WO2001007063A1 - Process for the extraction of valerian root - Google Patents
Process for the extraction of valerian root Download PDFInfo
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- WO2001007063A1 WO2001007063A1 PCT/US2000/020031 US0020031W WO0107063A1 WO 2001007063 A1 WO2001007063 A1 WO 2001007063A1 US 0020031 W US0020031 W US 0020031W WO 0107063 A1 WO0107063 A1 WO 0107063A1
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- 0 *[C@@](C([C@@]12OC1)[C@]1(*)C[C@@]2O)OC=C1NN=O Chemical compound *[C@@](C([C@@]12OC1)[C@]1(*)C[C@@]2O)OC=C1NN=O 0.000 description 1
Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
Definitions
- the present invention relates to a process for isolating a pharmaceutically-active extract from a plant root, and more generally, to a novel method for preparing a medicament containing this extract. More specifically, the present invention relates to a process for maximizing the yield of valeremc acid and other valeremc acids and their derivatives, while simultaneously minimizing the yield of valepotnates and valepotnates decomposition products or derivatives in an extract of the root of the plant Valeriana offtcinalis L Description of the Related Art Extracts of the root of the plant Valeriana officmalis L [V offtcinalis L.) have been used for medicinal purposes for over a century.
- valerian extracts including aqueous extracts
- aqueous extracts are known to have sedative and anxiolytic effects, but the active components have not been clearly and positively identified.
- Aqueous extract of valerian root [Valeriana officmalis L) improves sleep quality in man Pharmacology, Biochemistry and Behavior, 17:65 71, 1982; Leathwood P.D. and Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man Planta Medica, 2:144-148 (1985)]
- Such effects are described by Balandn ⁇ et al. in U.S.
- valerian extracts are available as dietary supplements; these dietary supplements primarily comprise dried root or extracts from the root, formulated into tablets or soft gelatin capsules. Each dose contains between approximately 50 g and approximately 1 gram of dried root or extract.
- the use of these dietary supplements is extensive, with an estimated 210 million doses sold annually in the United States and 125 million doses sold annually in Europe. See Grunwald, J., "The European Phytomedicmes Market - Figures, Trends Analyses" Herbal Gram, 1995.
- V. officmalis L. is a member of the Vale ⁇ anaceae family This plant grows from a short rhizome to approximately 2 meters in height, it flowers, and then dies back again in the winter Valeriana officmalis L. has pinnately-divided leaves, typically with six to ten pairs of lance shaped leaflets, and bears many small white or pink flowers in a dense head of several stalked clusters These heads bare small (5 millimeters) tapered seeds
- valepotnates indoids
- valeremc acid for example, acetoxyvaleremc acid and hydroxyvaleremc acid
- the valepotnates and valeremc acids are generally considered to contribute to the sedative action of valerian extracts, but have not been clearly and positively identified as such See Hend ks H et al "Pharmacological Screening of valerenal and some other components of essential oil of Valeriana officmalis" Planta Medica 42, 62 68 (1981 ); Bos R.
- Valepotnates are t ⁇ esters of polyalcohols with an indoid structure. They are unstable, thermoiabile compounds that decompose in alcoholic solutions and under acidic or alkaline conditions. See Bos R. et al. Analytical aspects of Phytotherapeutic Valerian preparation, 1996, 7.143 151.
- valepotnates The major decomposition products of diene type valepotnates are baldrmals, including bald ⁇ nal (from the valepotnates valtrate and acevaltrate) and homobaldnnal (from the valepotnate isovaltrate).
- valeremc acid and its derivatives for example, acetoxyvalerenic acid and hydroxyvalerenic acid
- valepotnates and valepotnate decomposition products or derivatives are found in many species of Valenananceae, Valeriana offtcinalis L. is the only species that has been identified as possessing extractable valeremc acid in its roots.
- the structures of valeremc acids and certain valepotnates and valepotnate decomposition products are presented below.
- Valeremc acid is a chemically stable compound that is used as an identification test for V. officmalis in the United States Pharmacopoeia (USP23 NF18, Supplement 8).
- USP23 NF18, Supplement 8 United States Pharmacopoeia
- Valeremc acid is a chemically stable compound that is used as an identification test for V. officmalis in the United States Pharmacopoeia (USP23 NF18, Supplement 8).
- USP23 NF18, Supplement 8 United States Pharmacopoeia
- a process for preparing a pharmaceutically active extract of the root of a plant of the family Valenanacae, specifically, Valeriana officinalis L. comprises the steps of adding the roots to an alcoholic extraction solvent to form a mixture, wherein the alcoholic extraction solvent comprises between approximately 50% to approximately 100% (v/v) ethanol in a remainder of water, and heating the mixture to a temperature of between approximately 70°C to approximately 80°C for a period of at least two hours.
- the extract contains valeremc acids and has a content of valepotnates and valepotnate degradation products that is substantially reduced with respect to the content of valepotnates in the roots, and may have a content of valeremc acids that is not substantially reduced with respect to the content of valeremc acids in the roots, and also may have a content of volatile oils that is not substantially reduced with respect to the content of volatile oils in the roots.
- the process may be performed at pH greater than about 3 0, greater than about 5.0, or greater than about 7.0.
