FIELD OF THE INVENTION

The present invention relates to polyherbal sleep inducing composition that induces and maintains sleep in humans. The present invention also relates to process for preparing the sleep inducing composition and to method of promoting sleep. The sleep inducing compositions according to the present invention exhibits improved characteristic such as effective induction and maintenance of sleep throughout the night without night awakenings, significant reduction in the morning hangover and day time drowsiness and prevention of habit forming adverse effects.

In addition, the present invention also related to a palatable polyherbal sleep inducing composition having improved sensory characteristics such as improved mouthfeel, taste and odour. The present invention also relates to process for preparing such composition.

BACKGROUND OF THE INVENTION

Sleep is a behavioral state that is a natural part of every individual's life. Sleep typically occupies about one-third of a person's life and affects a person's mental and physical well-being. Nonetheless, little is known about the importance of this essential activity.

Even though the precise functions of sleep remains ambiguous, sleep is important for normal motor and cognitive function. In fact sleep appears to be required for survival. It additionally affects mood, behavior and physiology. Sleep and the control of sleep is a complex process involving multiple chemicals and brain structures. It is a dynamic process involving distinct physiological changes and involves both positive and negative signaling.

The need for sleep is a biological drive similar to thirst or hunger. Interestingly though, the function of sleep is largely unknown, however some evidence indicates that sleep is required for learning (Stickgold R, James L, Hobson J A. Visual discrimination learning requires sleep after training. Nat Neurosci. 2000 December; 3(12): 1237-8.; Gais S, Plihal W, Wagner U, Born J. Early sleep triggers memory for early visual discrimination skills. Nat Neurosci. 2000 December; 3(12): 1335-9.). Additionally, sleep deprivation studies in rats have shown that when rats are not allowed to sleep, the end-result is death apparently related to immune system failure (Everson CA. Sustained sleep deprivation impairs host defense. Am J Physiol.

1993 November; 265(5 Pt 2):R1148-54.). In humans, similarly, mild sleep deprivation also results in indications of impaired immune system function (Irwin M, McClintick J, Costlow C, Fortner M, White J, Gillin J C. Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J. 1996 April; 10(5):643-53.). Although specific sleep requirements vary from individual to individual, sleeping less than six hours per day has been shown to increase the risk of glucose intolerance and diabetes (Gottlieb D J, Punjabi N M, Newman A B, ResnickH E, Redline S, Baldwin C M, Nieto F J. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005 Apr. 25; 165(8):863-7.).

Of the more than 70 known sleep disorders, the most common are insomnia, obstructive sleep apnea, narcolepsy, and restless legs syndrome. Large numbers of individuals suffering from these sleep disorders are unaware of and have not been diagnosed or treated for their disorder.

Trouble in falling asleep, unsatisfactory sleep quantity manifesting as difficulty in falling asleep or early morning awakening and/or poor sleep quality manifesting as increased number of nightly awakenings are generally known as insomnia. In an individual the episodes of insomnia may occur intermittently (episodic), may last up to 3 weeks (short-term) or be long-lasting (chronic). Insomnia can impact people of all ages, but elderly in particular are commonly affected with estimated prevalence ranging from 13 to 47%. In India alone, around 35% of adults are affected by insomnia out of which 10% suffers from chronic insomnia. Women are far more vulnerable to encounter insomnia than their male counterparts.

Sleeplessness can have many causes, but the biggest cause is due to stress. The use of stimulants, including caffeine, alcohol, nicotine or other over-the-counter or prescription medications will also cause sleeplessness. Prescription drugs, including some antidepressant, high blood pressure and steroid medications, can interfere with sleep.

Change in sleeping environment or work schedule and even long-term use of sleep medications may cause sleeplessness. Medical problems, including fibromyalgia or complex diseases of the nerves and muscles can make it very difficult to fall asleep and stay asleep.

Consequences of inadequate sleep includes tiredness, lack of energy, day time somnolence, poor concentration and performance, irritability and depression, emotional instability, reduced ability to enjoy life and increased risk of accidents and absenteeism from work.

There are many remedies available for treating sleeplessness such as yoga, meditation, good sleeping environment, single herbal remedies, nutritional advice, hydrotherapy exercise, etc. However, these remedies are not efficient over short period of time or may result in hangover. Modern drugs approved for treatment of insomnia does not seem to offer complete relief from the sleep related problems, not to mention the various adverse side effects including day time drowsiness, decreased concentration, dependence, withdrawal symptoms and even addiction to these drugs.

