Claims:WE CLAIM,
1. An extended release powder composition comprising Melatonin or pharmaceutically acceptable salt or derivative thereof and one or more pharmaceutically acceptable excipients.
2. An extended release powder composition according to claim 1 characterized in that the powder comprises extended release pellets having size between ASTM 60# and ASTM 170# comprising:
(a) Inert pellets with or without seal coating,
(b) Drug layer comprising Melatonin with one more pharmaceutically acceptable excipients surrounding said inert pellets, and
(c) Coating layer comprising rate controlling polymer surrounding said drug layer.
3. An extended release powder composition according to claim 1 characterized in that the powder optionally comprises extra granular material comprising one or more pharmaceutically acceptable excipients.
4. An extended release powder composition according to any one of claims 1 to 3, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising of fillers, binders, diluents, disintegrants, pore formers, lubricants, glidants, rate controlling polymers, suspension stabilizers, buffering agents, sweeteners, antioxidants, flavoring agents, viscosity modifying agent, surfactants, preservatives and plasticizers.
5. An extended release powder composition according to claim 2 characterized in that the extended release pellets comprise:
(a) Melatonin in the proportion comprising between 0.1 to 10% w/w;
(b) Diluent(s), optionally seal coated, in the proportion comprising between 50 to 98% w/w;
(c) Binder(s) in the proportion comprising between 0.1 to 10% w/w;
(d) Rate controlling polymer(s) in the proportion comprising between 5 to 25% w/w;
(e) Pore former(s) in the proportion comprising between 0.1 to 10% w/w; and
(f) Plasticizer(s) in the proportion comprising between 0.1 to 10% w/w.
6. An extended release powder composition according to claim 3 characterized in that the extragranular material comprises:
(a) Disintegrant(s) in the proportion comprising between 0.1 to 15% w/w;
(b) Binder(s) in the proportion comprising between 0.1 to 15% w/w;
(c) Colorant(s) in the proportion comprising between 0.001 to 5% w/w;
(d) Suspending agent(s) in the proportion comprising between 0.1 to 15% w/w; and
(e) Diluent(s) in the proportion comprising between 5 to 99% w/w.
7. An extended release powder composition according to any one of claims 1 to 6 characterized in that the composition is suitable for preparing solid dosage forms and liquid dosage forms.
8. An extended release powder composition according to any one of claims 1 to 7, wherein the powder is reconstituted with suitable aqueous media to form oral suspension.
9. An extended release powder composition according to any one of claims 1 to 8 for use in the treatment of primary insomnia and other sleep related disorders.
10. A process for the preparation of extended release powder composition according to any one of claims 1 to 9 characterized in that the process comprises following steps:
(a) Suitable filler is coated with a binder solution to obtain inert pellets with or without seal coating;
(b) Said inert pellets obtained from step (a) are further coated with a drug-binder solution to form drug layer;
(c) Drug layered pellets so obtained from step (b) are further coated with a rate controlling polymer with one or more pharmaceutically acceptable excipient to form coated layer; and
(d) Suitable disintegrant, binder, colorant, suspending agent and diluent are mixed in granulator with suitable solvent to prepare granular material.

Dated this 18th day of January, 2018

[KETANA BABARIA]
IN/PA-660
ATTORNEY FOR THE APPLICANTS , Description:FIELD OF THE INVENTION
The present invention relates, in general to the pharmaceutical field, and more precisely it relates to the pharmaceutical composition comprising Melatonin. In particular, the present invention relates to the solid Melatonin preparations especially extended release powder. The pharmaceutical composition of the present invention is useful for treating sleep disorders in patients suffering from such disorders.

BACKGROUND OF THE INVENTION
Melatonin is a hormone secreted by the pineal gland, a small pinecone-shaped gland located near the center of the brain. Melatonin is chemically known as N-acetyl-5-methoxytryptamine which is a derivative of the amino acid tryptophan and serotonin. Melatonin is a white to off-white crystalline powder slightly soluble in water; soluble in acetone, ethyl acetate and methanol. Melatonin has an empirical formula C13H16N2O2 and a molecular weight of 232.3 gm/mol having following structural formula:

The pineal gland secretes melatonin in a circadian rhythm-an approximately 24-hour cycle in the biochemical, physical or behavioral processes of an organism. Melatonin acts on the hypothalamus, a structure of the central nervous system that among other functions, also controls the sleep function and, just by means of substances like Melatonin, regulates the sleep-wake cycle. Among the first applications proposed for the synthetic Melatonin produced in laboratory there was therefore, several decades ago, the application as a drug for the treatment of insomnia and, more in general, for the regulation of sleep. The pharmaceutical forms proposed for these applications were those traditional forms already used for oral administration, such as capsules and tablets, wherein Melatonin was administered alone or in association with several other pharmaceutically active ingredients and with the typical excipients of these pharmaceutical forms. Over the years, many other therapeutic applications of Melatonin have been proposed, for instance in the treatment of Parkinson’s disease, depression, osteoporosis, migraine, and even in the treatment of tumour forms, generally including also in these cases the administration of Melatonin always by the oral route.

A circadian rhythm is an endogenous or built-in function that is adjusted by environmental stimuli, such as daylight. It is known that the body plasma concentration of melatonin is low during the daytime, starts to rise during the late evening, and is maintained at 25-120 pg/mL during the night (over 8 hours) until it returns to the daytime baseline [Int J Pharmaceuticals, 1995, 124, 119-127].

Exogenous, or synthetic, melatonin has been proposed to have clinical potential in human subjects to treat melatonin deficiency in the elderly, [Experimental Gerontology, 2001, 36, 1083-1100] circadian rhythm disorders, including sleep disorders, jet lag, shift work syndrome, and seasonal affective diseases [Int J Pharmaceuticals, 1995, 124, 119-127]. Some suggest that melatonin may also be effective in the treatment of breast cancer, fibrocystic breast diseases, and colon cancer. Melatonin has been shown to modify the immune response, the stress response, certain aspects of the aging process, sleep disturbances in Alzheimer's patients, and oxidative stress. This suggests a plethora of beneficial uses for melatonin.

Exogenous melatonin treatments encounter several problems. Melatonin is eliminated from the blood quickly once administered. It has a plasma elimination half-life of less than one hour [J Pharmaceutical Sci., 1997, 86(10), 1115-1119]. When administered orally, it shows low and variable bioavailability [J Pharmaceutical Sci., 1997, 86(10), 1115-1119]. As with most oral administrations, it can take more than 30 minutes after ingestion for the blood plasma concentration of melatonin to reach its peak. This is partly due to the need for release of the melatonin from the dosage form followed by permeation through the wall of the gastrointestinal tract (“G.I. tract”) for absorption to occur before the melatonin can enter the bloodstream.