- a pharmaceutically-active extract of the roots of a plant of the family Valerianaceae is also described.
- This extract is obtained by a process comprising the steps of adding the roots to an alcoholic extraction solvent to form a mixture, wherein the alcoholic extraction solvent comprises between approximately 50% (v/v) to approximately 100% (v/v) ethanol in a remainder of water, and heating the mixture to a temperature of between approximately 70°C to approximately 80°C for a period of at least two hours.
- This extract may then be used in a pharmaceutically active formulation preferably exhibiting sedative and/or muscle relaxant, and/or anxiolytic activity.
- One objective of the present invention is to provide a process by which valerenic acid and its derivatives (e.g., acetoxyvalerenic acid and hydroxyvalerenic acid) are isolated in an extract of the roots of plants of the Valerianaceae family. More specifically, plants of the species Valeriana officinalis L. are used.
- Another, objective of the present invention is to provide a process by which valepotnates (iridoids) are substantially reduced in an extract with respect to their content in the roots, and preferably are not purified and/or isolated in an extract of the above- described roots.
- Another objective of the present invention is to provide a relatively inexpensive process that can be performed at commercial scale for the production of an extract having valerenic acids specifically, and valerenic acid and its derivatives (for example, acetoxyvalerenic acid and hydroxyvalerenic acid) generally, from the above-described roots.
- Another object of the present invention is to provide an extract process through which the extracted roots may be chemically identified as the roots of Valeriana officinalis L.
- Yet another object of the present invention is to provide a process for preparing a medicament containing an extract of the above-described roots.
- the extract process of the present invention significantly reduces the amount of valepotnates in the extract and the amount of valerenic acid and/or valerenic acids is unaltered in the extract when compared to known processes.
- At least one of these objectives is met, at least in part, through an extraction process.
- methods for processing the root prior to extraction for forming a drug substance via the addition of excipient, for drying and milling the drug substance, and for formulating an ingestible entity, such as a tablet, capsule, tea, suspension, or other medicinal food, are described. These methods provide a medicament of the present invention, which contains the extract of the present invention.
- R and R' are defined as follows
- CNS central nervous system
- Valerenic acids are components of V officmalis extracts, and of extracts of other members of the family Valerianaceae, that are likely responsible for the sedative activity of valerian.
- the valerenic acids (for example, valeremc acid, acetoxyvalerenic acid and hydroxyvalerenic acid) of V officmalis may exert sedative properties.
- valerenic acid administered intrapentoneally (IP) at a dose of 100 mg/kg caused a decrease in motor activity, a decrease in respiratory rate, absence of righting reflex, ataxia, a decrease of abdominal muscle tone and a decrease in rotarod performance in mice See Hend ⁇ ck H, Bos R, Allersma D, Ma ngre T, and Koster A. Pharmacological Screening of Valerenal and some other Components of Essential Oil of Valeriana officmalis Planta
- valerenic acid influenced performance on both the rotarod and traction tests with statistical significance obtained at 100 mg/kg
- IP Valerenic acid was also shown to potentiate pentobarbital induced sleeping time at doses of 50 and 100 mg/kg, IP. See Hend cks H, Bos R, Woerdenbag H and Koster A, Central Nervous Depressant Activity of Valerenic Acid in the Mouse. Planta Medica 1985, 51 28 31 The anti convulsant properties of valeremc acid have been characterized, see Hilier K.
- One aspect of the current method is useful in verifying that the particular roots to be extracted are roots of the species V. officmalis L. and not of another plant, or more specifically of another member of the Valerianaceae family. And because many of the plants in this family are phenotypically similar and are therefore capable of being substituted for one another, a preferable means to identify V officmalis L is to identify valerenic acid directly in the extract.
- the present extraction method is therefore preferable to, and provides benefits not obtainable through the use of known water based extraction methods
- the present process allows for the extraction of a pharmaceutically-effective composition that can be independently verified as being from the roots of V. officinalis L., rather than from the roots of another plant or of a phenotypically-similar member of the Valerianaceae family.
- the amount of total valerenic acids or of a specific valeremc acid may be a marker for the strength/potency of the extract.
- 0.6% - 1.0% total valerenic acids may serve as such a marker.
- Volatile Oils Another preferred aspect of the extracts and extraction methods provided herein that is distinct from known valerian extractions and extraction methods concerns the yield of a measurable amount of volatile oil in the extract.
- the volatile oils of V. offic alis are very complex mixture of mostly mono and sesquiterpenoids. Over 150 compounds have been identified in the volatile oil fraction and have been described. See Bos R. Anaylytical and
- the volatile oil may contribute to the overall sedative properties of the extract.
- the amount of total volatile oils may be a marker for the strength/potency of the extract.
- approximately 0.6% to approximately 2.2% total volatile oil may serve as such a marker.
- the volatile oil content typically ranges from approximately 0 % to approximately 5.0%, and preferably approximately 0.6 to approximately 2.2% (v/w).