Over the last century, a variety of hypnotic agents have been introduced into medicine ranging from the bromides and chloral hydrate through the barbiturates and the benzodiazepines agents. Even though benzodiazepines are safe and effective in the short term, cognitive impairments and paradoxical effects such as aggression or behavioral disinhibition occasionally occur. Long-term use is controversial due to concerns about adverse psychological and physical effects, increased questioning of effectiveness and because benzodiazepines are prone to cause tolerance, physical dependence, and, upon cessation of use after long term use, a withdrawal syndrome. The elderly are at an increased risk of suffering from both short- and long-term adverse effects.

Commercially available sleep inducing tablets such as Zolpidem, a benzodiazepine like sedative-hypnotic drug and alprazolam, a benzodiazepine class of psychoactive drugs, which like other benzodiazepines binds to benzodiazepine site situated at the interface between the a- and y-subunits of a- and y-subunit containing GABAA receptors, exhibits potentially dangerous complex sleep-related behaviors similar to that of benzodiazepine (Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P. Evidence of Zolpidem abuse and dependence: Results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br J Clin Pharmacol 2007; 64:198-209).

On January 10, 2013, the Food and Drug Administration announced to cut the recommended dosage of Zolpidem in half for women after laboratory studies showed that the medicines can leave patients drowsy in the morning and at risk for car accidents {"FDA tells drugmakers to lower doses for Ambien, other sleeping pills". CBS News. Retrieved 10 January 2013).

Therefore, there is a need in the art for a natural and safe sleep inducing composition that can be administered for people of all age without the aforesaid side effects thus maintaining the quality of life. It is also essential that the composition is palatable and pleasant to be more appealing to consumers and easy to prepare.

SUMMARY OF THE INVENTION

The present invention according to one embodiment thereof, provides for a composition for inducing sleep. More specifically, the invention is directed towards a polyherbal sleep inducing composition for inducing and maintaining sleep throughout the night without night awakenings, morning hangover, day time drowsiness and habit forming adverse effects, thus further improving the quality of the person's life.

According to an embodiment, the present invention provides a composition comprising Valeriana officinalis, Passiflora incarnata and Humulus lupulus or derivatives thereof.

Advantageously, the ingredients of the composition are provided in amounts effective to promote good quality sleep.

In another embodiment, the present invention provides a palatable composition for inducing sleep having improved sensory characteristics such as improved mouthfeel, taste and odour.

According to an additional embodiment, the composition may include one or more of pharmaceutically acceptable excipients. The composition may include standard dosage forms e.g., a capsule, a tablet, a caplet, a liquid beverage, a powder beverage mix, or as a dietary gel.

In another embodiment, the present invention provides a process for preparing a composition comprising Valeriana officinalis, Passiflora incarnata and Humulus lupulus or derivatives thereof.

In a further embodiment, the present invention provides a process for inducing sleep with the composition according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention according to an embodiment thereof is advantageously directed towards a polyherbal sleep inducing composition which, for example, induces and maintains sleep throughout the night without night awakenings, does not cause morning hangover or day time drowsiness and prevents habit forming adverse effects, thus further improving the quality of the person's life.

In a particular embodiment, the sleep inducing composition comprising Valeriana officinalis, Passiflora incarnata and Humulus lupulus or derivatives thereof. Preferably, the sleep inducing composition of the present invention comprises:

70 to 75% of Valeriana officinalis,

15 to 20% of Passiflora incarnata, and

6 to 8% of Humulus lupulus

Compounds employed in the present invention have been shown to be active at receptor sites in the central nervous system that relate to the induction and maintenance of sleep.

Valeriana officinalis, especially the root, normally called valerian root, is a perennial herb grown in Europe & North America. The valerian root has been found to possess sedative, hypotensive, hypnotic, sleep promoting, anti-spasmodic and mild tranquilizer effects. The activity of valerian is attributed to a group of sedatives called monoterpenes, sesquiterpenes, valerenic acid and valpotriates.

Compounds from valerian interact with GABA, melatonin, and/or adenosine systems through binding to certain melatonin and serotonin receptor subtypes (Abourashed E A, Koetter U, Brattstrom A. In vitro binding experiments with a Valerian, hops and their fixed combination extract (Ze91019) to selected central nervous system receptors. Phytomedicine. 2004 November; ll(7-8):633-8.), particularly the 5-HT5A subtype (Dietz B M, Mahady G B, Pauli G F, Farnsworth N R. Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro. Brain Res Mol Brain Res. 2005 Aug. 18; 138(2): 191-7.). Interaction with this receptor is thought to be responsible for the sleep-inducing and maintenance effect of valerian root extract.

Valerian root extract has proven to be useful in several clinical trials. Subjective self-evaluation of sleep quality improved in a valerian supplemented group as part of a randomized controlled trial (Leathwood P D, Chauffard F, Heck E, Munoz-Box R.

Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav. 1982 July; 17(1):65-71.\ compared to control groups. In another clinical trial, the valerian group reported improved sleep over the placebo group, with 89% of participants reporting improved sleep (Lindahl O, Lindwall L. Double blind study of a valerian preparation. Pharmacol Biochem Behav. 1989 April; 32(4): 1065-6.). Sleep was additionally improved in children with various intellectual deficits, particularly those with hyperactivity (Francis A J, Dempster R J. Effect of valerian, Valeriana edulis, on sleep difficulties in children with intellectual deficits: randomised trial. Phytomedicine. 2002 May; 9(4):273-9.).

As used herein, "Valeriana officinalis" includes any of the fresh, dried, ground, or powdered parts of Valeriana Officinalis Linne, such as the rhizome, roots, and stolons, any extract or volatile oil obtained from Valeriana Officinalis, and any compounds collectively referred to as valerenic acids. Examples of compounds collectively referred to as valerenic acids are valerenic acid, hydroxyvalerenic acid, acetoxyvalerenic acid, valerenal, valeranone, kessyl glycol, and valepotriates, such as didrovaltrate, valtrate, and isovaltrate.

In an embodiment of the present invention, which is set forth in greater detail in Example 1 below, the composition may include valerian root. The composition may include from about 1.2 gm to about 300 mg of valerian root. The preferred dosage of the composition comprises about 300 mg of valerian Root.

Passiflora incarnata commonly known as Passion flower is a perennial vine with flowers and it is grown in North America, South America and Europe. Passion flower has been used for relaxation and as a sleep-aid as well as a treatment for anxiety. It possess anxiolytic, hypnotic, hypotensive, sleep inducing, analgesic, and anti spasmolytic effects. Passion flower contains flavonoids (Isovitexin) as an active principle and is a primary constituent for its relaxing and anti-anxiety effects. Other bioactive compounds in passion flower include alkaloids, phenols, cyanogenic compounds, etc. Passion flower has a complex activity on the central nervous system (CNS), which is responsible for its overall tranquilizing effect.

Passion flower also activates GABA receptors to mediate anxiolytic and sedative properties. Clinical trials in humans have demonstrated that Passionflower is effective in the treatment of anxiety (Akhondzadeh S, Naghavi H R, Vazirian M, Shayeganpour A, Rashidi H, Khani M. Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. JClinPharm Ther. 2001 October; 26(5):363-7.).

US Patent No. 6,080,410, entitled "Method for Reducing Daily Stress and Anxiety in Adults," describes a method of employing a novel dietary supplement which serves a general relaxant comprised of Kava root extract, and at least one of Passionflower, Chamomile Flower, Hops, and Schizandra Fruit. The method claims to reduce daily stress and anxiety in adults. It is administered in capsule format.

US Patent No. 5,681,578, entitled "Composition for Relieving Stress Anxiety, Grief, And Depression," describes a composition comprising gamma Aminobutyric acid, glutamine, glycine, magnesium, passionflower, primal officinalis and vitamin B6. The composition is purported to relieve stress, anxiety, grief and depression.

As used herein, "Passiflora incarnata" includes fresh, dried, ground, or powdered whole plant or parts thereof, such as the stem, roots, flowers, any extract or volatile oil obtained from Passiflora incarnata, such as benzoflavone, alkaloids, phenols, cyanogenic compounds, etc.

In an embodiment of the present invention, which is set forth in greater detail in Example 1 below, the composition may include Passionflower extract. The composition may include from about 800 mg to about 80 mg of Passionflower extract. The preferred dosage of the composition comprises about 80 mg of Passionflower extract.
Humulus lupulus, commoly known as hop plant, is a flowering vine used as a sedative to assist with anxiety reduction and sleep difficulties. In mice, hops extract displays sleep-enhancing and antidepressant activities (Zanoli P, Rivasi M, Zavatti M, Brusiani F, Baraldi M. New insight in the neuropharmacological activity of Humulus lupulus L. J Ethnopharmacol. 2005 Oct. 31; 102(l):102-6.). Pharmacology studies shows that the partial agonistic activity at A(l) Adenosine receptors may thus play a role in sleep inducing effects of hops (Muller CE et al (2002), Interactions of Valerian extracts and a valerian - hop extract combination with adenosine receptors, Life Sci. sep 6;71(16): 1939-49).

As used herein, "Humulus lupulus" includes fresh, dried, ground, or powdered cone, any extract including flavonoids (rutin 0-5%) or volatile oil (lupulin 0.3-1%) obtained from Humulus lupulus.

In an embodiment of the present invention, which is set forth in greater detail in Example
1 below, the composition may include hops cone extract. The composition may include from about 210 mg to about 30 mg of hops cone extract. The preferred dosage of the composition comprises about 30 mg of hops cone extract.

