WO2008046149A1

WO2008046149A1 - Herbal compositions for the prevention or treatment of restless leg syndrome

Info

Publication number: WO2008046149A1
Application number: PCT/AU2007/001582
Authority: WO
Inventors: Tracey Anne Seipel
Original assignee: Biologic Health Solutions Pty Ltd
Priority date: 2006-10-17
Filing date: 2007-10-17
Publication date: 2008-04-24

Abstract

The present invention relates to herbal compositions for the prevention or treatment of a Restless Leg Syndrome. Specifically, the invention provides compounds that contain Passionflower preparation and Valerian officiinalis preparation and methods of use thereof.

Description

HERBAL COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF RESTLESS LEG SYNDROME

FIELD OF THE INVENTION

The present invention relates to herbal compositions for the prevention or treatment of a restless leg syndrome (RLS).

BACKGROUND OF THE INVENTION

Restless leg syndrome (RLS) is a disorder characterized by sensory symptoms and motor disturbance of the limbs, mainly during rest. Although RLS affects about 10% to 15% of the US population, it is often unrecognized and misdiagnosed. It may begin at any age even as early as infancy, but most patients who are severely affected are middle- aged or older. Symptoms progress over time in about two thirds of patients and may be severe enough to be disabling. [1,2]

The most distinctive or unusual aspect of the condition is that lying down and trying to relax activates the symptoms. As a result, most people with RLS have difficulty falling asleep and staying asleep. Left untreated, the condition causes exhaustion and daytime fatigue. Many people with RLS report that their job, personal relations, and activities of daily living are strongly affected as a result of their exhaustion. They are often unable to concentrate, have impaired memory, or fail to accomplish daily tasks. [3]

Restless leg syndrome is usually associated with involuntary contractions of the legs during sleep, known as periodic limb movements. [4] More than 80 percent of people with RLS also experience periodic limb movement disorder (PLMD). [5] PLMD is characterized by involuntary leg twitching or jerking movements during sleep that typically occur every 10 to 60 seconds, sometimes throughout the night. The symptoms cause repeated awakening and severely disrupted sleep. Unlike RLS, the movements caused by PLMD are involuntary - people have no control over them. Although many patients with RLS also develop PLMD, most people with PLMD do not experience RLS. Like RLS, the cause of PLMD is unknown. [6]

Some people with RLS will not seek medical attention, believing that they will not be taken seriously, that their symptoms are too mild, or that their condition is not treatable. Some physicians wrongly attribute the symptoms to nervousness, insomnia, stress, arthritis, muscle cramps, or aging. Many people with RLS endure the symptoms and discomfort for years before seeking medical care, by which time they are in their 50s and 60s. [7] RLS occurs in both genders, although the incidence may be slightly higher in women. Although the syndrome may begin at any age, even as early as infancy, most patients who are severely affected are middle-aged or older. In addition, the severity of the disorder appears to increase with age. Older patients experience symptoms more frequently and for longer periods of time. [7,8]

Many patients with RLS have a first degree relative with the disorder. [1] People with familial RLS tend to be younger when symptoms start and have a slower progression of the condition.

In most cases, the cause of RLS is unknown (referred to as idiopathic); however, secondary forms of the syndrome are closely associated with other medical disorders or conditions such as iron deficiency, uremia, pregnancy, and polyneuropathy. RLS has also been less often reported in association with folate deficiency, diabetes mellitus, rheumatoid arthritis, fibromyalgia, hypothyroidism, Parkinson disease, and depression. [1,10] Certain medications - such as antinausea drugs (prochlorperazine or metoclopramide), antiseizure drugs (phenytoin or droperidol), antipsychotic drugs (haloperidol or phenothiazine derivatives), and some cold and allergy medications - may aggravate symptoms.

Researchers also have found that caffeine, alcohol, and tobacco may aggravate or trigger symptoms in patients who are predisposed to develop RLS. Some studies have shown that a reduction or complete elimination of such substances may relieve symptoms, although it remains unclear whether elimination of such substances can prevent RLS symptoms from occurring at all. [9,12]

The severity of RLS varies from patient to patient. Although pharmacologic treatment is helpful for many patients with RLS, those with mild symptoms may not need medications. [9] For those people, prevention is key, and many physicians suggest certain lifestyle changes and activities to reduce or eliminate symptoms. Decreased use of caffeine, alcohol, and tobacco may provide some relief. Physicians may suggest that certain individuals take supplements to correct deficiencies in iron, folate, and magnesium. [13] Others have found that a program of regular moderate exercise helps them sleep better; on the other hand, excessive exercise has been reported by some patients to aggravate RLS symptoms. Taking a hot bath, massaging the legs, or using a heating pad or ice pack can help relieve symptoms in some patients. Although many patients find some relief with such measures, rarely do these efforts completely eliminate symptoms

Because no single medication or combination of medications will work predictably for all patients, treatment must be individualized. Physicians and patients may need to work together over time to find the medication or combination of medications and the dosages that will work best. [9]

Common medications include: Dopaminergic agents:

Dopamine precursor combinations such as carbidopa-levodopa and Requip. [5] These can be used on a "one-time" basis or as circumstances may require. Useful for persons with intermittent RLS because dopamine agonists take longer to have an effect.

As many as 80% of patients who take carbidopa-levodopa may develop augmentation.

Augmentation is a worsening of RLS symptoms in the course of therapy. Symptoms may be more severe and start earlier in the day (e.g., afternoon rather than evening) than before treatment began and may spread to different parts of the body. Augmentation, which can start soon after therapy is begun or not until months or years later, has also been reported with dopamine agonists and may occur with other medications. [2,6,9,11] The therapeutic effect of dopaminergic agents may be reduced if they are taken with high-protein food. Side effects can include insomnia, sleepiness and gastrointestinal problems. Dopamine agonists such as pergolide, pramipexole, ropinirole are useful in moderate to severe RLS. Recent reports indicate high efficacy of dopamine agonists, but the role of their long-term use is unknown. They can cause severe sleepiness, which may limit their use during the daytime. [2,6,9,11]

Opioids: Opioids such as codeine, hydrocodone, oxycodone, propoxyphene, tramadol can be used on an intermittent basis. These may cause constipation, urinary retention, sleepiness or cognitive changes. Tolerance and dependence may occur with higher doses of stronger agents. [9,11]

Benzodiazepines: Benzodiazepines such as clonazepam, temazepam are helpful in some patients when other medications are not tolerated and may help improve sleep. They can cause daytime sleepiness and cognitive impairment, particularly in the elderly. Anticonvulsants:

Anticonvulsants such as carbamazepine, gabapentin can be considered when dopamine agonists have failed. They may be useful in individuals with coexisting peripheral neuropathy and/or when RLS discomfort is described as pain. Side effects vary, depending on the agent and include gastrointestinal disturbance such as nausea, sedation and dizziness. [9,11]

As described above, the current pharmacological treatments have numerous, undesirable side effects. There are currently no medications that specifically treat restless leg symptoms without having side effects elsewhere in the body. Accordingly, there is a need for the identification of new compositions for the prevention or treatment restless leg syndrome that do not exhibit the undesirable side effects of the compositions in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel herbal and mineral containing compositions for the prevention or treatment restless leg syndrome. It is to be appreciated therefore that certain aspects, modes, embodiments, variations and features of the invention described below in various levels of detail in order to provide a substantial understanding of the present invention. In general, such disclosure provides beneficial herb-containing compositions, combinations of such compositions with other dietary supplement compositions, and related methods of producing and using same. Accordingly, the various aspects of the present invention relate to therapeutic or prophylactic uses of certain particular herb-based compositions in order to prevent or treat a disease, injury or condition related to RLS. Accordingly, various particular embodiments that illustrate these aspects follow.