Melatonin is slightly soluble, has good permeability characteristics, and is in the class II category according to the Biopharmaceutics Classification System [Int. J Pharmaceutics, 2009, 378, 9-16]. Therefore, the amount of melatonin available for absorption into the bloodstream primarily depends on its solubility. Melatonin's solubility generally decreases in less acidic environments. Because the pH of the gastrointestinal tract varies significantly, different amounts of melatonin are available for absorption into the bloodstream, depending on the region of the G.I. tract the melatonin enters.

Orally administered immediate and controlled-release melatonin formulations exist. Studies indicate large inter-subject variability of melatonin in the blood plasma of human subjects given melatonin orally [J Pharmaceutical Sci., 1997, 86(10), 1115-1119]. Other problems reported include poor oral bioavailability and a nutritional status effect on the oral bioavailability [J Pharmaceutical Sci., 1997, 86(10), 1115-1119].

Various formulations of melatonin have been developed to provide release of melatonin over a 3 to 10 hour period to stimulate the natural (in vivo) release of melatonin. These formulations have not gained wide acceptance because of their variable response in patients. Patients may therefore experience middle of the night awakening, early morning grogginess, and sleep times of less than 5 hours.

Alternatives to conventional oral controlled-release dosage forms also exist. For example, a hydroxypropyl methylcellulose (“HPMC”) matrix tablet was reported to release melatonin at a rate that was comparable to two commercially available products [Drug Dev. and Ind. Pharmacy, 1999, 25(4), 493-501]. In another example, the controlled-release characteristics of melatonin in a pH-responsive amphiphilic hydrogel with interpenetrating polymer networks was reported to be a function of the pH of the external environment of the tablet [Int. J Pharmaceutics, 2006, 308, 205-209]. Such controlled-release dosage methodologies remain in their infancy.

Melatonin in state-of-the-art is known in various dosage forms for example US 20080254121 describes a solid orally administrable dosage form comprising: a first-layer comprising melatonin; a second-layer comprising melatonin, wherein the second-layer is disposed immediately adjacent the first-layer; and an inner-core comprising melatonin, wherein the inner-core is disposed immediately adjacent at least one of the group consisting of the first-layer and the second-layer. US 20130122092 describes a three-phase melatonin-releasing tablet and a process for the preparation thereof. US 20170165232 claims a process for the preparation of a tablet having an internal core and an external coating, both comprising melatonin at equal or different dosages. EP 2949322 describes a pharmaceutical composition in the form of a bilayer tablet comprising melatonin. EP 3127536 describes a method for the manufacturing of a solid formulation comprising melatonin as active pharmaceutical ingredient, said method comprises a melatonin dispersion step in one or more intra-granular excipients to form a melatonin blend, followed by a wet granulation step. CN 1488346 describes double release tablets of melatonin and process for the preparation thereof. CN 1628702 describes melatonin milk tablets preparation. CN 101143135 describes an orally disintegrating tablet of melatonin. CN 104248630 and CN 104306349 describes a melatonin containing osmotic pump tablets.

WO 2008122104 describes a sleep aid composition comprising; a capsule containing a liquid and a plurality of beadlets suspended therein; said liquid comprising at least a first dosage of melatonin; and said plurality of beadlets comprising at least a second dosage of melatonin. CN 101697968 describes melatonin soft capsule comprising melatonin, salad oil and water. CN 101966167 describes a melatonin soft capsule and process for preparing thereof.

US 5498423 describes a pharmaceutical controlled-release formulation in dosage form which consists essentially of melatonin in combination with at least one pharmaceutical carrier, diluent or polymeric coating. US 7858656 describes a controlled release tablet formulation of Melatonin. EP 1272177 describes use of melatonin in the manufacture of a controlled release medicament, for the prevention or treatment of symptoms of hypertension. WO 1995003043 and WO 2008148015 describes a sustained release melatonin formulation. WO 2012103411 describes a controlled release tablet formulation comprising Melatonin. CN 104546777 describes a process for producing melatonin sustained release composition. CN 1195525 describes a melatonin sustained-release preparation. CN 101874783 describes a sustained release pellet containing melatonin. CN 102018681 describes an extended release tablet composition of melatonin.

US 5362745 describes an oral pharmaceutical composition consisting of melatonin as the active principle in form of a micro-emulsion, L-a-phosphatidylcholine as an emulsifier and a solvent mixture consisting of ethanol, propylene glycol and water.

WO 2010062153 describes an oral solution to treat burns to internal tissues and organs caused by corrosive substances characterized in that it comprises Melatonin, Tween 80, Polyethylene Glycol (400), Acesulfame potassium, Sucrose, Chocolate flavour essence, the essence mint flavour, Sodium benzoate and Purified water. US 20160166543 describes a stable liquid formulation composition for oral administration comprising a therapeutic dose of first component diphenhydramine hydrochloride; a therapeutic dose of second component melatonin; and pharmaceutically acceptable excipients; wherein one of the excipients is hydroxypropylbetacyclodextrin. US 20170112810 describes a pharmaceutically acceptable composition comprising propylene glycol, polyethylene glycol and melatonin or a derivative, salt, pro-drug or solvate thereof.

WO 2012156565 describes a stable and sterile pharmaceutical composition for the parenteral administration of melatonin in the form of an aqueous solution. WO 2015135997 describes a parenteral formulation comprising Melatonin, one or more phospholipids selected from the group consisting of a phosphatidylcholine and a lecithin, and, optionally, one or more stabilization agents selected from the group consisting of a tocopherol, deoxycholic acid, a pharmaceutically acceptable salt of deoxycholic acid, and a C12 to C20 saturated or unsaturated fatty acid and mixture of mannitol and trehalose. WO 2016058985 describes substantially water free composition consisting of liquid preparation of melatonin. WO 2016139635 describes a stable and sterile pharmaceutical composition for the parenteral administration of melatonin in the form of an aqueous solution, comprising melatonin and physiological saline solution and it is completely free of any excipients, co-solvents and/or diluents different from said physiological saline solution.

WO 2008127609 describes a Melatonin tablet formulation for sublingual or buccal administration and process for the preparation thereof. JP 2014237700 describes a solid dosage form for sublingual or buccal administration of melatonin. US 20100256215 describes a thin film for the delivery of melatonin to a person's bloodstream via a mucosal membrane.
US 5939084 describes a stable, recrystallization-resistant dermatological/cosmetic composition which comprises a substantially ethanol-free aqueous phase, said aqueous phase comprising an active amount of solubilized melatonin or analog thereof and an amount of at least one glycol effective to dissolve said melatonin or analog thereof. US 20080131496 describes a pharmaceutical composition enabling delivery to the skin after topical application of a therapeutically effective amount of melatonin. EP 0820766 describes topical composition comprising melatonin or analogues thereof and a cosmetically or pharmaceutically acceptable support. WO 2016131784 describes a topical liquid composition comprising melatonin or an analog thereof or a pharmaceutically acceptable salt or solvate thereof; a buffer system and a first amino acid comprising at least one sulphur atom. JP 10067648 describes topical composition containing melatonin or its analogue. JP 2001058960 describes a transdermally applied melatonin characterized by blending an oleyl alcohol derivative.