- Valepotnates are tnesters of polyalcohols with an i doid structure and an epoxy group that have reported cytotoxic and mutagenic properties. Valepotnates are divided into two main groups: diene type (which include valtrate, isovaltrate, and acevaltrate) and monoene type (which include didrovaltrate and isovaleroxyhydroxydidrovaltrate (IVHD). Valepotnates are thermolabile and decompose under acidic, alkaline or alcoholic conditions. See Bos, 1996. Shown below are chemical structures of certain valepotnates. Diene Valepotnates
- valepotnates may contribute to the pharmaceutical activity of valerian extracts, valepotnates and their decomposition products are also potentially dangerous.
- valepotnates have been shown to be cytotoxic in vitro, and exhibit potential mutagemc activity. See Von der Hude W., Scheutwinkel-Reich M., Braun R., and Dittmar W "In vitro mutagenicity of valepotnates” Arch Toxicol 56 (1985) 267-71; Von der Hude W., Scheutwinkel-Reich M., and Braun R. "Bacterial mutagenicity of the tranquilizmg constituents of Valerianaceae roots.” Mutat Res 169 (1986) 23 7).
- valepotnates reach the brain and other organs in vivo, and have been shown to be capable of irreversibly alkylating DNA and proteins (Wagner, H. and Jurcic, K, Planta Med. (1980) 38:366-376).
- the present invention provides a method of control for the levels of this class of compounds. This process comprises adding the ground roots to an alcoholic extraction solvent and heating to a temperature between 70°C and 80°C for a period of at least three hours.
- the extract contains valerenic acids but has levels of valepotnates that are substantially reduced compared to the content of valepotnates that occur naturally in the roots of the plant.
- Valepotnates are not unique to the genus officmalis, but are known constituents of most Valeriana species.
- V. officinalis mainly contains valepotnates of the diene type (valtrate, isovaltrate, and some acevaltrate), whereas both V. wallichii and V. edulis also contain considerable amounts of the monoene type (didrovaltrate and isovaleroxyhydroxydidrovaltrate). See Houghton, 1997. A few studies explored the content of different valepotnates in V.
- Example 1 1 The data presented in Example 1 1 confirms the above information.
- a lower limit for total valepotnates in the extract may be set as a process condition.
- valtrate and isovaltrate may be quantitatively monitored because they are present in significant quantities in the V. officmalis biomass.
- Total valepotnate levels in the extract produced by the current process should preferably be ⁇ 0.1 %. This ensures that the current extraction process consistently reduces valepotnates in the extract regardless of the starting concentration in the original biomass.
- baldrmals Major decomposition products of the valepotnates are the baldrmals, including bald nal (from valtrate and acevaltrate) and homobald ⁇ nal (from isovaltrate). See Bos, 1996; Houghton, 1997. As described in Bos (1997), the baldrmals are chemically reactive and may subsequently form polymers, although no evidence of polymerization was provided. Chemical structures of exemplary baldrmals are provided below.
- Baldrinal C0CH 3 Homobaldrinal C0CH 2 CH(CH 3 ) 2
- valepotnates and valepotnate decomposition products such as baldrinals
- valerian refers to any plant of the Valerianaceae family possessing extractable valerenic acid in its roots, and therefore refers, at least to, the plant designated Valeriana officinalis L. or alternatively herein, V. officinalis L.
- This species includes all recognized subspecies of Valeriana officinalis L. Some of these subspecies are also commonly referred to, in alternative taxonomic systems, as: Valeriana exaltata J.C. Mikan, Valeriana nitida Kreyer, Valeriana palustris Wibel, Valeriana wolgenis Kazak, Valeriana grossheimii Vorosch, Valeriana collina Wallr, Valeriana Rossica P.A.
- Plants of the species Valeriana officinalis L. may be characterized as follows: These plant grows from a short rhizome to 2 m high, flowers, and then dies back again in the winter. These plant has pinnately-divided leaves with six to ten pairs of lance-shaped leaflets, and bears many small white or pink flowers in a dense head of several stalked clusters. These heads bare small (5 mm) tapered seeds.
- valerian extracts most generally refers to the composition isolated from the roots of plants of the Valerianaceae family according to a specified extraction procedure, and preferably refers to the composition isolated from the roots of valerian or Valeriana officinalis L. according to a specified extraction procedure.
- These extracts comprise essential oils , valerenic acids, valepotnates (iridoids), kessane derivatives, valera ⁇ one, valerenal, fatty acids, carbohydrates and certain amino acids.
- valerenic acids refers to all chemically stable derivatives of valerenic acid. In its most limited, and preferable, connotation, this term refers to valerenic acid, acetoxyvalerenic acid, and hydroxyvalerenic acid (these three compounds, in aggregate, are also referred to herein as "VA ⁇ s"). These compounds, either individually, in the aggregate, or based on their respective ratios, may be used as standards to evaluate the extract processes herein described and/or to evaluate the plant from which the extracted roots have been obtained. Valerenic acid, in particular, may be used to verify that the roots extracted are of the species Valeriana officinalis L.
- UV measurements at 220 nm may be used to determine the content of the valerenic acids in a given sample or aliquot.
- valepotnates these compounds, in aggregate, are also referred to herein as "VPs" refers to all chemically unstable, thermolabile tnesters of polyalcohols having an iridoid structure that may be found in the roots of members of the Vale ⁇ anaceae family.