It is to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean "substantial", which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.

DEFINITIONS

A "subject," as used herein, is preferably a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). An "effective amount" of a composition, as used herein, is a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, for example, an amount which results in the prevention of or a decrease in the symptoms associated with a disease that is being treated. The amount of composition administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Typically, aη effective amount of the compositions of the present invention, sufficient for achieving a therapeutic or prophylactic effect.

It is advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active composition calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the dietary supplement and the particular therapeutic effect to be achieved, and the limitations inherent in the art of producing such an active composition for the treatment of individuals. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. Oral doses can be taken three-times daily, until symptom relief is apparent. The compositions of the present invention can also be administered in combination with each other, or with one or more additional therapeutic compositions.

Valerian is an extremely polymorphous perennial herb represented by a complex of sub-species with natural populations dispersed over temperate and sub-polar Eurasian zones, naturalized in northeastern America, now extensively cultivated in Holland, Belgium, France, Germany, Eastern Europe, Japan, and the United States. Valerian is one of Germany's most important medicinal plant crops. The material of commerce is obtained from Belgium and France, the former U. S. S. R., and China. In one embodiment, Valerian root, consisting of fresh underground plant parts, or parts carefully dried below 40⁰C, of the species V. officinalis L [Fam. Valerianaceae] and its preparations in effective dosage. The roots contain essential oil with monoterpenes and sesquiterpenes (valerenic acids). Preparations of valerian used therapeutically (infusion, extract, fluidextract, and tincture) no longer contain the thermolabile and chemically unstable valepotriates. [14]

Passionflower is a perennial creeping vine, native to the tropical and semi-tropical southern United States (ranging from Virginia to Florida and as far west as Missouri and Texas), Mexico, and Central and South America, now cultivated in tropical and subtropical regions, including Florida, Guatemala, and India. The material of commerce is obtained from wild and cultivated plants, mainly from the United States, India, and the West Indies. Passionflower was first cultivated by Native Americans for its edible fruit. Spanish conquerors first learned of passionflower from the Aztecs of Mexico who used it as a sedative to treat insomnia and nervousness. The plant was taken back to Europe where it became widely cultivated and introduced into European medicine. [18] In one embodiment, Passionflower herb consists of fresh or dried aboveground parts of Passiflora incarnata L. [Fam. Passifloraceae] and their preparations in effective dosage. The preparation contains flavonoids (vitexin), maltol, coumarin derivatives, and small amounts of essential oil. The content of harman alkaloids varies; it must not exceed 0.01%. [18]

Magnesium is an important mineral for the electrical stability of cells, the maintenance of membrane integrity, muscle contractions, nerve conduction and the regulation of vascular tone. Magnesium plays a role in the biochemical reactions in the body, and is needed for nerve transmissions and for the control of muscle tension.

Because magnesium can carry an electric charge, it is used in many biological processes that rely on electrical signals - including the transmission of the nerve signals that control our muscles. Inadequate magnesium levels can affect the ability or our muscles to attract and relax properly. The results can include muscle cramps and spasms. The references cited throughout this application are incorporated herein by reference in their entireties.

HERB-CONTAINING COMPOSITIONS OF THE INVENTION

The present invention provides herb-containing compositions useful in a method of prevention or treatment of RLS. Specifically, the invention provides compositions that contain Passionflower and Valerian that are standardized for isovitexin and valereric acid content and useful in the prevention and treatment of RLS. Batch variation in the total isovitexin (i.e., isovitexin, vitexin, orientin and isoorientin) and valereric acid (i.e., hydroxyvalerenic acid, acetoyvaleric acid and valerenic acid) of Passionflower and Valerian herb preparations may cause variation in effectiveness. As such, this problem has been resolved by the present invention by providing an herb preparation with optimized, standardized for total isovitexin and valereric acid, respectively. Standardization of these components in the compositions of the present invention improve the consistency and effectiveness of the formulation compared to herbal compositions which are not standardized for these components.

Passionflower (Passiflora) herb consists of fresh or dried aboveground parts of the plant which has approximately 500 species useful in the compositions and methods of the present invention, which include, but are not limited to, P. affinis; P. alata; P. amalocarpa; P. amethystine; P. aurantia; P. caerulea; P. capsularis; P. coccinea; P. edulis; P. foetida; P. guatemalensis; P. hahnii; P. helleri; P. holosericea; P. incarnate; P. karwinskii; P. ligularis; P. lutea; P. maliformis; P. mixta; P. mucronata; P. murucuja; P. phoenicea; P. picturata; P. pinnatistipula; P. quadrangularis; P. racemosa; P. serratifolia; P. tarminiana; P. tenuifila; P. tripartite; P. tulae; P. vitifolia; P. yυcatanensis. In one embodiment of the invention, the composition comprises P. incarnata. In some embodiments, the compositions contain flavonoids (vitexin), maltol, coumarin derivatives, and small amounts of essential oil. The content of harman alkaloids can vary up to about 0.01 weight percent (% wt/wt). [18]

In one embodiment of the invention, the herb-containing composition of the invention is an oral supplement included in a dry delivery system, e.g., tablet, dry powder, and dry meal replacement mixture. In another embodiment, the herb-containing composition of the invention is an oral supplement included in a liquid delivery system, e.g., capsule, caplet, or beverage. In another embodiment, the herb-containing composition of the invention is an oral supplement included in a controlled-release vehicle, e.g., tablet, caplet, and capsule.