US 6007834 describes a pharmaceutical composition for intranasal administration, comprising melatonin and an additive selected from the group consisting of a cyclodextrin, glycerol, and admixtures thereof. EP 0867181 describes a pharmaceutical composition for nasal administration comprising melatonin and an additive selected from glycerol, cyclodextrin, and mixtures thereof. US 20040002536 describes an anesthetic composition comprising a pharmaceutically acceptable anesthetic carrier, and an anesthetic inducing effective amount of N-acetyl-5-methoxytryptamine (Melatonin), or a biologically active analogue thereof.

WO 1999047175 describes a pharmaceutical composition for the administration of melatonin comprising an inclusion complex of melatonin with polymeric materials. US 20140308357 describes a powder for use as a medicament, wherein it comprises melatonin, at least one water soluble excipient and at least one water soluble surfactant. WO 2014044896 describes an orodispersible solid pharmaceutical composition comprising melatonin. CN 1348758 describes a composition comprising melatonin and ß-glucan.

From the prior art, it can be seen that currently available preparations of Melatonin are solid oral preparations e.g. tablets, capsules etc. Liquid preparations of Melatonin are available either in the form of topical administration or in the form of parenteral administration. Other available Melatonin preparations include intranasal, buccal or sublingual. All these preparations have their own disadvantages and limitations, for example they are not suitable for all types of patient populations (e.g. pediatric and geriatric patients). Therefore, there is an existing need for oral liquid pharmaceutical composition comprising Melatonin having improved stability, palatability and patient acceptability. Further, the oral liquid preparations are more patient compliant as compared to oral solid dosage forms. Oral solid dosage forms may not be convenient for all types of patient populations (e.g. pediatric and geriatric patients) to take because of swallowing problems. Therefore it is preferable to administer active ingredient in pharmaceutical liquid dosage form.

Thus, looking at the existing need in the prior art for the preparation of an oral liquid composition comprising Melatonin, one of our research groups have developed an oral liquid solution of Melatonin comprising pharmaceutically acceptable excipients selected from the group consisting of preservatives, buffering agents, sweetening agents, flavouring agents and vehicles. Such an invention has been disclosed and claimed in our earlier patent application filed with number IN 201721029411. The said liquid dosage form is an immediate release solution comprising Melatonin.

Liquid dosage forms such as suspensions possess certain advantages over other dosage forms. Some drugs are insoluble in all acceptable media and must, therefore, be administered as a tablet, capsule, or as a suspension. Because of their liquid character, suspensions represent an ideal dosage form for patients who have difficulty swallowing tablets or capsules. This factor is of particular importance in administration of drugs to children and aged patients. Suspensions of insoluble drugs may also be used externally, often as protective agents. In addition, disagreeable tastes can be masked by a suspension of the drug or a derivative of the drug. Drugs in suspension are expected to be chemically more stable than in solution. This is particularly important with certain antibiotics and the pharmacist is often called on to prepare such a suspension just prior to the dispensing of the preparation.

Although conventional oral suspensions can be administered immediately, there is an important category of suspensions that requires mixing prior to administration. These suspensions are commercial dry mixtures that require the addition of water at the time of dispensing. The reconstituted system is the formulation of choice when the drug stability is a major concern. A number of commercial and official preparations are available as dry powder mixtures or granules that are intended to be suspended in water or some other vehicle prior to oral administration. Most of the drugs prepared as dry powders for oral suspension are antibiotics. The dry mix for oral suspension is prepared commercially to contain the drug, colorants, flavors, sweeteners, stabilizing agents, suspending agents and preserving agents that may be needed to enhance the stability of the formulation. Dry syrup form of drug also shows improved bioavailability as compared to tablets and capsules as it is in the dispersed state at the time of administration. The granules in the sachets must be taken as a suspension in a glass containing prescribed amount of ingestible liquid, mostly water. Although studies have demonstrated that the dry oral suspension after constitution in a liquid is stable for 24 hours after preparation, it is recommended that the suspension should be consumed immediately after preparation.

Liquid oral suspension is a bulk formulation therefore sometimes there are chances of inaccuracy in single dosing. Drug dose depends on various physical factors of the dosage form such as temperature of storage, sedimentation rate of the formulation, liquid flow properties like viscosity, pourability, re-dispersion, flocculation and content uniformity. Stability of the liquid suspension largely depends on the temperature of storage. Further, sometimes caking may also occur in liquid suspensions upon storage.

In case of dry granules for oral suspension, there is an accurate single dosing as the dose is packed in single dose sachets. Drug dose is comparatively independent of any physical factors like temperature, sedimentation rate and liquid flow properties. Packaging of the powder mixture is done in sachets making the formulation easy to carry and easy to handle by the pharmacists and the patients which makes such pharmaceutical preparation preferred over liquid dosage forms. Enhanced convenience of single dosage regimen is also an advantage which can be achieved. Colored, flavored, sweetened formulation is advantageous for administration to the pediatric population. Stable on storage and when reconstituted with an ingestible liquid for administration, the corresponding liquid suspension is stable for the duration for which the therapy is required.
Extended release dosage forms (often referred as ER or XR formulations) are the subgroup of modified release formulations (often referred as MR formulations). According to a definition from the U.S. Pharmacopeia (USP), ER or XR formulations can be referred to as dosage forms that allow at least a two-fold reduction in the dosing frequency compared to conventional dosage forms. Extended release oral drug formulations have been used since the 1960s to enhance the performance and increase patient compliance. By incorporating the dose for 24 hours into one dosage form from which the drug is slowly released, peaks of high plasma concentration and troughs of low plasma concentration can be prevented. This helps in avoiding the side effects associated with high concentrations and the lack of activity associated with low concentrations, giving better overall therapy. In addition, in the treatment of diseases those are asymptomatic, patients generally remember morning and evening medication, but tend to forget doses in between. Once or twice daily dosing thus improves therapy through the constant presence of the drug in the body.

As mentioned in above paragraph, one of our research groups have developed immediate release oral liquid solution of Melatonin. But, liquid formulations in the form of solutions of drug sometimes may not be an appropriate dosage form where the drug is required to be released from the dosage form in the time-dependent manner. In such cases, modified release liquid suspensions can be administered to the patients where the patients do not require to remember all the doses to be taken in a day. Further, as discussed above, conventional suspensions may also have some limitations for example ease of carrying (transportation), temperature of storage, sedimentation rate of the formulation, liquid flow properties like viscosity, pourability, re-dispersion, flocculation, content uniformity and dose uniformity. It may therefore be advantageous to develop a dry powder formulation of a drug which may be reconstituted in suitable liquid media for preparing an oral suspension which helps in overcoming above mentioned limitations of conventional suspensions.