- valepotnates are the diene type valepotnates, valtrate, acevaltrate, and isovaltrate
- decomposition products of valepotnates for example, baldnnal and homobaldrinal are not within the definition of "valepotnates,” but may be referred to as “valepoft ⁇ ate derivatives" or “valepotnate decomposition products " UV measurements at 200, 254, and 320 nm are preferably used to determine the content of valepotnates in a given sample or aliquot
- volatile oils refers to all oils in V officmalis that are volatile, for example valerenal, valerenol, camphene, bornyl derivatives, myrtenyl acetate, and kessane derivatives.
- the term “isolated” refers to the state of being free of other, dissimilar compounds with which the extracted components of the invention will normally be associated in their natural state, so that upon being “isolated” the pharmaceutically active components comprises at least about 0 25%, about 0.5%, about 1 %, about 2%, about 4%, about 5%, about 10%, about 20%, about 50%, and at least about 75% of the mass, by weight, of a given sample
- water refers to water, and preferably to potable water, which term includes purified and/or de-ionized water (DIW). Water, as used herein, may have dissolved within it a significant amount of any water-soluble solute, such as a salt or a sugar.
- alcoholic refers to a process of or an extract obtained from extraction in an alcoholic extraction solvent containing a significant percentage of alcohol.
- Alcohol extraction solvent refers to extraction solvent having greater than approximately 10% alcohol by volume, and preferably refers to extraction solvents having at least approximately 25%, 30%, 35%, 40%, 45%, or preferably 50% alcohol by volume Most preferably, “alcoholic extraction solvent” refers to an extraction solvent having alcohol content equal to or greater than approximately 70% by volume, and includes solvents that are 100% alcohol
- alcoholic extraction solvent refers to any C C 6 alcohol, for example, metha ⁇ ol, ethanol, butanol or propanol, or any combination thereof, and most preferably refers to denatured ethanol (approximately 95% ethanol and approximately 5% methanol). The term “ethanol” should be understood as referring to denatured alcohol unless specifically identified otherwise.
- roots refers to all of subterranean portion of a specifically or genencally identified plant, including, but not limited to, the roots, the rhizomes, and the stolons of the specifically or genencally identified plant. Where the term “roots” is not modified by a specifically or genencally identified plant, it will be understood that the term refers to the roots of the species, and sub species of, Valeriana officmalis L
- the extraction processes provided herein most generally involve heating a mixture of the roots and an alcoholic extraction solvent for an extended period of time to obtain valeremc acid and valerenic acid derivatives in the extract, and to significantly reduce the amount of valepotnates in the extract.
- These processes when compared to currently known processes, significantly reduce the amount of valepotnates in the valerian extract, while maximizing the amount of valerenic acid and of valerenic acid derivatives It is contemplated that the extract, isolated according to the method of the present invention, may ultimately be used for a pharmaceutically active formulation
- the method includes an extraction process An overall method for preparing such a pharmaceutically active formulation is described to place the extraction process in the context of the preparation of the pharmaceutically active formulation. The following five steps comprise a preferred method for preparing such a formulation: Pre
- the roots may be prepared for extraction by grinding, chipping, or pulverizing to a powder in a hammermill, or like an instrument, as will be appreciated by those of skill in the art. After such pre extraction processing, preferably at least 70%, 75%, or 80%, and most preferably 85% or 90% of the mass of the roots pass through a Tyler 20-mesh screen. Also preferably, the raw or processed roots are stored in a durable non-reactive, preferably plastic, and more preferably polyethylene, container or containers. These containers may be doubly lined with bags of like material and closed or closeable with a lid composed of like material. Extraction.
- the valerian root may be added to an extraction solvent.
- the root is added in a ratio of approximately one kilogram to approximately five liters of extraction solution.
- the extraction solvent preferably is an alcoholic extraction solution, comprising between approximately 30% to approximately 100% (volume/volume; v/v) alcohol and between approximately 70% (volume/volume; v/v) to 0% (v/v) water.
- the alcoholic extraction solvent comprises approximately 50% to approximately 100% (v/v), approximately 55% to approximately 95% (v/v), approximately 65% to approximately 85% (v/v), and approximately 65% to approximately 75% (v/v) alcohol.
- the alcoholic extraction solvent may comprise approximately 50% (v/v), approximately 60% (v/v), approximately 70% (v/v), approximately 80% (v/v), approximately 90% (v/v) alcohol and approximately 100% alcohol.
- the alcohol used in the alcoholic extraction solvent is fully miscible in water, and is preferably denatured ethanol (95% ethanol + 5% methanol), but may be any C, C 6 alcohol, including but not limited to methanol, ethanol, n-butanol, isobutanol, n-propyl alcohol, and isopropyl alcohol.
- the mixture of root and alcoholic extraction solvent may be stirred by any mechanical device conventionally known for such purpose, including but not limited to an overhead stirrer, a magnetic stirrer assembly, and/or a built-in stirrer, and may be suitable for or adapted to the particular extraction vessel employed.
- the mixture may be heated to between approximately 65°C and 85°C, and more preferably between approximately 70°C and 80°C, or alternatively, the temperature of reflux. Specifically, the mixture may be heated to 50°, 55°, 60°, 65°, 70°, 75°, 77°, or 80° or reflux.