In one embodiment of the invention, the herb-containing composition contains Valerian extract (dried rhizome and root) and passionflower herb extract (above ground parts). In one embodiment, the Passionflower herb extract is a 5.5:1 ethanol extract. In one embodiment, the Passionflower herb extract is standardized to contain between about 3% wt/wt to about 4.5% wt/wt isovitexin, vitexin, orientin and isoorientin expressed as isovitexin. In one embodiment, the Passionflower herb extract is standardized to contain at least about 3.5% wt/wt isovitexin, vitexin, orientin and isoorientin expressed as isovitexin. In one embodiment, the Valerian herb extract (rhizome and root) extract is a 5:1 ethanol extract. In one embodiment, the Valerian herb extract is standardized to contain at least about 0.8% wt/wt hydroxyvalerenic acid, acetoyvaleric acid and valerenic acid expressed as Valerenic acid. In one embodiment, the Valerian herb extract is standardized to contain between about 0.7% wt/wt to about 11% wt/wt hydroxyvalerenic acid, acetoyvaleric acid and valerenic acid expressed as Valerenic acid.

The components of the herb-containing composition of the invention are summarized below in Table 1. The components are commercially available.

Table 1 Composition of the Herb-containing Composition of the

Invention

In one embodiment, the herb-containing composition of the invention, contains a final concentration of Passionflower standardized herb extract (5.5:1 extract) as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of Passionflower standardized herb extract (5.5:1 extract) as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of Passionflower standardized herb extract (5.5:1 extract) as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of Valerian standardized herb extract (5:1 extract) as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of Valerian standardized herb extract (5:1 extract) as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of Valerian standardized herb extract (5:1 extract) as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium citrate as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium citrate as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium citrate as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium phosphate tribasic as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium phosphate tribasic as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium phosphate tribasic as defined in Range C of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium oxide as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium oxide as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium oxide as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium sulfate as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium sulfate as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of magnesium sulfate as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of thiamine nitrate as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of thiamine nitrate as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of thiamine nitrate as defined in Range C of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of riboflavin as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of riboflavin as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of riboflavin as defined in Range C of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of nicotinamide as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of nicotinamide as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of nicotinamide as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of calcium pantothenate as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of calcium pantothenate as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of calcium pantothenate as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of pyridoxine hydrochloride as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of pyridoxine hydrochloride as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of pyridoxine hydrochloride as defined in Range C of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of cyanocobalamin as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of cyanocobalamin as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of cyanocobalamin as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of folic acid as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of folic acid as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of folic acid as defined in Range C of Table 1.

In one embodiment, the herb-containing composition of the invention, contains a final concentration of d-alpha tocopherol succinate (vitamin E) as defined in Range A of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of d-alpha tocopherol succinate (vitamin E) as defined in Range B of Table 1. In one embodiment, the herb-containing composition of the invention, contains a final concentration of d-alpha tocopherol succinate (vitamin E) as defined in Range C of Table t

Extraction and Standardization of Passionflower and Valerian The Passionflower herb (above ground parts) was dried and ground. The active constituents of the herb were extracted with a 90% v/v ethanol solution. The extract was then purified and concentrated to a ratio of 5.5:1 , in relation to raw herb. The dried extract was also standardized to contain 3.5% wt/wt isovitexin, vitexin, orientin and isoorientin expressed as isovitexin. After extraction with ethanol the extract is partially concentrated and purified. It was then further concentrated to obtain Passiflora hydroalcoholic soft extract, which was dried and further analysed. Dehydrated glucose and Amorphous Silica is added to obtain the desired titre. Analysis of the finished product was performed by thin layer chromatography and verified by UV spectrophotometry.

The extract was a brown amorphous powder. In one embodiment, the herb- containing composition of the invention contains 90.9 mg of the passionflower extract

(Standardized to contain 3.5% wt/wt isovitexin) per oral dosage unit. This is equivalent to 500 mg of dry passionflower herb starting material. The Valerian herb (rhizome and root) was ground. The active constituents of the herb were extracted with a 60% v/v ethanol solution. The extract was then concentrated by drying to a ratio of 5:1 , in relation to raw herb. The dried extract was also standardized to contain >0.8% wt/wt hydroxyvalerenic acid, acetoyvaleric acid and valerenic acid expressed as valerenic acid. The standardization was verified using HPLC analysis technique for total Valerenic acids. The dried extract was a brown powder. In one embodiment, the herb-containing composition of the invention comprises 66.67mg of dried Valerian extract in each oral dosage unit. This is equivalent to 333 mg of Valerian (root and rhizome starting material), standardized to contain at least about 0.8% valerenic acid. MEDICINAL PROPERTIES AND USES OF COMPOSITIONS OF THE INVENTION

The present invention provides herb-containing compositions useful in a method of prophylaxis or treatment of RLS. Valerian is a traditional herbal sleep remedy that has been studied with a variety of methodologic designs using multiple dosages and preparations. Research has focused on subjective evaluations of sleep patterns, particularly sleep latency, and study populations have primarily consisted of self-described poor sleepers. Valerian improves subjective experiences of sleep when taken nightly over one- to two-week periods, and it appears to be a safe sedative/hypnotic choice in patients with mild to moderate insomnia. The evidence for single-dose effect is contradictory. Valerian is also used in patients with mild anxiety, but the data supporting this indication are limited. The adverse effects profile and tolerability of this herb is excellent. [15]

The German Commission E monographs approved the internal use of valerian for restlessness and sleeping disorders based on nervous conditions. Valerian is a sedative and hypnotic, spasmolytic, mild anodyne, hypotensive and carminative. [16,17] In traditional herbal medicine, Valerian herb has been recommended for insomnia, anxiety, depression, restlessness and specifically for conditions presenting nervous excitability and tension. [16] It has also been shown to improve sleep latency and sleep quality, lower periods of wakefulness, reduce anxiety and relax smooth muscle. [17] Valerian combines well with Passionflower for insomnia. [17] Traditionally Valerian has also been used to promote sleep and as an anxiolytic for nervous unrest, stress, neuralgia and other spasms of smooth muscle [17]

The German Commission E Monographs approved the internal use of passionflower for nervous restlessness. [18] The British Herbal Compendium indicates its use for sleep disorders, restlessness, nervous stress, and anxiety. It has sedative, hypnotic, muscle relaxant, hypnotic, anodyne and antispasmodic properties [16] Passionflower herb is more specific for anxiety, leg muscle discomfort and insomnia associated with anxiety. It has been indicated for neuralgia, nervous tachycardia and insomnia. [16] Magnesium is a muscle relaxant, antispasmodic, and sedative and has been shown to be clinically effective for the relief of RLS. [19] Magnesium is specifically recommended for insomnia and restless legs. The citrate form has shown some clinical effectiveness in relieving leg restlessness and promoting sleep. [20] Low levels of magnesium may contribute to symptoms of RLS and poor sleep. Phosphate, oxide and sulfate forms of magnesium are included in the invention to optimize magnesium absorption and effectiveness.

In one embodiment, the invention provides a method of treating or preventing RLS, wherein the oral dosage unit is administered to the subject in an amount sufficient to treat or prevent the RLS. In another embodiment , the oral dosage unit is administered to the subject at least once per day. In another embodiment, the oral dosage unit is administered to the subject between two and six times per day. In another embodiment, the oral dosage unit is administered three times per day.