Therefore, looking at the need for the time dependent release formulations of Melatonin in liquid suspension dosage forms which overcome all the above mentioned limitations associated with conventional suspensions and at the same time fulfill all the requirements and advantages of liquid dosage forms, it was one of the primary objects of the present inventors to develop a pharmaceutical preparation which retains all the advantages of the solid formulations as well as the liquid formulations. The present inventors have therefore developed an extended release pharmaceutical formulation comprising Melatonin in the solid dosage form preferably as dry powder which may further be useful for the preparation of extended release liquid suspensions suitable for oral administration.

OBJECTS OF THE INVENTION
Melatonin is approved in Europe as Circadin® for the short-term treatment of primary insomnia (persistent difficulty in getting to sleep or staying asleep, or poor quality of sleep) in patients aged 55 years and older. The product information for patients instructs that the tablet of Circadin® should be swallowed whole and Circadin® tablets should not be crushed or cut in half. Therefore it is one of the principal objects of the present invention to provide a liquid dosage form comprising Melatonin. The said dosage form is particularly convenient for the pediatric, geriatric and other patient population having swallowing problem or are unable to swallow other solid dosage forms of Melatonin.

Liquid formulations of drug in the form of solutions sometimes may not be an appropriate dosage form where the drug is required to be released from the dosage form in the time-dependent manner. In such cases, modified release liquid suspensions can be administered to the patients where the patients do not require to remember all the doses to be taken in a day. Another object of the present invention is therefore to provide an extended release liquid suspension comprising Melatonin.

Foregoing paragraphs describe advantages of dry powder compositions which make them preferable over conventional suspensions. Another object of the present invention is therefore to develop an extended release dry powder formulation comprising Melatonin. Such a dry powder formulation can further be used to prepare solid dosage forms such as tablets, capsules etc. or may be reconstituted in the suitable media to prepare liquid dosage forms.

A yet another object of the present invention is to provide a process for the preparation of Melatonin extended release dry powder formulations.

A yet another object of the present invention is to provide an extended release solid as well as liquid dosage forms of Melatonin which can be administered as once-daily or twice-daily.

A yet another object of the present invention is to use the extended release Melatonin powder according to the present invention as well as solid and liquid dosage forms prepared therefrom in the treatment of primary insomnia (persistent difficulty in getting to sleep or staying asleep, or poor quality of sleep) and other sleep related disorders.

DETAILED DESCRIPTION OF THE INVENTION
Melatonin has fascinated the researchers due to its remarkable functional versatility and protective role in several pathophysiological conditions. Indeed, it plays a central role in wide physiological functions, like orchestrating circadian rhythms, along with the regulation of visual, cerebrovascular, reproductive, neuro-endocrine, and neuro-immunological functions. Numerous studies have shown melatonin to promulgate a multitude of therapeutic functions that fight sepsis, neurodegenerative disorders, diabetes, biliary and pancreatic malfunctions, hepatotoxicity, cancer, inflammation, and oxidative stress. In addition, it is also a potent antioxidant and free radical scavenger. However, it is also known to regulate the levels of oxidative markers, endogenous antioxidant status, and pro-inflammatory cytokines. In humans, melatonin is an endogenous neuro-hormone secreted primarily from the pineal gland and to a lesser extent by extra pineal tissues such as the retina, harderian gland, and gastrointestinal tract. The non-clinical aspects of pharmacology (primary, secondary and safety pharmacodynamics of endogenous melatonin including in vitro and in vivo studies), pharmacokinetic and toxicokinetic studies of exogenous melatonin in animals are copiously available in the published literature and databank.

When melatonin is administered orally to rats, dogs and monkeys at 10 mg/kg, the absolute bioavailability appeared to be moderate in rats and high in dogs and monkeys [J Pineal Res, 1997, 22, 45-51]. Oral administration to human volunteers of up to 3 times 80 mg of melatonin/person in one hour showed that the compound is rapidly absorbed and distributed throughout the human body, the half-life for the first part of the biphasic distribution phase being in the order of minutes. Highest melatonin values were measured in serum, 60 to 150 minutes after oral administration. Elimination of the molecule appeared to be slower than in rodents, since the concentration plateau lasted for several hours. The half-life of the first part of the biphasic elimination phase was found to be 20 to 50 minutes [Neuroendocrinology, 1984, 39, 307-313]. When a lower dose of 3 mg of melatonin/volunteer was administered orally, an increase in serum melatonin within 20 minutes after oral administration was reported, followed by a rapid decrease at 240 minutes [Psychiatry and clinical neur, 1998, 52, 266-267]. Some authors [Biopharm Drug Dispos, 2000, 21, 15-22] reported a terminal half-life of 36 to 45 minutes when melatonin was measured in plasma after oral administration of a dose of 250 µg/person to human volunteers. In literature is reported that maximum blood and saliva concentrations of melatonin were reached 60 minutes after oral uptake of 100 mg of melatonin. The half-life of the molecule in blood was determined as around 41 minutes [Life Sciences, 1985, 37(5), 489-495]. When 2 or 4 mg melatonin/person were administered to human volunteers, only 15% of the ingested dose actually reached the systemic circulation. Most of administered melatonin disappears through the presystemic metabolization [Journal of Clinical Pharmacology, 2000, 40, 781-784] and is excreted in urine as sulphatoxy-melatonin, the major conjugation product of 6-hydroxymelatonin. Unchanged melatonin renal clearance was lower than 1% [Biopharm Drug Dispos, 2000, 21, 15-22].

Extended release formulations help in avoiding the side effects associated with high concentrations and the lack of activity associated with low concentrations giving better overall therapy. In addition, in the treatment of diseases those are asymptomatic, patients generally remember morning and evening medication, but tend to forget doses in between. Once or twice daily dosing thus improves therapy through the constant presence of the drug.

Because of their liquid character, suspensions represent an ideal dosage form for patients who have difficulty swallowing tablets or capsules. This factor is of particular importance in administration of drugs to children, aged patients and other patients having swallowing problem. Dry powder mixtures or granules of drug offer improved bioavailability as compared to tablets and capsules as it is in the dispersed state at the time of administration. Dry powder mixtures or granules for oral suspension also offer an accurate single dosing as the dose is packed in single dose sachets. Drug dose is comparatively independent of any physical factors like temperature, sedimentation rate and liquid flow properties.

Therefore, in one of the principal embodiments, the present invention provides an extended release solid pharmaceutical formulations comprising Melatonin and one or more pharmaceutically acceptable excipients. In one of the further aspects of the present invention, the solid pharmaceutical formulations are dry powders.

In one of the further aspects of the present invention, dry powders comprising Melatonin and one or more pharmaceutically acceptable excipients are suitable for the preparation of extended release oral liquid suspension dosage forms of Melatonin.

In one of the further aspects of the present invention, dry powders comprising Melatonin and one or more pharmaceutically acceptable excipients are also suitable for the preparation of extended release oral solid dosage forms of Melatonin such as tablets, capsules etc.