- Various conventional methods may be used to heat the mixture, including but not limited to heating mantels or other resistive heating coils.
- the mixture is heated to any of the above-described temperature for at least one, one and one- half, two, two and one-half, three, three and one half hours, four, or up to five hours.
- the final valepotnate level may be obtained and may also be compared to that found in commercial valerian extracts
- the mixture may then be cooled, preferably to room temperature or alternatively to a temperature above room temperature, including 30°C, 35°C, 40°C, 45°C, and 50°C
- the solids may then be separated from the liquid (by filtration or centrifcerol, or centrifer
- the filtrate containing the extracted material may be concentrated to an oily consistency under reduced pressure, including approximately 0 9, 0 8, 0 7 0 6, and 0 5 atmospheres (atms), at a temperature above room temperature, including 30°C, 35°C, 40°C, 45°C, and 50°C Optimally, a final volume of approximately 0.15 liters for each kilogram of root extracted is obtained.
- the concentrate may be mixed with an excipient to facilitate drying
- the excipient may be chosen from any commercially available excipient or mixtures thereof, but is preferably selected from the following maltodext ⁇ n NF, t ⁇ calcium phosphate, silicon dioxide, dicalcium phosphate, microcrystalli ⁇ e cellulose, silicified microcrystalline cellulose, various ion exchange resins as will be understood by those of skill in the art, PVP/citrate, sodium citrate, pre gelatinized corn starch (also known as Starch 1500), polyethylene glycol (PEG), sugar/polyol (also known as manmtol), TRIS buffer, sodium bicarbonate, porous silica, and combinations of the above listed excipients and/or buffers, or other conventional excipient and any combination or mixture thereof as will be recognized by those of skill in the art
- the excipient will preferably comprise between approximately 10% and 40%, and more preferably between 20% and 25%, of the drug substance
- drying of the extract may be accomplished by spray drying or any other conventional drying method as will be understood by one of ordinary skill in the art
- V officinalis L Certain of the constituents of V officinalis L have been identified as sesquiterpe ⁇ es (in the volatile oils) and indoids (known as valepotnates)
- the total content of volatile oil varies widely within a single species, and also may vary between different species
- the oil typically consists of mixtures of monoterpene and sesquiterpene derivatives
- the amount of valepotnates also varies
- the process of the present invention has been shown to reduce the amount of valepotnates when compared to currently practiced valerian extraction processes.
- valerenic acid, acetoxyvalerenic acid, and hydroxyvalerenic acid are preferably used as marker compounds for analysis of the extract and later formulations based on the extracts.
- the process of the present invention significantly reduces the amount of valepotnates, while optimizing the yield of valeremc acid, acetoxyvalerenic acid, and hydroxyvalerenic acid either alone or in the aggregate.
- Active constituents of the extract of the present invention include, but are not limited to, valerenic acid and its derivatives (for example, acetoxyvalerenic acid and hydroxyvalerenic acid), kessane derivatives, valeranone, valerenal, small chain carboxyhc acids, fatty acids and ammo acids; the extract may also contains sugars and trace amounts of other aliphatic acids, alkaloids, phenolic acids, flavonoids, free fatty acids, sugars, and salts.
- Solvent composition 70%:30% (v/v) EtOH/H 2 0 was used as the extraction solvent. However at EtOH concentrations between 50% and 100%, statistically similar recoveries of valeremc acids were recorded. Solvent volume Similar amounts of valerenic acids were extracted when from four to seven volumes (one volume being 1 m ⁇ ll ⁇ l ⁇ ter/l gram of roots) of extraction solution were used. A volume of five times the mass of the roots was preferred.
- Root powder and 70%:30% v/v EtOH/H 2 0 were added to the flask and the overhead stirrer was started. A 1.5 mL standard sample was removed and centnfuged. The temperature was continually monitored with a calibrated thermometer or thermocouple. When the temperature of the slurry reached 70-75°C, timing was started. 1.5 mL samples were removed at 30-m ⁇ nute intervals, and the temperature was maintained at approximately 70-75°C. After
- Example 1 Conditions identical to those listed in Example 1 were created, except for the following- The root solvent mixture was refluxed for 3 hours (77 79°C) rather at 70 75°C as in the previous four demonstration runs; the amount of maltodextnn used was reduced by approximately two thirds, i e , 67 g rather than 200 g was used; the product was dried in a vacuum oven at 50°C under a vacuum of 25 26 in of mercury (Hg) Summary of the Results from Examples 1 through 5. Examples 1 , 2, 3, 4, and 5 are meant to exemplify protocols and process parameters under which the objectives of the present invention may be achieved. Certain of the process parameters of Examples 1 , 2, 3, 4, and 5 of the Valerian Root Extraction Processes are provided in Table 3.
- valepotriate levels decreased during the heating of the extraction mixtures. The reduction in valepotriate levels was much faster at reflux temperature (77-79°C) than at 70-75°C. After three hours the valepot iate levels in Example 5 were 23%-30% of those in Example 1 , 2, 3, and 4. The levels of valerenic acids were not affected by extraction temperature or time. They reached their maximum by the time the extracts attained the target temperatures and remained constant during the three hour heating period. Table 10 shows the average levels of total valerenic acids observed in the unfiltered extracts. The amounts appeared to be greater in Examples 1 and 2 than in Examples 3, 4, and 5. However these differences may be attributed to differences in the standard curves employed for acetoxyvalerenic acid.