FORMULATIONS OF THE HERB-CONTAINING COMPOSITION OF THE INVENTION

The herb-containing compositions of the present invention can be used alone or further formulated with pharmaceutically acceptable compositions, and vehicles with a favorable delivery profile, i.e., suitable for delivery to a subject. Such compositions typically comprise the herb-containing composition of the invention and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal compositions, isotonic and absorption delaying compositions, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. The use of such media and compositions for biologically active substances is well known in the art. Except insofar as any conventional media or composition is incompatible with the active composition, use thereof in the compositions is contemplated. Supplementary active compositions can also be incorporated into the compositions.

A composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include, e.g., oral or transmucosal administration. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules, caplets or compressed into tablets. For the purpose of oral therapeutic administration, the herb-containing composition of the invention can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the composition in the fluid carrier is applied orally and swished and expectorated or swallowed. Compatible binding compositions can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compositions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating composition such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening composition such as sucrose or saccharin; or a flavoring composition such as peppermint, methyl salicylate, or orange flavoring.

In one embodiment, the herb-containing compositions of the invention are prepared with carriers that will protect the composition against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The invention is further defined by reference to the following examples, which are not meant to limit the scope of the present invention. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, may be practiced without departing from the purpose and interest of the invention.

EXAMPLES

Example 1 Clinical Trial of a Herb and Mineral Containing Natural Therapeutic Capsule for Restless Leg Syndrome

GENERAL

This study will be conducted to investigate the effectiveness of a herb and mineral containing natural therapeutic oral capsule in treating the symptoms of Restless Leg Syndrome (hereinafter, .test preparation). The test preparation contains 333 mg (equivalent dry weight) Valerian Herb (Standardized to contain 0.8% Valerenic acid), 500 mg (equivalent dry weight) Passionflower herb, 367 mg Magnesium citrate, 16.7 mg Thiamine nitrate (B1), 10 mg Riboflavin (B2), 16.7 mg Nicotinamide (B3), 33.3 mg Calcium panthothenate (B5), 16.7 mg Pyridoxine hydrochloride (B6), 67 meg Cyanocobalamin (B12), 167 meg Folic acid, 33.3 mg d-alpha tocopherol succinate.

MATERIALS AND METHODS Study Design

The study will be conducted according to the TGA's "Guidelines for Good Clinical Research Practice (GCRP) in Australia". The study has been approved by the Australian College of Natural Medicine Ethics Committee. The interviews are being conducted at the Naturopathic Clinic at the Australian College of Natural Medicine, Brisbane. Ten (10) participants (men and women) experiencing symptoms of RLS were recruited to the study.

Inclusion Criteria

Male or Female Persons aged between 20 and 75 years old

Persons that meet the criteria of the International Restless Legs Scale (IRLS) total score. Persons who meet the criteria of Johns Hopkins Restless Legs Severity Scale (JHRLSS). Persons that are not currently taking medications for treatment of Restless Leg Syndrome Persons who are capable of Informed Consent Exclusion Criteria

Persons whose life expectancy is severely limited due to pre-existing malignancy or other disease (<1 year).

Women who are pregnant or breastfeeding Persons taking the following medications (as they affect RLS or sleep): antinausea drugs

(prochlorperazine or metoclopramide), antiseizure drugs (phenytoin or droperidol) Persons with a history of alcohol or drug abuse, primary sleep or movement disorders, or medical conditions affecting RLS (multiple sclerosis, muscular dystrophy, epilepsy, fibromyalgia) Persons currently enrolled in another investigational study Persons unlikely to comply with study requirements Persons that have had Investigational drugs used for diagnosis or evaluation of health status during preceding 30 days

Treatment protocol: Participants will receive 1 tablet/capsule three times daily (one morning and two at night) with meals for a period of 4 weeks.

Assessment Procedures:

Participants attended interviews and completed clinical data forms and validated questionnaires prior to and during treatment. Serum Magnesium levels were also measured prior to commencement and at completion of the study

The Validated Questionnaires to be used at each time point to evaluate symptom severity include:

1. International Restless Legs Scale (IRLS) total score 2. Clinical Global Impression-Improvement scale

3. Johns Hopkins Restless Legs Severity Scale (JHRLSS)

4. Medical Outcomes Study Sleep Scale

5. RLS Quality of life score

The baseline data gathered prior to intervention was compared to the data collected during the intervention period, and analyzed to establish effectiveness of the formula. 1. International Restless Legs Scale (IRLS) total score

Symptoms and symptom relief will be assessed primarily using the validated International Restless Leg Scale (IRLS) score which was designed to monitor the prevalence and severity of the clinical features of Restless Leg symptoms. This scale was developed and validated by the International Restless Legs

Syndrome Study Group (IRLSSG) and comprises 10 questions about restless legs syndrome symptoms and their impact on daily activities and mood (Table 2). All the responses are graded in the range 0 to 4 (0 = absence of a problem, 4 = very severe problem), giving a maximum score of 40. (Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121- 32.)

Table 2

Restless Legs Syndrome Rating Scale

2. Clinical Global Impression-Improvement scale

The CGI scale is a clinical-rated instrument that consists of four subscales. The CGI-lmprovement is traditionally used as an endpoint in clinical trials for responder analyses while the other subscales are less used. The global assessment of overall severity of illness, of the overall therapeutic effect and of interference of side effects with functioning, provides additional information of the overall effectiveness of a drug treatment

3. Johns Hopkins Restless Legs Severity Scale (JHRLSS; Table 3)

Table 3

B.) Johns Hopkins Restless Legs Severity Scale

Score Usual time of day when RLS symptoms start

0 (never) No symptoms

1 (mild) At bedtime and/or during the sleep period. (Symptoms may occur within 60 minutes before the usual bedtime or simply at the time of going to red or during the night after in bed.)

2 (moderate) In the evening (6 PM or later). Symptoms may start anytime between 6 PM and the usual bedtime. (The definition of evening may need to be adjusted for patients who routinely have much later bedtimes, such as these who have an afternoon siesta.)

3 (severe) Afternoon (before 6 PM). Symptoms may start in the afternoon or may be present all day long.

4. Medical Outcomes Study Sleep Scale

1. How long did it usually take for you to fall asleep during the past 4 weeks?

0-15 minutes 1

16-30 minutes 2 31-45 minutes 3

46-60 minutes 4

More than 60 minutes 5

2. On the average, how many hours did you sleep each night during the past 4 weeks? How often during the past 4 weeks did you...

