract at a dose of 300 mg / kg, followed by pentobarbital.

[0063] Experimental Design & Methodology: Treatment I: According to the experimental design and methodology, the groups were dichotomized into two groups of treatments: Treatment I and Treatment II: 1) Monitor the effects of caffeine and valerian compositions on brain activity 2) Monitor the effects of valerian compositions on sleep parameters

[0064] To monitor the effects of the caffeine and valerian compositions on brain activity, EEG recordings were performed. Mice were stabilized under a stereotaxic frame, and an incision was made in the skin along the anterior-posterior line of the skull. The left cortex was gently removed with a dental drill. Two Ag-AgCl spherical electrodes were placed on the left hemisphere, with a reference electrode attached above the pinna.

[0065] Working solutions of caffeine, melatonin and valerian were prepared daily and administered intraperitoneally (ip). Based on previous studies, caffeine-induced insomnia was dose-dependent, with 7.5 mg / kg ip caffeine maintaining wakefulness for at least 2 hours. Brain electrical activity was monitored for 90 min after caffeine injection, and spike frequency / spike amplitude analysis was performed with Labchart 7.3.3 program. 90 min after caffeine injection, animals were deeply anesthetized with 4% isoflurane (30% O2, balance N2O). Brains were rapidly removed, frozen on dry ice and stored at -80°C for further analysis.

[0066] A. Biochemical and oxidative stress markers Serum melatonin, serotonin, and dopamine were measured by ELISA kits. MDA brain levels were measured by HPLC. Brain activities of SOD, CAT, and GPHz were measured using ELISA kits.

[0067] B. Protein Analysis Protein concentrations were determined using Western blot analysis. 50 μg of protein was electrophoresed on a 4-15% Tris-glycine polyacrylamide gel, transferred to an Immobilon-P PVDF membrane, blocked in 5% skim milk for 1 h, and incubated overnight at 4°C with GABA. A R2, GABA B R1, GABA B The membranes were incubated with either -R2, 5HT1A, GluA1, GluN1, GluN2 A, Bcl-2, Bax, or Caspase-3. The membranes were then incubated with horseradish peroxidase (HRP)-conjugated IgG secondary antibodies. Bands were quantified using Image software and normalized to actin as a loading control.

[0068] Procedure II The group was administered the valerian composition, and 45 minutes later, pentobarbital (hypnotic dose, 42 mg / kg) was injected into the left flank. After injection, the mice were placed in individual cages and subjected to measurement of sleep onset latency and duration. Sleep onset latency was defined as the period between pentobarbital injection and sleep onset, and sleep duration indicated the time elapsed between loss of righting reflex and recovery. Mice that did not fall asleep within 10 minutes after pentobarbital injection were excluded from the experiment.

[0069] Data Analysis Method Data are presented as mean±SEM. Sample size was calculated based on a power of 85% and a p-value of 0.05. Given that assumption, a sample size of 5 per treatment was calculated and data was analyzed using the GLM procedure of SAS (SAS Institute: SAS User's Guide: Statistics). Treatments were compared using ANOVA and Student's unpaired t-test; P<0.05 was considered statistically significant.

[0070] Results and conclusions: 1) Effects of melatonin and valerian extract (VA) on brain electrical activity. Analysis of spike frequency and amplitude based on ECoG recordings.

[0071] [Table 5] Figure 1. Values ​​are expressed as mean ± SEM for each group, n=5. A) Spike amplitude (%) and B) spike frequency (%).

[0072] Conclusion: ECoG recordings were first analyzed to assess electrical electroencephalograms, spike frequency and spike amplitude. The caffeine (C) group had the highest spike frequency but the lowest amplitude throughout the entire recording.

[0073] Spike amplitude (%) was higher at all time points for the 300 mg / kg (CVA2) group when compared to all groups. In addition, the 100 mg / kg (CVA1) also showed the highest amplitudes at the 15-30 min, 30-45 min, 45-60 min, and 60-75 min intervals compared to the C group. CVA2 performed better than the CM group at all time points.

[0074] The spike frequency was recorded lower in both the 100 mg / kg (CVA1) and 300 mg / kg (CVA2) groups compared to group C. Furthermore, both CVA1 and CVA2 performed almost similarly to the CM group.

[0075] 2) Effects of melatonin and valerian extract (VA) on sleep duration (A) and sleep onset latency (B) after pentobarbital administration

[0076] [Table 6] Figure 2. Each bar represents the mean and standard error of the mean. Tukey's post-hoc test was used to compare the results between the different treatment groups, and statistical significance between groups is indicated by: ### P < 0.001; #### P<0.0001 compared with the P group. + P<0.05 compared with the PM group. &&& P < 0.001; &&&&P<0.0001 compared with the PVA I group.

[0077] Conclusion: Both PVA1 and PVA2 groups showed a significant increase in sleep duration and a significant decrease in sleep onset latency compared to the P group. PVA2 was significantly better than PVA1 for both sleep duration and sleep onset latency measures. Furthermore, no statistical differences were observed between the PM and PVA1 groups and the PM and PVA2 groups. It can be concluded that both PVA1 and PVA2 have beneficial effects on sleep.