- Example 5 The effects of temperature and vacuum on valerenic acids recovery were investigated in a small-scale experiment carried out with aliquots of filtrate from Example 4. Samples of filtrate were dried under the conditions described in Table 3 and then reconstituted and analyzed for valerenic acids. The results indicated that there were no significant losses, even at 50°C under vacuum for 72 hours, and that vacuum tray drying could be used without appreciable loss of valerenic acids. This result was confirmed in Example 5 where the product was dried at 50°C under house vacuum and a valerenic acids recovery was 92% (Table 7). However, under these conditions the drying process was very slow, requiring 3.5 days. The two step concentrating procedure used in Example 4 was determined to be non-optimal due to the time required to complete the forced air drying and due to the difficulty of mixing the excipient with the residue.
- Table 8 provides a summary of the total dissolved solids (TDS) in the filtrates (determined using 5.00 mL samples) and the weight of solids (minus excipient) recovered in the final dried product.
- the extracted solids in the final product ranged from 17.9% to 20.0% of the weight of the roots.
- Example 1 Amount of Excipient Added.
- the final product contained approximately 52% maltodextrin by weight.
- Example 5 the amount of maltodextrin was reduced accordingly and this resulted in a substantial increase in the weight percentage of valerenic acids in the final powder (Table 18).
- the maltodextrin content may be reduced to 25% of the final powder weight.
- the valerian root powder does not contain water-extractable valerenic acid, acetoxyvalerenic acid, or hydroxyvalerenic acid.
- EXAMPLE 7 EXTRACTION IN WATER DOES NOT YIELD VALERENIC ACIDS The following procedure was used to determine the yield of valerenic acids from valerian root powder extracted at room temperature with a 50%/50% (v/v) mixture of alcohol and water, and to compare said extraction with a 100% water extraction.
- valerian root powder was stirred at room temperature with 30 mL of 95% ethanol:5% methanol plus 30 mL of deionized water for 2 hours with a magnetic stirrer.
- One mL of the suspension was centrifuged and a 250x dilution of the suspension was prepared in deionized water.
- a second sample of powder root was prepared from the same lot in deionized water in the following manner:
- EXAMPLE 8 EXTRACTION IN WATER DOES NOT YIELD VALERENIC ACIDS Between 200 and 250 mg of root powder were added to three separate 10 mL volumetric flasks. In the first flask, deionized water was added. To the second flask, an equal volume of 50% ethanol/50% water (v/v) was added. To the third flask, an equal volume of HPLC grade pure ethanol was added. Each flask was stirred at room temperature for 15 mm and then filtered through 0.45 m filters into HPLC vials. The resulting HPLC analysis led to the approximated results shown in Table 9.
- valerenic acids remained behind with the valerian root
- the "spent" valerian root biomass was extracted subsequently with 330 mL of denatured ethanol (about 70% ethanol, final concentration) for 10 to 15 mm.
- the ethanohc extract was analyzed for valeremc acids and the results, shown in last row of Table 10.
- the process described in the current invention was duplicated and the amounts of total valerenic acids were quantitated by liquid chromatography, as follows: 25 gm of finely powdered roots of V. officmalis was extracted with
- V. officmalis makes a major contribution towards the sedative activity of valerian extract (Houghton 1997).
- the current process will yield a product rich in volatile oil and thus would be superior to the product obtained by the process of U.S. Patent No. 5,21 1 ,948.
- Valepotnate content Two lots of V. officinalis root were analyzed for Valepotnate content as follows. At the time of analysis, approximately 6 months to approximately 18 months had passed from the date of harvesting. Valtrate and isovaltrate were measured in each biomass sample utilizing an HPLC method coupled to a diode-array detector, while didrovaltrate (which is present in trace amounts) was analyzed using a more sensitive LC/MS/MS method. Reference standards, made at Ancile Pharmaceuticals, Inc , San Diego, CA, for each of these valepotnates were used, and Standard HPLC and LC/MS/MS methods were employed as follows .
- valepotnates isovaltrate and valtrate were analyzed by an HPLC method using a C-18 reverse phase column (4.6 x 250 mm, 4 m particle size) Valepotnates were monitored at their UV absorbance maximum of 254 nm. The retention time of isovaltrate and valtrate under the LC conditions were about 28.9 and 30.1 mm, respectively. Didrovaltrate was analyzed by a LC/MS method using a C-18
- Valepotnate peaks were identified based on their relative elution times as compared to the standards as well as their characteristic UV absorption spectrum. See Bos R et al , Analytical aspects of Phytotherapeutic Valerian preparation, 1996; 7:143 151 ) and/or molecular mass The quantitative results are summarized in Table 13. Valtrate and isovaltrate were shown to be present in low amount ( ⁇ 0.5%), whereas the monoene valepotnate, didrovaltrate, was present in trace quantities ( ⁇ 0.005%) in addition, analysis of the extract, revealed that following the extraction process, the content of didrovaltrate is below the limit of detection ( ⁇ 7 ppm) of LC/MS/MS methods. Table 13. Valepotriate Content in V officmalis Dried Roots
- EXAMPLE 12 As described earlier, the present extraction process significantly reduces the levels of valepotnates in the extract with respect to the content in V offic alis biomass. To demonstrate that this process does not result in the accumulation of potentially toxic baldrmals, the extract was analyzed for its baldnnal and homobaldrinal content. Homobaldrinal is present in an extract according to the invention at only 5.9 ppm, and the level of baldnnal is below the limit of detection of the assay ( ⁇ 3 ppm) Similar results were obtained for the content of isovaltrate and valtrate in this extract. In contrast, the starting biomass contained 4000 ppm isovaltrate and 490 ppm valtrate.