(Circle One Number On Each Line)

1. All of the Time

2. Most of the Time

3. A Good Bit of the Time 4. Some of the Time

5. A Little of the Time

6. None of the Time

3. Feel that your sleep was not quiet (moving restlessly, feeling tense, speaking, etc., while sleeping)? 1 2 3 4 5 6

4. Get enough sleep to feel rested upon waking in the morning?

1 2 3 4 5 6

5. Awaken short of breath or with a headache? 1 2 3 4 5 6

6. Feel drowsy or sleepy during the day? 1 2 3 4 5 6 7. Have trouble falling asleep? 1 2 3 4 5 6

8. Awaken during your sleep time and have trouble falling asleep again?

1 2 3 4 5 6 9. Have trouble staying awake during the day? 1 2 3 4 5 6

10. Snore during your sleep? 1 2 3 4 5 6

11. Take naps (5 minutes or longer) during the day? 1 2 3 4 5 6

12. Get the amount of sleep you needed? 1 2 3 4 5 6 MOS Sleep Scale Copyright, 1986, RAND

Hays, R. D., & Stewart, A. L. (1992). Sleep measures. In A. L. Stewart & J. E. Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study approach (pp. 235-259), Durham, NC: Duke University Press.

5. RLS Quality of Life Questionnaire The following are some questions on how your Restless Legs Syndrome might affect your quality of life. Answer each of the items below in relation to your life experience in the past 4 weeks. Please mark only one answer for each question.

In the past four weeks: 1. How distressing to you were your restless legs?

Q Not at all D A little D Some G Quite a bit D A lot

2. How often in the past 4 weeks did your restless legs disrupt your routine evening activities?

D Never D A few times D Sometimes D Most of the time D All the time 3. How often in the past 4 weeks did restless legs keep you from attending your evening social activities?

D Never D A few times D Sometimes D Most of the time D All the time

4. In the past 4 weeks how much trouble did you have getting up in the morning due to restless legs? D None D A little D Some G Quite a bit D A lot

5. In the past 4 weeks how often were you late for work or your first appointments of the day due to restless legs?

D Never D A few times G Sometimes G Most of the time G All the time

6. How many days in the past 4 weeks were you late for work or your first appointments of the day due to restless legs?

Write in number of days:

7. How often in the past 4 weeks did you have trouble concentrating in the afternoon?

G Never G A few times G Sometimes D Most of the time D All the time 8. How often in the past 4 weeks, did you have trouble concentrating in the evening?

G Never D A few times D Sometimes D Most of the time D All the time

9. In the past 4 weeks how much was your ability to make good decisions affected by sleep problems? D None D A little D Some D Quite a bit Q A lot

10. How often in the past 4 weeks would you have avoided traveling when the trip would have lasted more than two hours?

D Never D A few times D Sometimes D Most of the time D All the time

11. In the past 4 weeks how much interest did you have in sexual activity? D None D A little D Some D Quite a bit D A lot D Prefer not to answer

12. How much did restless legs disturb or reduce your sexual activities?

D None D A little G Some D Quite a bit D A lot D Prefer not to answer

13. In the past 4 weeks how much did your restless legs disturb your ability to carry out your daily activities, for example carrying out a satisfactory family, home, social, school or work life?

G Not at all G A little G Some D Quite a bit D A lot

14. Do you currently work full or part time (paid work, unpaid or volunteer)? (mark one box)

D YES If Yes please answer questions #15 through #18 D . NO, because of my RLS - Please finish

D . NO, due to other reasons - Please finish

15. How often did restless legs make it difficult for you to work a full day in the past 4 weeks?

D Never D A few times D Sometimes D Most of the time D All the time 16. How many days in the past 4 weeks did you work less than you would like due to restless legs?

Write in number of days:

17. On the average, how many hours did you work in the past 4 weeks? Write in number of hours per day: 18. On days you worked less than you would like, on average about how many hours less did you work due to your restless legs?

Write in number of hours per day

SCORING

A summary score can be calculated for the RLS quality of life questionnaire based on the following items: 1-5, 7-10 and 13. All items must be recoded such that 1 equals most severe and 5 equals least severe, so that lower scores indicate worse quality of life. The score is then transformed to a 0-100 score using the following algorithm:

[(Actual raw score - lowest possible raw score)/Possible raw score range] X 100. If more than two items are missing from the summary scale, the summary scale score cannot be calculated and is set to missing. If one or two items from the summary scale are missing, then a person-specific estimate is substituted for that missing item. This person-specific estimate is the average score, across the completed items in the summary scale, for that respondent.

Items 6 and 16-18 are scored as continuous variables, as written by the patient.

For items 6 and 16, the minimum number of days is 0 and the maximum number of days is 28. For items 17 and 18, the minimum number is 0 hours and the maximum number is

24 hours. If the response to one of these items is missing or out of range, than that item is set to missing. Items 14-18 are work-related items, thus if patients reply "2" or "3" to item 14, they are not expected to reply to items 15-18. Thus, the missing data rates for items 15-18 will be artificially inflated.

Items 11 , 12 and 15 should be scored as categorical variables. Finally, item 14 can also be treated as a categorical variable as follows: "yes" = 1 ; "no, because of my RLS" = 2; "no because of other reasons" = 3. If a response to one of these items is missing, then no score can be calculated for that item.

RESULTS AND DISCUSSION

This study is directed to evaluating the effectiveness of the test preparation to prevent or treat RLS. Where the IRLS score, CGI scale score, JHRLSS or RLS Quality of Life Questionnaire score of one or more participants (i.e., test subjects) is lower after administration of the test preparation compared with the participant's scores for any one of these tests prior to administration of test preparation means that the test preparation of the invention is useful to prevent or treat RLS.

Example 2 Clinical Trial of a Herb and Mineral Containing Natural Therapeutic Capsule for Restless Leg Syndrome

GENERAL

This study will be conducted to investigate the effectiveness of a herb and mineral containing natural therapeutic oral capsule in treating the symptoms of Restless Leg Syndrome (hereinafter, .test preparation ). The test preparation contained 333 mg (equivalent dry weight) Valerian Herb (Standardized to contain 0.8% Valerenic acid), 500 mg (equivalent dry weight) Passionflower herb (Standardized to contain 3.5-4.28% isovitexin), 367 mg Magnesium citrate, 16.7 mg Thiamine nitrate (B1), 10 mg Riboflavin (B2), 16.7 mg Nicotinamide (B3), 33.3 mg Calcium pantothenate (B5), 16.7 mg Pyridoxine hydrochloride (B6), 67 meg Cyanocobalamin (B12), 167 meg Folic acid, 33.3 mg d-alpha tocopherol succinate.

MATERIALS AND METHODS Study Design

The study will be conducted according to the TGA's "Guidelines for Good Clinical Research Practice (GCRP) in Australia". The study was approved by the Australian College of Natural Medicine Ethics Committee. The interviews are being conducted at the Naturopathic Clinic at the Australian College of Natural Medicine, Brisbane. Ten (10) participants (men and women) experiencing symptoms of RLS were recruited to the study.