In one of the further aspects of the present invention, extended release Melatonin powder for oral liquid suspension dosage form is for once daily or twice daily administration, preferably once daily administration which comprises active ingredient (i.e. Melatonin) in particles, granules, pellets, beads or micro particles which would be additionally mixed with the appropriate additives such as viscosity modifying agents that provide suspending properties in the liquid dosage form, sweetening agents which would mask undesirable taste and feel of the active ingredient, glidants which provides flow properties and also prevents caking when present in the liquid composition, and optionally other additives such as buffering agents, lubricants, surfactants etc.

In one of the further aspects of the present invention, the extended release dry powder comprises of inert pellet, active ingredient, rate controlling polymer and other pharmaceutically acceptable excipients. In one of the further aspects, the extended release dry powder comprises inert pellets. In one of the further aspects inert pellets are with or without seal coating.

In one of the further aspects of the present invention, the inert pellets with or without seal coating are loaded with active ingredient along with pharmaceutically acceptable additives (i.e. non-functional coating), and these drug loaded pellets are further coated with rate controlling polymers to yield extended release pellets of the active ingredient (i.e. functional coating). Optionally, the extended release pellets obtained can be further coated with drug-binder solution. The pellets so obtained may optionally be coated with alkali soluble coating and/or with an acid soluble polymer coating.

In one of the further aspects, the present invention provides extended release Melatonin powder which comprises: extended release pellets, which comprises:
a) Inert pellets, with or without seal coating,
b) Drug layer surrounding the inert pellets of step (a) comprising pharmaceutically active ingredient with one or more pharmaceutically acceptable excipient, and
c) Coating layer surrounding the drug layer comprising rate controlling polymer,
wherein the extended release pellets may additionally mixed with extra granular material comprising viscosity modifying agent or suspending agent or thickening agent or suspension stabilizers in addition to other pharmaceutically acceptable excipients selected from the group comprising of binders, sweeteners and colorants.

In one of the further aspects, the extended release powder according to the present invention comprises pellets having size between ASTM 60# and ASTM 170#.

The present invention in one of the further embodiments, provides process for the preparation of an extended release Melatonin pellets. The process for the preparation of the extended release Melatonin pellets comprises one or more following optional steps;
a) Suitable fillers are coated with a binder solution to obtain seal coated inert pellets;
b) Seal coated inert pellets obtained from the step (a) are further coated with a drug-binder solution to form drug layering; and
c) Drug layered pellets so obtained from step (b) are further coated with a rate controlling polymer with one or more pharmaceutically acceptable excipient to form coated layer;
wherein, step (a) is omitted when inert pellets are used without seal coating. Such inert pellets without seal coating are coated with a drug-binder solution to form drug layering.

In one of the further aspects, the present invention also provides process for the preparation of the extra granular material comprising viscosity modifying agent or suspending agent or thickening agent or suspension stabilizers in addition to other pharmaceutically acceptable excipients selected from the group comprising of binders, disintegrants, diluents, sweeteners and colorants which is additionally mixed with the extended release pellets of Melatonin. Such extra granular material can be prepared according to any standard granulation processes known to the person skilled in the art.

In one of the further aspects, the present invention provides the extended release liquid oral suspension dosage form of Melatonin which comprises of inert pellet, active ingredient, rate controlling polymer and other pharmaceutically acceptable excipients.

In one of the further aspects, the present invention provides process for the preparation of liquid suspension comprising extended release Melatonin dry powder formulation.

In one of the further aspects, the extended release pellets or granules or particles prepared according to any of the herein described embodiments are suspended along with or without other additives in an aqueous or non-aqueous solvent or solution or dispersing agent or suspending media. In the preferred aspects the suspending media or aqueous solvent is water.

In one of the further aspects, the present invention provides use of the liquid suspension comprising extended release dry powder formulation of Melatonin in the treatment of primary insomnia (persistent difficulty in getting to sleep or staying asleep, or poor quality of sleep) and other sleep related disorders.

In one of the further aspects, the present invention provides non-caking extended release Melatonin powder for oral suspension and non-caking oral liquid suspensions prepared therefrom.

The term “one or more pharmaceutically acceptable excipients” as used herein includes diluents, disintegrants, solvents, processing aids, buffering agents, colorants, flavorings, solvents, coating agents, binders, carriers, glidants, lubricants, granulating agents, gelling agents, polishing agents, suspending agent, sweetening agent, anti-adherents, preservatives, emulsifiers, antioxidants, plasticizers, surfactants, viscosity agents, enteric agents, wetting agents, thickening agents, stabilizing agents, solubilizing agents, bioadhesives, film forming agents, essential oils, emollients, dissolution enhancers, dispersing agents, or combinations thereof.

In one of the preferred aspects of the present invention, one or more pharmaceutically acceptable excipients may be selected from the group comprising of fillers, binders, disintegrants, diluents, rate controlling polymers, lubricants, glidants, viscosity modifying agents, plasticizers, stabilizers, , pore formers, preservatives, buffering agents, sweeteners, flavoring agents or a mixture thereof.

A variety of materials may be used as diluents. Non-limiting examples are spray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. starch 1500), cellulose (e.g. microcrystalline cellulose; AVICEL®), and others as known in the art. Preferred diluent in accordance with the present invention for preparing extended release pellets is microcrystalline cellulose whereas a preferred diluent in accordance with the present invention, which also functions as a sweetener in the compositions of the present invention, is dextrose. The amount of the diluent used in the powder compositions of the present invention is typically in the range of from about 5% to about 99% w/w based on the total weight of the powder composition.

Fillers which can be used in the present invention is selected without limitation from the group comprising of cellulose and cellulose derivatives like microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol and other materials known to one of ordinary skill in the art or mixture thereof. The filler may be present in the range from about 0.1% to about 50% w/w based on the total weight of the powder composition.
Binders or binding agents which can be used in the present invention is selected without limitation from the group comprising of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose (low viscosity grade), methyl cellulose, ethyl cellulose, starch, pregelatinized starch, modified corn starch, polyacryl amide, poly-N-vinyl amide, sodium carboxymethyl cellulose, polyethylene glycol, gelatin, polyethylene oxide, poly propylene glycol, tragacanth, alginic acid, and other materials known to one of ordinary skill in the art or mixture thereof. The binder may be present in the range from about 0.1% to about 25% w/w based on the total weight of the powder composition.

Lubricants or glidants which can be used in the present invention is exemplified without limitation by magnesium stearate, calcium stearate, glyceryl stearate, zinc stearate, talc, polyethylene glycols, hydrogenated vegetable oil, mineral oil, stearic acid, glyceryl behenate, cornstarch, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, sodium stearyl fumarate, glyceryl palmitostearate, stearic acid, and other materials known to one of ordinary skill in the art or mixture thereof. The glidant, lubricant and anti-adherent may be individually present in the range from about 0.01% to about 20% w/w based on the total weight of the powder composition.