- Sample A was extracted at 30°C
- Sample B was extracted at 40°C
- Sample C was extracted at 50°C
- Sample D was extracted in 90 mL of extraction solvent at room temperature
- Sample E was extracted at room temperature
- Sample F was extracted in absolute ethanol
- Sample G was extracted at 43°C for two days. Results are shown in Table 15 and 16.
- This Example was conducted to evaluate an extraction at 60°C and to determine if similar amounts of valerenic acids and valepotnates are extracted as compared to extraction at lower temperatures.
- EXAMPLE 16 pH DEPENDENCE OF EXTRACTION This Example was conducted to evaluate the effects of acidic pH and/or 70°C temperature on valepotriate content, and more specifically to evaluate whether the valepotnates in root extracts could be removed by heating the extracts at 70°C and maintaining the pH at 2-3.
- Experiment D the sample obtained from Experiment 2 was rinsed with 30 mL cake wash; the pH of the filtrate was adjusted to 2.3 with 1 N HCI. The sample was stirred for 1 hour.
- EXAMPLE 17 EFFECT OF REFLUX AND THE DURATION OF REFLUX ON EXTRACT This Example was conducted to determine whether the content of valeremc acids, of valepotnates, and of extracted solids are effected after refluxmg ground valerian root for 3 hours in 70% ethanol.
- the obtained samples were centrifuged. A portion of the supernatant was diluted 100x in extraction solvent and a UV/VIS spectrum was obtained. The remaining filtrate was mixed with 20 grams of maltodextrin and dried at 35°C, at reduced pressure, overnight.
- Table 23 shows data used on the refluxed root powder in this Example. The data in Table 23 were used as a standard.
- EXAMPLE 18 EFFECT OF HEATING DURATION ON EXTRACT VALEPOTRIATE CONTENT
- the extraction mixture was heated at reflux for three and one-half hours.
- This Example was conducted to determine if there are significant differences in the levels of valepotnates between three and one-half hours of reflux and the durations exemplified in the previous example.
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Abstract
Description
Priority Applications (7)
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MXPA02000643A MXPA02000643A (en) | 1999-07-21 | 2000-07-21 | Process for the extraction of valerian root. |
CA002379395A CA2379395A1 (en) | 1999-07-21 | 2000-07-21 | Process for the extraction of valerian root |
NZ516531A NZ516531A (en) | 1999-07-21 | 2000-07-21 | Process for the extraction of valerian root |
JP2001511946A JP2003505426A (en) | 1999-07-21 | 2000-07-21 | Valerian root extraction method |
IL14733300A IL147333A0 (en) | 1999-07-21 | 2000-07-21 | Process for the extraction of valerian root |
AU63668/00A AU6366800A (en) | 1999-07-21 | 2000-07-21 | Process for the extraction of valerian root |
EP00950580A EP1235583A1 (en) | 1999-07-21 | 2000-07-21 | Process for the extraction of valerian root |
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US35837599A | 1999-07-21 | 1999-07-21 | |
US09/358,375 | 1999-07-21 |
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PCT/US2000/020031 WO2001007063A1 (en) | 1999-07-21 | 2000-07-21 | Process for the extraction of valerian root |
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US (2) | US6383526B1 (en) |
EP (1) | EP1235583A1 (en) |
JP (1) | JP2003505426A (en) |
AU (1) | AU6366800A (en) |
CA (1) | CA2379395A1 (en) |
IL (1) | IL147333A0 (en) |
MX (1) | MXPA02000643A (en) |
NZ (1) | NZ516531A (en) |
WO (1) | WO2001007063A1 (en) |
Cited By (5)
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WO2002092113A1 (en) * | 2001-01-29 | 2002-11-21 | Ancile Pharmaceuticals, Inc. | Alcoholic valerian extract for improving sleep quality and efficiency, and methods of preparing it |
WO2003061678A1 (en) * | 2002-01-25 | 2003-07-31 | Universtiy Of Strathclyde | Sedative materials and treatments |
WO2013143843A1 (en) * | 2012-03-30 | 2013-10-03 | Axel Brattstroem | New valerian extracts and uses thereof |
CN107530273A (en) * | 2015-04-28 | 2018-01-02 | 库泰克有限责任公司 | Composition containing Valerian root P.E |
WO2019050436A1 (en) * | 2017-09-11 | 2019-03-14 | Павел Павлович ХОРОШУТИН | Method for producing dry extracts from plant raw material |