Inclusion Criteria

Male or Female

Persons aged between 20 and 75 years old

Persons that meet the criteria of the International Restless Legs Scale (IRLS) total score. Persons who meet the criteria of Johns Hopkins Restless Legs Severity Scale (JHRLSS). Persons that are not currently taking medications for treatment of Restless Leg Syndrome Persons who are capable of Informed Consent

Exclusion Criteria

Women who are pregnant or breastfeeding

Persons taking the following medications (as they affect RLS or sleep): antinausea drugs (prochlorperazine or metoclopramide), antiseizure drugs (phenytoin or droperidol)

Persons with a history of alcohol or drug abuse, primary sleep or movement disorders, or medical conditions affecting RLS (multiple sclerosis, muscular dystrophy, epilepsy, fibromyalgia)

Persons currently enrolled in another investigational study

Persons unlikely to comply with study requirements

Persons that have had Investigational drugs used for diagnosis or evaluation of health status during preceding 30 days Treatment protocol:

Participants will receive 1 tablet/capsule three times daily (one morning and two at night) with meals for a period of 4 weeks.

Assessment Procedures: Participants will attended interviews and complete clinical data forms and validated questionnaires prior to and during treatment. Serum Magnesium levels will also be measured prior to commencement and at completion of the study. The Validated Questionnaires to be used at each time point to evaluate symptom severity:

3. Johns Hopkins Restless Legs Severity Scale (JHRLSS)

4. Medical Outcomes Study Sleep Scale

5. RLS Quality of life score

The baseline data gathered prior to intervention was compared to the data collected during the intervention period, and analysed to establish effectiveness of the formula.

These assessment procedures are set out in Example 1.

SCORING A summary score can be calculated for the RLS quality of life questionnaire based on the following items: 1-5, 7-10 and 13. All items must be recoded such that 1 equals most severe and 5 equals least severe, so that lower scores indicate worse quality of life. The score is then transformed to a 0-100 score using the following algorithm:

[(Actual raw score - lowest possible raw score)/Possible raw score range] X 100.

If more than two items are missing from the summary scale, the summary scale score cannot be calculated and is set to missing. If one or two items from the summary scale are missing, then a person-specific estimate is substituted for that missing item. This person-specific estimate is the average score, across the completed items in the summary scale, for that respondent.

For items 6 and 16, the minimum number of days is 0 and the maximum number of days is 28. For items 17 and 18, the minimum number is 0 hours and the maximum number is 24 hours. If the response to one of these items is missing or out of range, than that item is set to missing. Items 14-18 are work-related items, thus if patients reply "2" or "3" to item 14, they are not expected to reply to items 15-18. Thus, the missing data rates for items 15-18 will be artificially inflated.

RESULTS AND DISCUSSION

Example 3 Clinical Trial of a Herb and Mineral Containing Natural Therapeutic Capsule for Restless Leg Syndrome

GENERAL

Studies are being conducted to investigate the effectiveness of a herb and mineral containing natural therapeutic oral capsule in treating the symptoms of Restless Leg Syndrome (hereinafter, test preparation).

The test preparation contains 333 mg (equivalent dry weight) Valerian Herb (Standardized to contain 0.8% Valerenic acid), 500 mg (equivalent dry weight) Passionflower herb (Standardized to contain 3.5-4.28% isovitexin), 133 mg Magnesium citrate, 67 mg Magnesium oxide, 33.3 mg Magnesium sulphate, 133 mg Magnesium phosphate tribasic, 16.7 mg Thiamine nitrate (B1), 10 mg Riboflavin (B2), 16.7 mg Nicotinamide (B3), 33.3 mg Calcium panthothenate (B5), 16.7 mg Pyridoxine hydrochloride (B6), 67 meg Cyanocobalamin (B12), 167 meg Folic acid, 33.3 mg d-alpha tocopherol succinate. MATERIALS AND METHODS Study Design

The study is being conducted according to the TGA's "Guidelines for Good Clinical Research Practice (GCRP) in Australia". The study was approved by the Australian College of Natural Medicine Ethics Committee. The interviews are being conducted at the Naturopathic Clinic at the Australian College of Natural Medicine, Brisbane. Ten (50) participants (men and women) experiencing symptoms of RLS were recruited to the study.

Inclusion Criteria

Male or Female Persons aged between 20 and 75 years old

Exclusion Criteria

Women who are pregnant or breastfeeding

Persons currently enrolled in another investigational study Persons unlikely to comply with study requirements

Persons that have had Investigational drugs used for diagnosis or evaluation of health status during preceding 30 days

Treatment protocol:

Participants will receive 3 tablet/capsules daily (1 morning and 2 at night) with meals for a period of 4 weeks. Assessment Procedures:

Participants attend interviews and complete clinical data forms and validated questionnaires prior to and during treatment. Serum Magnesium levels will also be measured prior to commencement and at completion of the study. The Validated Questionnaires to be used at each time point to evaluate symptom severity:

1. International Restless Legs Scale (IRLS) total score

2. Clinical Global Impression-Improvement scale

3. Johns Hopkins Restless Legs Severity Scale (JHRLSS)

4. Medical Outcomes Study Sleep Scale 5. RLS Quality of life score

These assessment protocols are set out in Example 1.

The baseline data gathered prior to intervention was compared to the data collected during the intervention period, and analyzed to establish effectiveness of the formula.

SCORING

Items 6 and 16-18 are scored as continuous variables, as written by the patient. For items 6 and 16, the minimum number of days is 0 and the maximum number of days is 28. For items 17 and 18, the minimum number is 0 hours and the maximum number is 24 hours. If the response to one of these items is missing or out of range, than that item is set to missing. Items 14-18 are work-related items, thus if patients reply "2" or "3" to item 14, they are not expected to reply to items 15-18. Thus, the missing data rates for items 15-18 will be artificially inflated. ltems 11 , 12 and 15 should be scored as categorical variables. Finally, item 14 can also be treated as a categorical variable as follows: "yes" = 1 ; "no, because of my RLS" = 2; "no because of other reasons" = 3. If a response to one of these items is missing, then no score can be calculated for that item.

RESULTS AND DISCUSSION

Example 4 Clinical Study: Efficacy of the herbal and mineral containing natural therapeutic composition in treating the symptoms of Restless Leg Syndrome.