[0078] 3) Effects of melatonin and valerian extract (VA) on serum serotonin, dopamine, and melatonin

[0079] [Table 7] Figure 3. ANOVA and Tukey's post-hoc test were used to compare the results between the different treatment groups, and statistical significance between groups is indicated by: ** P < 0.01; *** P < 0.001; **** P<0.0001 compared with the control group. ### P < 0.001; #### P<0.0001 compared with group C. ++++ P<0.0001 compared with the CM group.

[0080] Conclusion: The CVA1, CVA2 and CM groups showed a significant increase in serum serotonin and dopamine levels compared with group C. No significant differences were found between the CM-CVA1 or CM-CVA2 groups for serum serotonin and dopamine levels.

[0081] Furthermore, the CM group reported significantly higher melatonin levels in serum compared to all other groups. Furthermore, both the CVA1 and CVA2 groups showed no significant differences compared to the C group.

[0082] 4) Effects of melatonin and valerian extract (VA) on brain tissue MDA (A), SOD (B), CAT (C), and GPx.

[0083] [Table 8] Figure 4. ANOVA and Tukey's post-hoc test were used to compare the results between the different treatment groups, and statistical significance between groups is indicated by: *** P < 0.001; **** P<0.0001 compared with the control group. ## P < 0.01; ### P < 0.001; #### P<0.0001 compared with group C. ++ P < 0.01 compared with the CM group. & P<0.05 compared with CVA I group.

[0084] Conclusion: CVA1, CVA2 and CM groups showed significant increases in antioxidant enzymes such as SOD, CAT and GPx compared to group C. No significant differences were found between CM-CVA1 or CM-CVA2 groups for SOD, CAT and GPx.

[0085] Furthermore, the CVA1, CVA2 and CM groups recorded a significant decrease in MDA levels compared to the C group. Furthermore, CVA2 performed significantly better than the CM and CVA1 groups. CVA1 showed no significant difference compared to the CM group. It can be concluded that both CVA1 and CVA2 reduced oxidative stress.

[0086] 5) GABAergic receptors in brain tissue A R2(A), GABA B R1(B), GABA B R2 (C), and the effects of melatonin and valerian extract (VA) on serotonergic 5-HT1A (D).

[0087] [Table 9] Figure 5. ANOVA and Tukey's post-hoc test were used to compare the results between the different treatment groups, and statistical significance between groups is indicated by: **** P<0.0001 compared with the control group. # P < 0.05; ## P < 0.01; ### P < 0.001; #### P<0.0001 compared with group C. + P < 0.05; +++ P < 0.001; ++++ P<0.0001 compared with the CM group. && P < 0.01; &&&& P<0.0001 compared with CVA I group.

[0088] Conclusion: The CVA1, CVA2 and CM groups showed significantly higher GABA A R2, GABA B R1 and GABA B Furthermore, CVA2 showed a significant increase in R2. A R2 and GABAB R2 showed significantly better results than CVA1. A R2 was significantly lower in the CVA1 group compared to the CM group. B Both R1 and GABAB R2 were significantly increased in the CVA2 group compared with the CM group.

[0089] 5-HT1A levels were significantly increased in the CM and CVA2 groups compared to the C group. CVA2 showed significantly higher levels of 5-HT1A than CVA1. CVA2 performed significantly better than the CM group, while the CVA1 group had significantly lower 5-HT1A expression than the CM group.

[0090] It can be concluded that valerian extract increased the caffeine-induced decreased levels of inhibitory receptors.

[0091] 6) Effects of melatonin and valerian extract (VA) on brain GluA1 (A), GluN2A (B), and GluN1 (C).

[0092] [Table 10] Figure 6. ANOVA and Tukey's post-hoc test were used to compare the results between the different treatment groups, and statistical significance between groups is indicated by: ** P < 0.01; **** P<0.0001 compared with the control group. #### P<0.0001 compared with group C. + P < 0.05 compared with the CM group. &&&& P<0.0001 compared with CVA I group.

[0093] Conclusion: The CVA1, CVA2 and CM groups showed significant increases in GluA1 and GluN1 receptors compared to group C. Furthermore, only the CVA2 and CM groups showed significant increases in GluN2A receptors compared to group C.

[0094] No significant differences were found between the CM, CVA1 and CVA2 groups for the expression of GluA1 and GluN1 receptors.

[0095] The expression of GluN2A receptors was significantly lower in the CVA1 group compared to the CM group, while CVA2 showed significantly higher levels of GluN2A receptors compared to CVA1.

[0096] It can be concluded that both valerian extract and melatonin increase glutamate receptors after caffeine-induced depletion.

[0097] 7) Effects of melatonin and valerian extract (VA) on brain Bax (A), Bcl-2 (B), and caspase-3 (C).