Plasticizers which can be used in the present invention for providing flexibility to the extended release polymer coating layer. Different kinds of plasticizers that can be used in the present formulation are selected without limitation from low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, polypropylene glycol, multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include ethylene glycol, 1, 2-butylene glycol, 2, 3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol, monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. Also the combination of the plasticizers can be used in the present invention. The plasticizer may be present in the range from about 0.1% to about 25 % w/w based on the total weight of the powder composition.

Pore formers which can be used in the present invention are typically used to create a certain amount of diffusion through an insoluble coating of a tablet, pellet or particle to achieve a sustained release profile. When a sustained or extended drug release profile is developed, a common way to achieve it, is the combination of an insoluble coating with a soluble pore former. While the coat itself will remain intact throughout its passage, the pore former will dissolve at the targeted point in the body, allowing the active ingredient in the core to diffuse out of the dosage form. The more the pore former is used, the more pores the coat will have. The speed of the drug release will consequently increase. If a pH-independent soluble pore former is used, the drug release will commence as soon as the dosage form reaches the stomach. If an enteric pore former is used, the pores will not open until the dosage form reaches the intestines, creating a sustained/extended-release profile tailored to the intestinal tract. Preferred pore former according to the present invention without limitation include polyvinyl pyrrolidone. Pore former when used in the present invention is typically present in the range from about 0.1% to about 20% w/w based on the total weight of the powder composition.

Disintegrants which can be used in the present invention refers to any material that facilitates the breakup of the granules prepared according to the present invention when placed in contact with an aqueous medium. Suitable disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose, pregelatinized starch, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic acid and mixtures thereof. The disintegrant may be present in the range from about 0.1% to about 25% w/w based on the total weight of the powder composition.

Viscosity modifying agents or thickening agents or suspending agents are one of the most important constituents of the extended release Melatonin dry powder dosage form according to the present invention. These agents are also called as suspension stabilizers and they are intended to ensure that the individual doses removed have constant active ingredient content. A large variety of agents can be used for the above purpose like colloidal silicates having a high aluminum and magnesium content, such as bentonite, Veegum or Gel White; colloidal silica, for example Aerosil (Degussa), Cabosil (Cabot); organic stabilizers, for example swelling agents, such as alginates, sodium alginate, calcium alginate or propylene glycol alginate, gum arabic, tragacanth, karaya gum, sterculia gum, carrageen, guar gum, xanthan gum or agar; synthetic or semi synthetic swelling agents, for example 1, 2-epoxide; polymers, in particular ethylene oxide homopolymer having a degree of polymerization of about 2,000-100,000, which are known, for example, under the trade name Polyox (Union Carbide), preferably swellable cellulose ethers, for example methyl- or ethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl- or ethylhydroxyethyl cellulose, carboxymethyl cellulose or an alkali metal salt thereof, or microcrystalline cellulose, or water-soluble polyvinyl compounds, such as polyvinyl acetate, polyvinyl alcohol or polyvinylpyrrolidone or combination thereof. Preferably xanthan gum is used as the suspension stabilizers. The amount of the suspending agent used in the powder for oral suspension compositions of the present invention is typically in the range of from about 0.01% to about 20% w/w based on the total weight of the powder composition.

Dispersing agents may also be used to facilitate formation of a suspension. Among suitable dispersing agents are included, for example, colloidal silicon dioxide and other pharmaceutically acceptable dispersing agents. In preferred aspects, a dispersing agent is not included in the powder for oral suspension.

The “rate controlling polymer” according to the present invention can be selected from hydrophilic polymer, hydrophobic polymer or the mixture thereof. The rate controlling polymer can be used as a matrixing agent or as a coating agent. Hydrophilic polymer that can be used in the present invention can be exemplified as hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate, carbomer, sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, polyvinyl alcohol and hydroxypropyl methylcellulose. The preferred hydrophilic rate controlling polymer that can be used in the present invention is hydroxypropyl cellulose. The matrix forming polymer comprises from about 1% to about 70% w/w, preferably from about 5% to about 50% w/w based on the total weight of the powder composition. The hydrophilic polymer described above may also be used as a constituent of the coating layer.

Hydrophobic polymer that can be used in the present invention are selected from the group comprising of cellulose ether such as ethyl cellulose, cellulose acetate, polyvinyl acetate, methacrylic acid esters neutral polymer, polyvinyl alcohol-maleic anhydride copolymers, hydroxypropyl methyl cellulose phthalate, EUDRAGIT® RSPO, EUDRAGIT® S 100, hydrogenated castor oil, waxes and the like. Even the commercially available dispersion of film formers namely, EUDRAGIT® L-30D, EUDRAGIT® NE 30D, AQUACOAT® ECD-30, SURELEASE® E-7, EUDRAGIT® RS 30D, EUDRAGIT® RL 30D, etc. may be used for the purpose of providing extended release composition. Preferably the hydrophobic polymer that can be used in the present invention is ethyl cellulose, hydroxypropyl methyl cellulose phthalate, EUDRAGIT® RSPO, EUDRAGIT® S 100 and hydrogenated castor oil.

Acid soluble polymer that can be used in the present invention is selected from the group of EUDRAGIT® E 100, EUDRAGIT® E 12, 5 and EUDRAGIT® EPO. Preferably EUDRAGIT® E 100 is used as the acid soluble polymer. These polymers also provide pH dependent drug release, protection of sensitive active ingredient, taste and odor masking, moisture protection etc. Preferably EUDRAGIT® E 100 is used as the acid soluble polymer.

Alkali-soluble polymers which can be used in the present invention are selected from EUDRAGIT® S or L, EUDRAGIT®- SI 00, EUDRAGIT® LI 00, EUDRAGIT® LI 00-55 EUDRAGIT® L30D, hydroxypropyl methyl cellulose phthalate etc. Preferably EUDRAGIT® LI 00-55 is used as the alkali soluble polymer.

According to the present invention aqueous solvent or non-aqueous solvent dispersing agent or suspending media which can be used are selected from water, alcohols, oils or mixtures thereof. Edible oils that can be used in the present invention are selected from edible oils of animal or plant origin, such as but not limited to mono, di, and triglycerides, acetylated monoglycerides, pharmaceutically acceptable esters of aliphatic hydroxyacids, fatty acids; tocopherol and tocopherol esters, glycol esters, squalane, squalene, corn oil, limonene, crill oil, oregano oil and lipid soluble vitamins and the like. Preferred aqueous solvent or suspending media is water.

A common problem associated with liquid pharmaceutical dosage forms is the often disagreeable taste which may manifest itself when the drug is administered in a liquid dosage form. This taste may be overcome by the addition of sweeteners or flavoring agents to the formulation which mask the bitter or unpleasant taste of the drugs.