This Example details the interim (month 1) results for the study into the efficacy of a herbal composition containing 333 mg Valerian Herb (Standardized to contain 0.53 mg Valerenic acid, 500 mg Passionflower Herb (Standardized to contain 3.45 mg isovitexin), 133 mg Magenesium citrate, 133 mg Magnesium phosphate tribasic, 67 mg Magnesium oxide, 67 mg Magnesium sulfate, 16.7 mg Thiamine nitrate (B1), 10 mg Riboflavin (B2), 16.7 mg Nicotinamide, 33 mg Calcium panthothenate, 16.7 mg Pyroxidine hydrochloride (B6), 67 meg Cyanocobalamine (B12), 166 mg Folic acid and 33.3 mg d-alpha tocopherol succinate in treating the symptoms of Restless Leg Syndrome.

Demographics:

The number of participants in this study was 26 (20 women and 6 men). They were aged between 33 and 84 years (average age 58 years). Results:

1. IRSS (validated questionnaire)

The IRLS was developed and validated by the International Restless Legs Syndrome Study Group. Subsequent validation studies were conducted for the IRLS which confirmed the reliability, validity and responsiveness of the IRLS. The IRLS consists of 10 questions concerning the patient's symptoms and the impact of these symptoms on daily activities and mood. Responses range from 0 to 4, with 0 representing the absence of a problem and 4 representing a very severe problem. The IRLS questionnaire is provided in Table 2 of Example !

Group results:

The group results for symptom severity are summarized in Table 4.

The distribution of symptom severity at Baseline is: Mild - 2, Moderate -12 , Severe - 8, Very Severe - 4. The average IRSS Score for this group at baseline was 21.3 (Severe category).

After one month of treatment, the average IRSS score reduced to 14.9 (to Moderate category). One (1) participant reported no symptoms at all. There were 8 people experiencing mild symptoms and only 7 (compared to 12 at baseline) reporting Severe or Very Severe Restless Leg Symptoms.

Overall, there was an average of 30% reduction in symptom severity for this group Table 4: The IRSS Severit Scores at Baseline and at Month 1 of treatment.

Individual results:

The individual results for the IRSS are summarized in Table 5.

These results indicated that 21 of the 26 participants reported a reduction in symptom severity, with 13 of these translating to a reduction in classification of the symptom severity.

One participant reported a complete absence of restless leg symptoms after 1 month of treatment using the IRSS. The comments given by the participant (RLS03) at the interview were: "I have experienced an amazing amount of relief within the first week. This stuff really works. Don't need a body pillow".

The majority of participants experienced a level of relief between 20 -70 % (n = 14). The comments from people in this group included:

* (RI_S01) "more peaceful in bed, good nights, more alert during the day, calm approach to activities"

^* (RLS015) "sleep improved, more energy during the day" * (RLS018) "no RLS early evening, fall asleep straight away, significant improvement * (RLS020) "RLS reduced. Better sleep and feel refreshed during the days" ^* (RLS023) "the pain in the legs has disappeared, all symptoms relived by day 4 of taking product"

A smaller number of participants reported small changes at this stage (between 5 and 19% reduction, n = 5), while 5 participants reported minimal or no change at this time.

One participant (RLS024) who reported no symptom relief has been diagnosed with hypothyroidism. Interestingly, another participant (RSL013) who is on medication with normal thyroid function did experience a 42.9% reduction in symptoms.

Table 5: Individual results for the IRSS

Rating

IRSS Value IRSS Value % Reduction Rating change

Baseline Month 1 Baseline Month 1

RLS01 20 7 65.0 Severe Mild

RLS02 26 24 7.7 Severe Severe

RLS03 33 1 100.0 V Severe Mild

RLS04 12 10 16.7 Moderate Mild

RLS05 14 11 21.4 Moderate Moderate

RLS06 19 9 52.6 Moderate Mild

RLS07 20 18 10.0 Moderate Moderate

RLS08 24 18 25.0 Severe Mild

RLS09 31 21 32.3 V Severe Severe

RLS010 29 21 27.6 Severe Severe

RLS011 19 7 63.2 Moderate Mild

RLS012 16 16 0.0 Moderate Moderate

RLS013 21 12 42.9 Severe Moderate

RLS014 18 14 22.2 Moderate Moderate

RLS015 35 18 48.6 V Severe Moderate

RLS016 8 8 0.0 Mild Mild

RLS017 24 17 29.2 Severe Moderate

RLS018 16 16 0.0 Moderate Moderate

RLS019 19 9 52.6 Moderate Mild

RLS020 26 22 15.4 Severe Severe

RLS021 26 21 19.2 Severe Severe

RLS022 31 31 0.0 V Severe V Severe

RLS023 19 10 47.4 Moderate Mild

RLS024 11 13 -18.2 Moderate Moderate

RLS025 13 10 23.1 Moderate Mild

RLS026 24 23 4.2 Severe Severe

Average 21.3 14.9 30.1% The group average for each of the actual questions in the IRSS was also analyzed. These results are shown in Table 6 and demonstrate that there was improvement in all areas of Restless Leg Symptoms. Overall, these results show that better quality of sleep has an overall positive effect on quality of life.

Table 6: Average result for each individual question in the IRSS

Baseline Mo

Q1 2.6 1.8

Q2 2.4 1.6

Q3 2.3 1.9

Q4 2.3 1.4

Q5 2 1.3

Q6 2.4 1.8

Q7 3 2.3

Q8 2.3 1.8

Q9 1.2 0.6

Q10 1.2 0.6

2. Sleep Clinic Results:

One participant was also having Sleep Clinic evaluations at the same time as participating in the study. The Sleep Clinic results indicated that there was significantly less leg movements during the night after one month of treatment compared to the same test taken 6 weeks prior to starting the treatment.

3. Relationship to serum magnesium levels.

Prior to commencement of treatment, all participants had serum magnesium levels tested. Magnesium deficiency has been cited as a possible cause of Restless Leg Syndrome. The serum magnesium levels were within reference range for all participants (0.7 - 1.1 mmol/L). 4. Adverse Effects:

There have been no adverse side effects reported with use of this product. One participant stated that taking the capsules later in the evening seemed to make it more difficult to get to sleep.

REFERENCES

Avecillas, J. F., Golish, J.A., Giannini, C, & Yataco, J. C, Restless Legs Syndrome: Keys to recognition and Treatment. Cleveland Clinic Journal of Medicine. 2005., Vol. 72. No. 9. Evidente, V.G.H., Adler, CH. How to Help Patients with Restless Leg Syndrome: Discerning the indescribable and relaxing restless. 1999. Vol. 105, No. 3.

NINDS Restless legs Fact sheet. Publication date April 2001

Silber et. al. An Algorithm for the Management of Restless Legs Syndrome. Mayo Clinic Proc. 2004; 79 (7):916-922 Rados, Carol, Treating Restless Legs Syndrome, FDA Consumer Rockville: 2006. vol. 40, Iss. 3:26.

Trenkwalder, C, Paulus, W., & Walters, A. S., The Restless Legs Syndrome. 2005. Vol. 4.