[0098] [Table 11] Figure 7. ANOVA and Tukey's post-hoc test were used to compare the results between the different treatment groups, and statistical significance between groups is indicated by: **** P<0.0001 compared with the control group. ### P < 0.001; #### P<0.0001 compared with group C. + P < 0.05; ++++ P<0.0001 compared with the CM group. &&&& P<0.0001 compared with CVA I group.

[0099] Conclusion: Compared with group C, groups CVA1, CVA2 and CM showed significant increases in Bax and caspase-3, and significant decreases in Bcl-2.

[0100] CVA1 showed significantly lower levels of Bax expression compared to the CM group, whereas no significant difference was found between the CVA2 and CM groups. Furthermore, CVA2 showed significantly higher levels of Bax expression compared to CVA1.

[0101] CVA2 showed significantly higher levels of caspase-3 expression compared with both the CVA1 and CM groups, while no significant differences were found between the CVA1 and CM groups.

[0102] CVA2 showed significantly lower levels of Bcl-2 expression compared with both CVA1 and CM groups, while no significant difference was found between CVA1 and CM groups, leading us to conclude that CVA2 showed higher neuroprotective activity than all other groups.

[0103] Abbreviation: ELISA: Enzyme-linked immunosorbent assay MDA: Malondialdehyde SOD: Superoxide dismutase CAT: Catalase GPHx: glutathione peroxidase GABA A R2: gamma-aminobutyric acid type A receptor subunit 2 GABA B R1: gamma-aminobutyric acid type B receptor subunit 1 GABA B -R2: gamma-aminobutyric acid type B receptor subunit 2 5HT1A: serotonin 1A receptor GluA1: glutamate receptor 1 GluN1: glutamate [NMDA] receptor subunit zeta-1 GluN2 A: glutamate [NMDA] receptor subunit zeta-1 Bcl-2: B-cell lymphoma 2 Bax: a regulator of apoptosis Caspase-3: Cysteine-dependent aspartate-directed protease-3

Claims

1. A composition comprising an extract of valerian officinalis L, wherein valerenic acid is in the range of 5% w / w to 20% w / w of said extract.

2. i) valerian extract in an amount ranging from 20% to 26% w / w of said composition; ii) at least one hydrophilic carrier or diluent in an amount ranging from 30% to 73% w / w of said composition; and iii) an anti-caking agent in an amount ranging from 0.01% to 1% w / w of the composition; A composition comprising:

3. 10. The composition of claim 1, further comprising a pharma- ceutically or nutraceutically acceptable excipient selected from the group consisting of hydrophilic carriers, diluents, anti-caking agents, solvents and mixtures thereof.

4. 4. The composition of claim 3, wherein the hydrophilic carrier or diluent is selected from the group consisting of hydroxypropyl methylcellulose and cellulose derivatives, microcrystalline cellulose, polyacrylates, polyethylene glycol, povidone, starch and starch derivatives, chitosan, gums, polyvinyl alcohol, dextran, polylactic-co-glycolic acid, polyethylene glycol, maltodextrin and / or combinations thereof.

5. 4. The composition of claim 3, wherein the anti-caking agent is selected from the group consisting of silicon dioxide, dicalcium phosphate, magnesium stearate, stearic acid, mannitol, and combinations thereof.

6. 4. The composition of claim 3, wherein the solvent used is selected from water, methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, methylene dichloride, and / or combinations thereof.

7. i) valerian extract in an amount ranging from 26.2% w / w of said composition; ii) hydroxypropyl methylcellulose in an amount of 73.2% w / w of the composition; iii) colloidal silicon dioxide (aerosol) in an amount of 0.5% w / w of the composition The composition of claim 1 comprising:

8. 2. A method for treating a subject in need thereof comprising administering to a subject the composition of claim 1. A method for preventing and / or ameliorating sleep disorders.

9. 11. A method for improving sleep quality, improving sleep time, improving sleep duration, reducing sleep disturbances, and maintaining healthy stress levels in a subject, comprising administering to a subject in need thereof the composition of claim 1.

10. The method of claim 9 , wherein the subject is a human and / or an animal.

11. The composition of claim 1, in a dosage form comprising 50 mg / kg to 400 mg / kg of the subject's body weight.

12. 13. A process for the preparation of the composition of claim 1, comprising: a) preparing a dispersion of a valerian extract in a suitable solvent; b) preparing a solution of the carrier or diluent in a suitable solvent; c) adding the dispersion obtained in step a to the solution of step b followed by stirring to obtain a homogenous dispersion; d) spray drying the dispersion obtained in step c) to obtain a free-flowing powder; e) adding an anti-caking agent to the powder resulting from step d to produce the composition of claim 1. The process includes:

13. 1. A valerian officinalis L. composition comprising a valerian extract, the valerian extract comprising: (i) valerenic acid in an amount ranging from 1% w / w to 20% w / w of said valerian extract; (ii) hydroxyvalerenic acid in an amount ranging from 0% w / w to 5% w / w of said valerian extract, and (iii) acetoxyvalerenic acid in an amount ranging from 0% w / w to 10% w / w of the valerian extract. A composition comprising:

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