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US6395303B1 (en) * | 1996-06-10 | 2002-05-28 | Edward Mendell Co., Inc. | Process for preparing a directly compressible solid dosage form containing microcrystalline cellulose |
JP2003505426A (en) * | 1999-07-21 | 2003-02-12 | アンシル ファーマシューティカルズ,インコーポレイテッド | Valerian root extraction method |
EP1397186B1 (en) * | 2001-06-06 | 2007-01-03 | Naturel Corporation, LLC | A low temperature process for extracting principal components from plants |
US6753017B2 (en) * | 2001-11-07 | 2004-06-22 | Jrs Pharma Lp | Process for preparing dry extracts |
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US7179488B2 (en) * | 2001-11-29 | 2007-02-20 | Bob Sherwood | Process for co-spray drying liquid herbal extracts with dry silicified MCC |
US20050003025A1 (en) * | 2003-06-30 | 2005-01-06 | Hargens Robert D. | Method of mitigating the odor of valerian extracts |
WO2005041869A2 (en) * | 2003-10-24 | 2005-05-12 | Josef Rettenmaier & Soehne Gmbh & Co., Kg | Process for co-spray drying agents with dry silicified mcc |
US20060198872A1 (en) * | 2005-03-07 | 2006-09-07 | Chioma Ikonte | Plant based dietary supplement for improving the duration and quality of sleep |
US7225168B2 (en) * | 2005-05-24 | 2007-05-29 | Siemens Aktiengesellschaft | Method and system for providing a service on demand |
KR100861473B1 (en) | 2006-11-14 | 2008-10-06 | 전남대학교산학협력단 | Process for producing Valeriana fauriei roots, Valeriana fauriei roots produced by the process, and process for producing valerenic acids and valepotriates from the roots |
US9532952B2 (en) | 2011-01-28 | 2017-01-03 | Physician's Seal, LLC | Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients |
US8691275B2 (en) | 2011-01-28 | 2014-04-08 | Zx Pharma, Llc | Controlled-release melatonin compositions and related methods |
JP6174885B2 (en) * | 2013-03-29 | 2017-08-02 | 花王株式会社 | Sleep improver |
WO2017125919A1 (en) * | 2016-01-18 | 2017-07-27 | My Nutra Ltd. | Compositions comprising melatonin |
WO2017125924A1 (en) * | 2016-01-18 | 2017-07-27 | My Nutra Ltd. | Anxiolytic compositions |
RU2018142019A (en) | 2016-05-06 | 2020-06-08 | ФИЗИШН`С СИЛ, ЭлЭлСи | VALERIAN COMPOSITION AND RELATED METHODS |
WO2021064132A1 (en) | 2019-10-01 | 2021-04-08 | Besins Healthcare Ireland Limited | Treatment of menopausal syndrome and/or symptoms associated with menopause |
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2000
- 2000-07-21 JP JP2001511946A patent/JP2003505426A/en active Pending
- 2000-07-21 AU AU63668/00A patent/AU6366800A/en not_active Abandoned
- 2000-07-21 MX MXPA02000643A patent/MXPA02000643A/en unknown
- 2000-07-21 CA CA002379395A patent/CA2379395A1/en not_active Abandoned
- 2000-07-21 EP EP00950580A patent/EP1235583A1/en not_active Withdrawn
- 2000-07-21 WO PCT/US2000/020031 patent/WO2001007063A1/en not_active Application Discontinuation
- 2000-07-21 IL IL14733300A patent/IL147333A0/en unknown
- 2000-07-21 US US09/620,801 patent/US6383526B1/en not_active Expired - Fee Related
- 2000-07-21 NZ NZ516531A patent/NZ516531A/en unknown
-
2002
- 2002-04-11 US US10/122,472 patent/US6913770B2/en not_active Expired - Fee Related
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002092113A1 (en) * | 2001-01-29 | 2002-11-21 | Ancile Pharmaceuticals, Inc. | Alcoholic valerian extract for improving sleep quality and efficiency, and methods of preparing it |
WO2003061678A1 (en) * | 2002-01-25 | 2003-07-31 | Universtiy Of Strathclyde | Sedative materials and treatments |
WO2013143843A1 (en) * | 2012-03-30 | 2013-10-03 | Axel Brattstroem | New valerian extracts and uses thereof |
CN107530273A (en) * | 2015-04-28 | 2018-01-02 | 库泰克有限责任公司 | Composition containing Valerian root P.E |
WO2019050436A1 (en) * | 2017-09-11 | 2019-03-14 | Павел Павлович ХОРОШУТИН | Method for producing dry extracts from plant raw material |
Also Published As
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CA2379395A1 (en) | 2001-02-01 |
US6383526B1 (en) | 2002-05-07 |
MXPA02000643A (en) | 2003-07-21 |
JP2003505426A (en) | 2003-02-12 |
EP1235583A1 (en) | 2002-09-04 |
IL147333A0 (en) | 2002-08-14 |
AU6366800A (en) | 2001-02-13 |
US6913770B2 (en) | 2005-07-05 |
US20030017220A1 (en) | 2003-01-23 |
NZ516531A (en) | 2002-10-25 |
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