The polyherbal sleep inducing composition according to the present invention is unique in that the present inventors have identified that activation of combination of receptors are necessary for achieving the required result. The three essential ingredients of the present composition such as Valeriana officinalis, Passiflora incarnata and Humulus lupulus induces sleep by specifically activating GAB A receptors and A(l) Adenosine receptors. These non-benzodiazepine agents enhance the natural effect of GABA thereby reducing the neural activity even further.
A(l) Adenosine receptors have important roles in the brain. Its activation inhibits the release of neurotransmitters such as dopamine and glutamate from primary afferents thereby slowing the metabolic activity. Glutamate serves as the precursor for the synthesis of the inhibitory GABA in GABA-ergic neurons. This reaction is catalyzed by glutamate decarboxylase (GAD), which is most abundant in the cerebellum of the brain.

Thus inhibition of glutamate release is essential for better activation of GABA receptors in the brain.

Stimulation of the Al receptor also has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate.

The benzoflavones of Passiflora incarnate was also shown to significantly reduce symptoms of withdrawal from, and addiction and dependence of benzodiazepines, alcohol, morphine, nicotine and cannabis (Kamaldeep Dhawan (2003). "Drug/substance reversal effects of a novel tri-substituted benzqflavone moiety (BZF) isolated from Passiflora incarnata Linn. - a brief perspective". Addiction Biology 8 (4): 379-386.)

These were considered to be of particular interest by the present inventors because the unique blend of the polyherbal sleep inducing composition according to the present invention reacts in a synergistic manner to induce and maintain sleep throughout the night without night awakenings by enhancing the activation of the GAB A receptors both directly by binding to it and indirectly by activating adenosine receptors. The composition of the present invention also significantly reduces morning hangover, day time drowsiness and habit forming adverse effects because of the distinctive mechanism of action of the ingredients of the composition on the GABA receptors in conjunction with the neurosteroidal mechanism of the benzoflavones of Passiflora incarnate.

The present invention according to another embodiment provides the composition for inducing sleep in highly palatable form having improved sensory characteristics such as improved mouthfeel, taste and odour. It is essential that the composition according to the present invention is palatable, pleasant and as well easy to prepare.

A problem associated with Valeriana officinalis, one of the major ingredients of the present inventive, is that it exhibits strong, identifying, characteristic and unpleasant smell or odor and an related disagreeable taste. Its extract has an odor that is often described as being similar to dirty socks. The origin of the word "pew" is said to come from the foul odor of the valerian root, which a first century AD Roman physician, Dioscorides, called phu. The volatile oils that form the active ingredient are extremely pungent, somewhat reminiscent of well-matured cheese. Though some people may remain partial to the earthy scent, some finds it to be unpleasant, comparing the odor to that of unwashed feet (Harrington, H.D., Edible Native Plants of the Rocky Mountains,

The University of New Mexico Press, 1967, LCCN 67-29685, p. 225). Hence valerian extract are generally found to be extremely distasteful and are difficult to swallow when taken orally. This fact has been confirmed by many people who have been prescribed

Valeriana officinalis for various indications and is the major cause for discontinuation of the treatment. This characteristic odor and/or this characteristic taste make consuming sufficient therapeutic quantities of Valeriana officinalis difficult for a substantial percentage of the population.

Methods are known for masking odors of smelly substances are known. For example, and most typically, coating the substance with pharmaceutically-inert coat useful in masking the odor may be coated in to the medicament to change the taste of oral medications.

Alternative methods to change the smell or taste of medicaments are available, such as smell masking or taste masking. One of the common goals of these various methods of taste and smell masking is to make the medication more appealing to consumers. This goal may lead to an increase in consumer compliance with prescribed and/or recommended dosing regimens.

U.S. Patent No. 5,211,948 reported effort to mask the smell of Valeriana extract, by identifying the degradation products of valepotriates as the odor causing agents in the aqueous extraction of valerian root. This reference describes that the odors may be eliminated by, for example, concentrating the aqueous extract and precipitating the resultant extract with acetone. The precipitated components may then be removed from the rest of the extract via centrifugation. The reference describes that the valerenic acids found in the roots remain present in the resulting extract, and that the resulting extract has a neutral taste and smell. However, U.S. Patent Application Serial No. 60/173,983 describes that (1) when an aqueous extract of valerian root was produced according to a method of the US '948 patent, it was observed that the extract still contained the significant, distinctive, characteristic and pungent smell and associated taste of Valeriana.

Certain conventional approaches for masking odors of medicinal preparations, especially tablets, also utilize sugar-coating technology. Such conventional technology typically requires the use of a non-perforated coating pan and generally requires extensive materials, long processing times, multiple stages/layers, and experienced scientists to obtain products with acceptable quality, i.e. odor masking and smooth appearance. Thus the present inventors are now presented with a new challenge of providing the composition of the present invention in more palatable form having improved sensory characteristics in a cost effective way.