Sweeteners are used to mask the bitter taste of the active ingredients or to impart sweetness to the liquid dosage form. Sweeteners that can be used in accordance with the present invention are selected without limitation from sugar such as monosaccharide or disaccharides, for example D-glucose, D-fructose, D-xylose, maltose or sucrose; polyols, such as glycerol, dulcitol, mannitol, sorbitol or xylitol, or artificial sweeteners, such as saccharine or the corresponding sodium, potassium or calcium salt, cyclamate or the corresponding sodium or calcium salt, aspartame, or acesulfame or the potassium salt thereof, furthermore Dulcin or ammonium glycyrrhizinate. Generally sweeteners are present in higher percentage in the dosage form. Sweeteners used in the present formulation ranges from about 2% to about 60 % w/w, preferably from about 5% to about 50% w/w, more preferably from about 5% to about 30% based on the total weight of the powder composition.

Flavouring agents may also be used in the present invention. Flavouring agents may be selected without any limitation from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants leaves, flowers, fruits, and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. Solid forms, such as spray dried forms of flavouring agents, may also be useful in the powder for oral suspension compositions disclosed herein. The amount of flavouring may depend on a number of factors including the organoleptic effect desired. The amount of the flavouring agent can be used in the powder for oral suspension compositions of the present invention typically in the range from about 0.01% to about 5% w/w based on the total weight of the powder composition.

Colorants may include iron oxide red, titanium dioxide and/or dyes suitable for pharmaceutical & food such as those known as F. D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth. A colorant may be an optional ingredient in the powder for oral suspension compositions disclosed herein but, when used, will generally be present in the range from about 0.001% to about 5% based on the total weight of the powder composition.

The powder composition of the present invention may also contain wetting agents such as sorbitan monolaurate, polysorbate 80, and sodium lauryl sulfate; the amount of wetting agent, when employed, is typically in the range from about 0.3% to about 3% w/w based on the total weight of the powder composition and may also include an anti-foaming agent such as simethicone or dimethicone in amounts typically from about 0.1% to about 4% w/w based on the total weight of the powder composition.

All percentages mentioned herein, unless otherwise indicated, are on a w/w basis, i.e., as a percentage of the total weight of the powder composition.

The specifically mentioned pharmaceutically acceptable excipients in the foregoing lists are intended to be exemplary, not exhaustive, of specific excipients that may be used in the practice of the disclosed invention. It is further understood that more than one of any particular type of excipient may be used in the powder for oral suspension compositions described herein. For example, the compositions may include more than one sweetener, colorant, etc. Also, a single excipient may provide multiple functions, as mentioned hereinabove.

The term “comprise/comprises/comprising” as used herein mean that other ingredients, steps, etc. are optionally present. When reference is made herein to a method comprising two or more defined steps, the steps can be carried in any order or simultaneously (except where the context excludes that possibility), and the method can include one or more steps which are carried out before any of the defined steps, between two of the defined steps, or after all of the defined steps (except where the context excludes that possibility).

The term “Melatonin” as used herein, unless the context requires otherwise, includes Melatonin, its pharmaceutically acceptable salts and chemical derivatives of Melatonin such as polymorphs, hydrates, solvates, prodrugs, chelates, and complexes. The extended release compositions of the present invention comprise Melatonin in a range of from about 0.1% to about 10% w/w based on total weight of the composition.

The term “non-functional coating” as used herein, is a coating that does not affect the release rate of the drug. Examples of a non-functional coating without limitation include microcrystalline cellulose, hydroxypropyl cellulose, hypromellose or polyvinyl alcohol. In certain embodiments, the non-functional coating is Opadry® Clear, which contains, hydroxypropyl methylcellulose and polyethylene glycol.

The term “functional coating” as used herein, is a coating that affects the release rate of the drug from the dosage form. Examples of a functional coating without limitation include ethylcellulose and polyvinyl pyrrolidone (PVP K30).

The term “extended release” as used in the present invention defines a release profile of an active agent over an extended period of time. The terms “modified-release”, “controlled-release”, “prolonged-release”, “sustained-release”, “extended-release” and “delayed release” are used interchangeably herein.

“Seal coated inert pellet” according to the present invention are inert pellets coated with a polymer, for e.g. ethylcellulose, methylcellulose etc. The seal coating provides a film over the pellets, which improves the strength of the pellets. So, during the coating/layering process, the pellets do not get deformed or distorted.

“Drug-binder solution” according to the present invention is a solution of drug and one or more binding agent.

The term “inert core” or “inert cores” or “inert particles” or “inert pellets” herein refers to inert particles made from sugar spheres also known as non-peril seeds or other equivalents conventionally used for the preparation of dosage form like microcrystalline cellulose, dibasic calcium phosphate, mannitol or other suitable polyols or glass beads and the like.

The term “non-caking” as used herein means that when constituted in aqueous media, for example, the formed suspension has a smooth consistency and doesn't contain any caking or clumping particles, by visual inspection. Also, the powder for oral suspension in accordance with the present invention does not cake or clump during manufacture, i.e., when mixed with excipients. Nor does it cake or clump upon storage, even under relatively humid conditions, e.g., a relative humidity of about 75% or greater and when stored for relatively long periods such as about 6 months or longer and even at elevated temperatures of about 40°C or greater, or at any combination of such humidity, time and temperature parameters. Thus, the powders for oral suspension in accordance with the present invention will remain free flowing and non-caking during typical storage and use conditions.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The term “about,” as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

The powder for oral suspension compositions of the present invention are non-caking as defined hereinabove. Generally, the powder for oral suspension compositions are sold as powders, i.e., before constitution in a suspending medium. The actual suspension is typically prepared by a pharmacist or the patient. The oral suspension is thus the actual dosage form that is ingested by the patients.

The powder for suspension may be packaged in a suitable package such as a bottle or a sachet. Further, the sachet can be filled as a unit dose or a multi-dose sachet. The present invention further includes a co-package or a kit comprising two components, wherein one package or one component comprises a powder for suspension and another package or another component comprises a suspension base or a pharmaceutically acceptable vehicle.

The extended release Melatonin powder compositions described herein may be administered to a mammal, preferably a human, in a pharmaceutically effective amount for the treatment of sleep related disorders.

The pharmaceutical composition of the present invention can further be used for preparing solid dosage forms of Melatonin such as tablets, capsules etc. Such other dosage forms can be prepared using formulation techniques known to a person skilled in the art. One or more excipients from the pharmaceutical composition of the present invention can be omitted and other excipients from the same class or other classes can also be used in place of such omitted excipients as per the requirement and suitability of such other formulations (such as tablets, capsules etc.) intended to prepare. Thus, such other solid dosage forms are also covered within the scope of the present invention.