Paulson, George. W., Restless Legs Syndrome: How to Provide Symptom Relief with Drug and Non-Drug Therapies. Geriatrics 2000. vol. 55, Iss. 4:35 Earley, CJ. , Restless Legs Syndrome. The New England Journal of Medicine. 2003. vol. 348, Iss. 21 :2103.

American Family Physicians. Restless Legs Syndrome: Detection & Management in Primary Care. 2000; 62:108-14.

Clark, Mathew. M., Restless Legs Syndrome. J Am Board Family Practice. 2001; 14: 368- 74.

Chesson, et.al. Practice Parameters for the Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder: Sleep. 1999, vol. 22, no. 7.

Mathis, Johannes. Update on Restless Legs. Swiss Medical Weekly. 2005; 135: 687-696.

Werbach, M. R., Nutritional Influences on Sleep. Townsend Letter for Doctors and Patients. April. 2004.

German Commission E Monograph: Valerian herb, Integrative Medicine Communications, Inc. 2000)

Hadley, S. & Petry, J., Valerian. The American Academy of Family Physicians. 2003;67:1755-8. British Herbal Pharmacoepia.scientific committee, BHMA, 1983, p.226, Principles and Practice of Phytotherapy, Mills & Bone, 2000.

German Commission E Monograph: Passionflower herb, Integrative Medicine •Communications, Inc. 2000 The Therapeutic Research Faculty. Natural Medicines Comprehensive Database: Magnesium 2004.

Hornyak, M., Voderholzer, U., Hohagen F., Berger M and Riemann D. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep. 1998. Aug 1 ; 21 (5): 501-5. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4: 121-32.)

EQUIVALENTS

While the invention has been described in connection with the specific embodiments thereof, it will be understood that it is capable of further modification. Furthermore, this application is intended to cover any variations, uses, or adaptations of the invention, including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains, and as fall within the scope of the appended claims.

Claims

We claim:

1. A method of preventing or treating a restless leg syndrome, the method comprising administering to a subject afflicted with or at risk of the restless leg syndrome a herb-containing composition comprising: at least about 13.96 weight percent final concentration of a Passionflower herb 5.5:1 extract preparation standardized to contain at least about 3.5 weight percent isovitexin and at least about 10.24 weight percent final concentration of a Valerian officinalis herb 5:1 extract preparation standardized to contain at least about 0.8 weight percent valerenic acid; wherein administration of the composition reduces the symptoms of the restless leg syndrome.

2. The method of claim 1 , wherein the herb-containing composition is formulated in a dry delivery system.

3. The method of claim 1 , wherein the herb-containing composition is formulated in a liquid delivery system.

4. The method of claim 1 , wherein the herb-containing composition is formulated in a controlled-release vehicle.

5. The method of claim 1 , wherein the oral dosage unit is selected from the group consisting of: a tablet; dry powder; capsule; and caplet.

6. The method of any one of claims 1-5, wherein the herb-containing composition further comprises at least one compound selected from the group consisting of:

(a) magnesium citrate present at a concentration of at least about 20.48 weight percent final concentration;

(b) magnesium phosphate tribasic present at a concentration of at least about 20.48 weight percent final concentration;

(c) magnesium oxide present at a concentration of at least about 10.24 weight percent final concentration;

(d) magnesium sulfate present at a concentration of at least about 5.12 weight percent final concentration (e) thiamine nitrate present at a concentration of at least about 2.56 weight percent final concentration;

(f) riboflavin present at a concentration of at least about 1.54 weight percent final concentration;

(g) nicotinamide present at a concentration of at least about 2.56 weight percent final concentration

(h) calcium pantothenate present at a concentration of at least about 5.12 weight percent final concentration; (i) pyridoxine hydrochloride present at a concentration of at least about 2.56 weight percent final concentration; (j) cyanocobalamin present at a concentration of at least about 0.01 weight percent final concentration; and (k) folic acid present at a concentration of at least about 0.026 weight percent final concentration.

(I) d-alpha tocopherol succinate present at a concentration of at least about 5.12 weight percent final concentration.

7. An herb-containing composition, comprising:

(a) a Passionflower herb 5.5:1 extract preparation standardized to contain at least about 3.5 weight percent isovitexin present at least about 13.96 weight percent;

(b) a Valerian officinalis herb 5:1 extract preparation standardized to contain at least about 0.8 weight percent valerenic acid present at a concentration of at least about 10.24 weight percent; and

(c) at least one compound selected from the group consisting of:

(i) magnesium citrate present at a concentration of at least about

20.48 weight percent final concentration; (ii) magnesium phosphate tribasic present at a concentration of at least about 20.48 weight percent final concentration; (iii) magnesium oxide present at a concentration of at least about 10.24 weight percent final concentration; (iv) magnesium sulfate present at a concentration of at least about 5.12 weight percent final concentration (v) thiamine nitrate present at a concentration of at least about 2.56 weight percent final concentration; (vi) riboflavin present at a concentration of at least about 1.54 weight percent final concentration; (vii) nicotinamide present at a concentration of at least about 2.56 weight percent final concentration (viii) calcium pantothenate present at a concentration of at least about

5.12 weight percent final concentration; (ix) pyridoxine hydrochloride present at a concentration of at least about

2.56 weight percent final concentration; (x) cyanocobalamin present at a concentration of at least about 0.01 weight percent final concentration; and (xi) folic acid present at a concentration of at least about 0.026 weight percent final concentration.

(xii) d-alpha tocopherol succinate present at a concentration of at least about 5.12 weight percent final concentration.

8. A herb-containing composition, comprising:

(a) a Passionflower herb 5.5:1 extract preparation standardized to contain at least about 3.5 weight percent isovitexin present at a concentration of about 13.96 weight percent;

(b) a Valerian officinalis herb 5:1 extract preparation standardized to contain at least about 0.8 weight percent valerenic acid present at a concentration of about 10.24 weight percent;

(c) magnesium citrate present at a concentration of about 20.48 weight percent final concentration;

(d) magnesium phosphate tribasic present at a concentration of about 20.48 weight percent final concentration;

(e) magnesium oxide present at a concentration of about 10.24 weight percent final concentration;

(f) magnesium sulfate present at a concentration of about 5.12 weight percent final concentration

(g) thiamine nitrate present at a concentration of about 2.56 weight percent final concentration; (h) riboflavin present at a concentration of about 1.54 weight percent final concentration; (i) nicotinamide present at a concentration of about 2.56 weight percent final concentration (j) calcium pantothenate present at a concentration of about 5.12 weight percent final concentration; (k) pyridoxine hydrochloride present at a concentration of about 2.56 weight percent final concentration; (I) cyanocobalamin present at a concentration of about 0.01 weight percent final concentration; and (m) folic acid present at a concentration of about 0.026 weight percent final concentration.

(n) d-alpha tocopherol succinate present at a concentration of about 5.12 weight percent final concentration.