This is achieved according to the present invention which is based on the unexpected finding that a flavoring agent, preferably ethyl vanillin incorporated into the sleeping composition according to the present invention improved sensory characteristics, such as improved mouthfeel, taste and odor. In addition the unpleasant lingering flavours, regurgitation and eructation are reduced in compositions of the invention. Many flavoring agents may be known to be useful in masking the unpleasant odor of smelly substances.

However, there is no recognition of particular flavoring agent that could effectively mask the unbearable odor of the Valeriana officinalis. Surprisingly the ethyl vanillin has been found to contain significant flavour masking properties so that the characteristic flavor of the compositions is considerably reduced.

This method provides an advantage of allowing for the use of conventional technique and the advantage of improved odor-masking efficiency when compared to commercially available valerian tablets. According to the present invention, odor reduction may be achieved with ethyl vanillin compared to the commercially available products.

In a particular embodiment, the palatable sleep inducing composition in addition to Valeriana officinalis, Passiflora incarnata and Humulus lupulus or derivatives, comprises ethyl vanillin compound. Preferably, the sleep inducing composition of the present invention comprises at least 0.012% of ethyl vanillin.

In a particular embodiment the present invention provides a process for preparing a composition comprising Valeriana officinalis, Passiflora incarnata and Humulus lupulus or derivatives thereof. Advantageously, the process comprises the steps of:

a) sieving Valeriana officinalis, Passiflora incarnata, Humulus lupulus and the pharmaceutical excipients separately;

b) admixing povidone with isopropyl alcohol to produce isopropyl alcohol-povidone mixture;

c) mixing Valeriana officinalis, Passiflora incarnata, Humulus lupulus and the pharmaceutical excipients manually or in a mixer;

d) adding the isopropyl alcohol-povidone mixture of step b) to the mixture of step c) and mixing thoroughly till granules are formed;

e) the granules are then allowed for air drying by any conventional method;

f) the partially dried granules of step e) are transferred into tray drying;

g) lubricants are added subsequently to the dried granules and mixed thoroughly;

h) the above mixture is compressed into tablets using conventional compression equipment.

In a particular embodiment, the present invention may include pharmaceutical excipients, wherein the excipients includes, without being limited to, conventionally available excipients for formulating the composition into standard dosage forms, e.g., a capsule, a tablet, a caplet, a liquid beverage, a powder beverage mix, or as a dietary gel. Suitable liquid forms include, but are not limited to, solutions, emulsions, and suspensions. Suitable tablets include, but are not limited to, soft and hard, chewable and non-chewable forms. The preferred dosage form of the present embodiment is a tablet.

The pharmaceutical composition are prepared using a pharmaceutically acceptable "carrier" composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The "carrier" is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term "carrier" includes but is not limited to diluents, binders, lubricants, desintegrators, fillers, and coating compositions.

"Carrier" also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants.

Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phtlialate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name

Eudragit® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.

Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.

Diluents, also termed "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar.

Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not, limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydorxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidpne.
Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAP Chemical Corp).

Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include/but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol mpnostearate, propylene glycol
1 A myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, , P5G-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene oetylphenylether,, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene, gjycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polypxyethylene hydrogenated tallow amide.

Examples of amphoteric surfactants include sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta,-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

If desired, the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.

The immediate release dosage unit of the dosage form~i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form-contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads). A preferred method for preparing immediate release tablets (e.g., as incorporated into a capsule) is by compressing a drug-containing blend, e.g., blend of granules, prepared using a direct blend, wet-granulation or dry-granulation process. Immediate release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, preferred tablets herein are manufactured using compression father than molding. A preferred method for forming immediate release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, colorants or the like. As an alternative to direct blending, a drug-containing blend may be prepared by using a wet-granulation or dry-granulation processes. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical method for preparing drug-containing beads involves blending the active agent with conventional pharmaceutical excipients such as microcrystalline cellulose, starch, polyvinylpyrrolidone, metjiylcellulqse, talc, metallic stearates, silicone dioxide, or the like. The admixture is used to coat a bead core such as a sugar sphere (or so-called "non-pareil") having a size of approximately 20 to 60 mesh. An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrfolidone, talc, magnesium stearate, a disintegrate, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads. The amount of active agent released in each dose will be a therapeutically effective amount.

The extended release dosage formulation and the delayed release dosage formulations may be prepared by conventional techniques such as described in references "Remington

- The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, which provides information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.

The devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, granules, etc. An immediate release portion can be added to the extended release system by means of either applying an, immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.

In a particular embodiment, the pharmaceutical composition of the present invention
comprises the following:

Valeriana officinalis - 300 mg

Passiflora incarnata - 80 mg

Humulus lupulus - 30 mg

Microcrystalline Cellulose - 60 mg

Povidone - 10 mg

Sodium benzoate - 0.5 mg

Starch - 50 mg

Isopropyl Alcohol - 28000 ml

In another embodiment, the above composition contains 0.012 % of ethyl vanillin as masking agent.

As set forth above, the dosage form of the composition, in accordance with the example embodiment set forth below, may be provided in accordance with customary processing techniques for herbs, wherein the active ingredients are suitably processed into a desired form.

A kit is provided wherein the pharmaceutical composition of the invention is packaged accompanied by instructions. The packaging material may be a box, bottle, blister package, tray, or card. The kit will include a package insert instructing the patient to take a specific dose at a specific time, for example, a first dose on day one, a second higher dose on day two, a third higher dose on day three, and so on, until a maintenance dose is reached. A preferred kit comprises the composition according to the present invention with dosage instructions.

The present invention, according to an embodiment thereof, provides a process for inducing sleep which includes the step of consuming a composition, wherein the process may, for example, speedily induce sleep, as well as provide for maintenance of sleep thereby promoting a good quality, restful sleep. In an embodiment of the present invention, the method includes the daily consumption, prior to going to sleep with the intent of a full night's sleep, of the composition according to the present invention. The amount of the active ingredients to be administered is chosen based on the amount which provides the desired dose to the patient in need of such treatment to alleviate symptoms or treat a condition.

Although the following example illustrates the practice of the present invention one of its embodiments the example should not be interpreted as limiting the scope of the invention. Other embodiments of the present invention will be apparent to those of skill in the art form consideration of the specification and example.

EXAMPLES

Example 1:

A polyherbal sleep inducing composition in the dosage forms of tablets

Batch size: 100000 Tablets

Example 2:

Preparation of polyherbal sleep inducing tablets

Step a): Add povidone with isopropyl alcohol at least 1 hour before to start the
formulation and mix thoroughly till povidone is dissolved in isopropyl alcohol.

Step b): Pass all the raw materials of Valeriana officinalis, Passiflora incarnata, Humulus lupulus inlOO mesh.

Step c): Pass the excipients in 40 mesh separately.

Step d): After sieving load all the extracts of step b) and excipients of step c) into

Planetary Mixer and allow to run for 30 minutes.

Step e): Slowly add the isopropyl alcohol-povidone mixture of step a) to the mixture of

step d) and mix thoroughly till it becomes hard.

Step f): The mixture forms granules after prolonged mixing.

Step g): The granules of step f) are shifted into trays and allowed for open air drying for 2 hours.

Step h): The partially dried granules of step g) are then transferred into tray drier for drying at a temperature of up to 50°C. To avoid lumps formation, temperature should be observed every 10 minutes.

Step i): The dried granules of step h) are passed through the shifter.

Step j): Lubricants such as Talc and Magnesium Stearate are sieved in 60 mesh and are added sequentially to the dried granules.

Step k): The final mixture of step j) is passed through the Planetary Mixer and allowed run for 20 minutes.

Step 1): The granules obtained from step k) are unload from the Planetary Mixer, packed in the PVC drum having double poly bag and are labeled.

Step m): The above mixture is compressed into tablets using conventional compression equipment.

Example 3:

Tablet weight and physical appearance

The tablets that are prepared according to the example 2 are checked for weight and physical appearance and are preceded for coating process.

Example 4:

Methods for masking the unpleasant taste and smell of the composition

Any of the following procedure can be performed for masking the unpleasant taste and smell of the composition:

a) Procedure for sugar coating the tablets: Ethyl vanillin flavor is dissolved in 200ml of Iso Propyl Alcohol and coated onto the tablets using any convention coating equipment know in the art. During each stage of coating i.e., seal coating, dusting, smoothing and colouring, additional 5gm of the ethyl vanillin flavor is added.

(i) Preparation of seal coat:

To 16.00 liters of Iso Propyl Alcohol in Stainless Steel vessel 2.520 kgs of OPADRY
2IK (White) is added and stirred for 5 minutes. To the above mixture 31.000 liters of
methylene chloride is added and stirred for 10 minutes. The mixture is ready for seal
coating.

Preparation plain svrup:

12.000 liters of purified water is allowed to boil in a steam pan. To the boiling mixture 24.000 kg sugar is added and mixed thoroughly till a clear solution is formed. Adjust the weight the plain syrup to 26.0 liters or 36.000 kg. The syrup is ready for coating using any conventional technique.

Preparation of dusting svrup:

1 kg of Gum Acacia is choked in 1.5 liters of Purified Water in a vessel. 2.000 liters of purified water is allowed to boil in a steam pan. To the warm mixture, sugar and gelatin are added and mixed thoroughly to make a clear solution. The water choked Gum Accacia is then added to the sugar syrup and allowed to boil to get clear thick dusting syrup. The syrup is then unloaded in a vessel and allowed for cooling. The cooled syrup is passed through 200 # mesh. The syrup is ready for coating using any conventional technique.

Preparation of dusting powder:
4.800 kg of talc and 3.700 kg of calcium carbonate (L) was passed through 30 # mesh and load into Planitery mixture and mixed for 30 minutes. The dusting powder is ready for coating using any conventional technique.

Preparation of smoothing solution:

Talc, Calcium Carbonate (L) and colour Ponceau(4 R) are passed through 30 # mesh and mixed well in a SS vessel. To this 14.000 liters of Plain Syrup is added and mixed well and then passed through 200 # mesh to get a paste without any lumps. The smoothing solution is ready for coating using any conventional technique.

Preparation of colouring solution:

Colour Ponceau 4 R is taken in a SS vessel and 8.000 liters of Plain Syrup is added and mixed well by using homogenizer for 30 minutes. The resulting solution is then passed through 200 # mesh to get lump-less solution. The colouring solution is ready for coating using any conventional technique.

Preparation of polishing solution:

Beeswax and Carnauba Wax are melted in a SS vessel. To the melted wax 3.000 liters of
chloroform is added and mixed well to get a clear solution. The polishing solution is ready for coating using any conventional technique.

Example 5:

Comparative examples of the efficacy of the polyherbal sleep inducing composition with a benzodiazepine-like modern sedative-hypnotic drug, Zolpidem.

Material and Methods:

The study was designed as a prospective, parallel group, double-blind, randomized controlled trial. Adult patients of either gender, attending the outpatient clinic of General Medicine of a teaching hospital, with sleep problems, were screened. Those diagnosed with primary insomnia according to DSMIV criteria, an average night sleep time of <6 hours and insomnia severity index <7 were enrolled in the study. Careful clinical history and examination were undertaken to exclude patients with psychiatric illnesses, major organ disease, or on concomitant drugs that affect sleep. Patients with known dependence on any sedative-hypnotic drugs, history of smoking or substance abuse, use of tobacco or caffeinated beverages during nighttime awakenings and night shift workers were also excluded.

Each polyherbal sleep inducing tablet (herein after referred to as "NSF-3 group") according to the present invention contains 410 mg of polyherbal extract in the form of 300 mg valerian extract (standardized to 0.8% total valerinic acid), 80 mg passion flower extract (4% isovitexin) and 30 mg hops extract (0.35% rutin). Zolpidem (herein after referred to as "Zolpidem group") was purchased from a pharmaceutical distributor as SOBRIUM tablet (each containing 10 mg) which is marketed by M/s Ranbaxy Laboratories, Gurgaon. Patients were advised as a double-blinded study to take one tablet daily at bedtime. Subjects were randomized in blocks of 20 in 1:1 ratio using WinPepi (version 10.1, 2010) software.

Each subject underwent 4 study visits, namely screening, baseline, 7-day follow-up and end-of-study visits. At screening, subjects enrolled were given a sleep diary and instructed carefully to fill in the time to go to bed, approximate time of falling asleep, time at which he/she woke up next morning and also total number of night time awakenings. Average sleep latency, total night sleep duration and number of nightly awakenings, for 1 week prior to the visit, were estimated on the basis of this sleep diary.

Each patient was treated for 2 weeks. The insomnia severity index and Epworth sleepiness scale score were calculated at baseline, follow-up and end-of-study visits to assess quality of life and daytime sleepiness respectively. The sleep diary was scanned at each of these visits to record the efficacy parameters. Safety was evaluated at each visit by taking thorough history and conducting clinical examination. Complaints of the patient as well as adverse events noted by the investigators were noted as treatment emergent adverse events. In addition routine blood counts and tests of hepatorenal function were done at baseline and at study end. Compliance with study medication was assessed through the pill count method at the 7 day follow up and end of study.

Results:

A total of 134 patients were screened of which 91 were randomized into two groups, and 39 in each group completed the study. As seen from Table 1, demography and baseline characteristics were comparable in the two groups.

Table 1: Comparison of demographic and baseline characteristics between study groups
P value calculated by Student's independent samples t test for the numerical variables and by Fisher's exact test for gender distribution.

The changes in outcome parameters are depicted in Table 2 and Table 3. Change in the average night sleep duration after two weeks of treatment was significant in both the groups.

However, no statistically significant difference between groups was observed. Similarly, sleep latency decreased individually in both arms without intergroup difference. The quality of life impairment was evaluated using Insomnia Severity Index, which also showed statistically significant decline individually in the two groups without intergroup difference, either at baseline or at study end.

Table 2: Comparison of the efficacy parameters between the study groups

At the end of the study, more than 50% of the subjects had no insomnia (total night sleep duration >6 hours) in both the groups. However, a proportion (6/39 patients in NSF-3 group and 10/39 patients in Zolpidem group) still had significant insomnia with a total night sleep duration <4 hours and/ or sleep latency >30 minutes. These results do not differ significantly between groups.

Table 4 depicts the Epworth Sleepiness scale scores as a measure of day time sleepiness.

There was no difference between groups for sleepiness scores at baseline, follow-up or study end. Also there was no statistically significant change in score within groups.

Table 4: Changes in epworth sleepiness scale score over the 2-week study period

Table 5 depicts the various treatment emergent adverse events observed in the study population. Most were mild to moderate in severity. Physical examination revealed no significant abnormalities in any patient as compared to baseline. Comparison of body weight, heart rate and blood pressure showed no differences. None of the laboratory parameters changed significantly from baseline in either group. No serious adverse events were encountered.

Table 5: Frequency of individual adverse events in the two study groups

The compliance levels were defined a priori as excellent, good or fair if not more than 2, 4 and 6 of scheduled doses are missed respectively. Poor compliance level was defined as any situation worse than fair. Excellent compliance was shown by 26 (66.67%) subjects on NSF-3 and 34 (87.18%) subjects on Zolpidem. Rest of the subjects all showed good compliance. There were no complaints regarding organoleptic tolerability of either preparation.

Conclusion:

This is the first randomized controlled study to compare a polyherbal sedative, containing extracts of the three plants as stated above, with the modern sedative-hypnotic Zolpidem.

The results suggest that the effectiveness of NSF-3 in alleviating sleep related problems is comparable to Zolpidem, while causing minimal adverse effects. Lack of significant daytime sleepiness can be an added advantage since many of the currently used sedative-hypnotics cause day time daytime drowsiness that may impair quality of life and have other undesirable sequels in chronic insomnia.

We claim:

1. A polyherbal sleep inducing composition comprising 70 to 75% of Valeriana officinalis, 15 to 20% of Passiflora incarnata, and 6 to 8% of Humulus lupulus

2. The sleep inducing composition as claimed in claim 1, a unit dose of which comprises 1200 mg to 300 mg of Valeriana officinalis, 800 mg to 80 mg Passiflora incarnate and 210 mg to 30 mg Humulus lupulus, the balance being excipients.

3. The sleep inducing composition as claimed in any of the preceding claims, wherein it further comprises ethyl vanillin as masking agent.

4. The sleep inducing composition as claimed in claim 3, wherein the ethyl vanillin is present in an amount of 0.012%.

5. The sleep inducing composition as claimed in any of the preceding claims, a unit dose of which comprises 300 mg of Valeriana officinalis, 80 mg Passiflora incarnate, 30 mg Humulus lupulus and 0.2 mg of ethyl vanillin, the balance being excipients.

6. The sleep inducing composition according to claim 1, which is in the form of capsule, tablet, caplet, liquid beverage, powder beverage mix or dietary gel.

7. A process of preparing a polyherbal sleep inducing composition comprising the steps of:

a) sieving Valeriana officinalis, Passiflora incarnata, Humulus lupulus and the pharmaceutical excipients separately;

b) admixing povidone with isopropyl alcohol to produce isopropyl alcohol-povidone mixture;

c) mixing Valeriana officinalis, Passiflora incarnata, Humulus lupulus and the pharmaceutical excipients manually or in a mixer;

d) adding the isopropyl alcohol-povidone mixture of step b) to the mixture of step c) and mixing thoroughly till granules are formed;

e) the granules are allowed for air drying by any conventional method;

f) the partially dried granules of step e) are transferred into tray drying;

g) lubricants are added subsequently to the dried granules and mixed thoroughly;

h) the above mixture is compressed into tablets using conventional compression equipment.

8. The process of preparing a polyherbal sleep inducing composition as claimed in claim 7, wherein the povidone is mixed with isopropyl alcohol at least 1 hour before to start the formulation and mix thoroughly till povidone is dissolved in isopropyl alcohol.

9. The process of preparing a polyherbal sleep inducing composition as claimed in claim 7, wherein the mixing of step c) is performed in a Planetary Mixer for 30 minutes.

10. The process of preparing a polyherbal sleep inducing composition as claimed in claim 7, wherein the tray drying of step f) is performed at a temperature of up to 50°C.

11. The process of preparing a polyherbal sleep inducing composition as claimed in claim 7, wherein the mixing of step g) is performed in a Planetary Mixer for 20 minutes.

12. A method for masking the unpleasant taste and smell of the polyherbal sleep inducing composition comprising coating the tablets produced according to claim 7 with ethyl vanillin flavor dissolved in isopropyl alcohol.