The pharmaceutical compositions of the present invention can be described as following general formula:
Table-1: General formula of the pharmaceutical compositions of the present invention
Sr. No. Ingredient % w/w
Extended release pellets
1 Melatonin 0.1-10
2 Diluent(s) (optionally seal coated) 50-98
3 Binder(s) 0.1-10
4 Solvent(s) Q.S.
5 Rate controlling polymer(s) 5-25
6 Pore former(s) 0.1-10
7 Plasticizer(s) 0.1-10
8 Solvent(s) Q.S.
Extra granular material
9 Disintegrant(s) 0.1-15
10 Binder(s) 0.1-15
11 Colorant(s) 0.001-5
12 Binder(s)/Suspending agent(s) 0.1-15
13 Diluent(s) 5-99
Q.S. = Quantity Sufficient

The present invention is further exemplified by the following non-limiting examples.

BEST MODE OF CARRYING OUT THE INVENTION
EXAMPLES
The pharmaceutical compositions of the present invention are explained in more detail with reference to the following examples. These examples are provided by way of illustration only and should not be construed as to limit the scope or spirit of the claims in any manner.
Example-1: Preparation of an extended release Melatonin powder composition comprising inert pellets without seal coating
Table-2: Composition of an extended release Melatonin powder
Sr No Name of Ingredient mg/unit
1 Melatonin 2.00
2 Celphere CP 102 80.00
3 Opadry Clear 4.00
4 Water Q.S.
5 Isopropyl alcohol Q.S.
Total weight of drug coated pellets 86.00
6 Ethocel E45 P 11.68
7 PVP K30 1.46
8 PEG 4000 1.46
9 Isopropyl alcohol Q.S.
10 Purified water Q.S.
Total weight of functional coated pellets 100.60
Extra granular material for sachets
1 Cross linked polyvinyl pyrrolidone (Crospovidone) 15.00
2 Hydroxypropyl cellulose 15.00
3 Iron oxide Red 0.015
4 Xanthan gum 3.00
5 Dextrose 1466.985
Total 1500
Q.S. = Quantity Sufficient

Method of Preparation:
Drug solution preparation:
1. Mix required quantities of purified water and isopropyl alcohol.
2. Add required quantity of opadry clear 190003 into step (1) under continuous stirring to get clear solution.
3. Add required quantity of Melatonin into step (2) under continuous stirring to get clear solution.
Drug coating:
4. Load the solution obtained in step (3) on Celphere CP 203.
Functional coating:
5. Dissolve required quantity of Ethocel E45 Premium into required quantity of isopropyl alcohol under continuous stirring to get clear solution.
6. Dissolve required quantities of PEG-4000 and Kollidon K30 in required quantity of purified water under continuous stirring.
7. Add mixture obtained in step (6) into step (5) under continuous stirring to get clear solution.
8. Load the solution obtained in step (7) on drug loaded pellets of step (4).
Extra-granular material preparation:
9. Weigh required quantities of Crospovidone, Hydroxypropoyl cellulose, Iron oxide RED, Xanthan gum and Dextrose. Sift the ingredient through 30#.
10. Load the ingredient of step (9) in rapid mixture granulator with purified water to prepare granular material.

Example-2: Stability studies of the extended release formulations prepared according to Example-1
Stability of the extended release Melatonin powder formulations were tested under different storage conditions. It was surprisingly found that the extended release formulations according to the present invention are stable at least for six months when stored under different storage conditions. The stability study results are provided in the table below.

Table-3: Stability studies and dissolution profile of an extended release Melatonin powder (Batch No. MLTL1045)
Dosage
Form Stability
Condition Month Assay
(%) RS
(%Total) 10
Mins 1
Hr 2
Hrs 3
Hrs 4
Hrs 6
Hrs 8
Hrs 10
Hrs 12
Hrs
Sachet (Extra
Granular) Initial 106.6 0.03 9.6 30.4 50.2 63.4 72.4 83.5 89.5 93.2 95.5
40°C/75% RH 1 104.0 0.08 15.5 37.9 56.2 67.7 75.5 85.2 90.8 94.2 96.3
3 98.3 0.23 15.1 37.4 53.3 64.0 71.6 81.9 87.9 92.0 94.6
6 100.0 0.26 12.6 26.3 40.6 51.1 59.2 70.7 78.1 83.5 87.0
30°C/65% RH 3 103.6 0.19 12.3 33.4 51.5 63.6 71.8 82.3 88.4 92.2 94.8
6 102.7 0.18 12.1 30.6 49.1 61.6 71.7 81.6 88.2 92.3 94.9
25°C/60% RH 3 106.1 0.15 11.0 29.3 48.8 62.1 71.3 82.7 89.3 93.4 95.9
6 101.6 0.13 10.6 30.3 49.8 62.7 71.3 81.4 87.0 89.9 90.8
Active Pellets Initial 103.9 ND 6.7 29.0 55.8 - 73.1 85.0 91.7 96.0 98.5
40°C/75% RH 1 101.1 0.10 13.7 41.0 60.1 72.7 81.2 91.7 97.6 99.3 102.0
3 100.6 0.16 13.2 38.2 55.9 67.4 75.4 85.0 90.4 93.8 96.1
6 99.6 0.11 14.8 39.0 56.3 67.3 74.9 84.5 89.6 92.8 94.6
30°C/65% RH 3 100.8 0.21 10.2 33.6 52.4 64.4 72.8 83.2 88.8 92.3 94.4
6 100.3 0.08 11.8 33.4 51.4 63.2 71.2 81.4 87.0 90.5 92.8
25°C/60% RH 3 101.9 0.16 9.2 32.3 51.5 64.3 73.1 83.7 89.5 93.1 95.4
6 101.9 0.06 10.8 33.0 51.5 63.2 71.2 81.4 87.2 90.5 92.6

Example-3: Preparation of an extended release Melatonin powder composition comprising inert pellets with seal coating
Table-4: Composition of an extended release Melatonin powder
Sr No Name of Ingredient mg/unit
1 Sugar Spheres (60/70 mesh) 82.00
2 Surelease 3.375
3 Methocel E6 P 0.375
4 Water Q.S.
Total weight of seal coated pellets 85.75
5 Melatonin 2.00
6 Opadry Clear 4.00
7 Water Q.S.
8 Isopropyl alcohol Q.S.
Total weight of drug coated pellets 91.75
9 Ethocel E45 P 12.48
10 PVP K30 1.56
11 PEG 4000 1.56
12 Isopropyl alcohol Q.S.
13 Purified water Q.S.
Total weight of functional coated pellets 107.35
Extra granular material for sachets
1 Cross linked polyvinyl pyrrolidone (Crospovidone) 15.00
2 Hydroxypropyl cellulose 15.00
3 Iron oxide Red 0.015
4 Xanthan gum 3.00
5 Dextrose 1466.985
Total 1500
Q.S. = Quantity Sufficient

Example-4: Stability studies of the extended release formulations prepared according to Example-3
Stability of the extended release Melatonin powder formulations were tested under different storage conditions. It was surprisingly found that the extended release formulations according to the present invention are stable at least for six months when stored under different storage conditions. The stability study results are provided in the table below.

Table-5: Stability studies and dissolution profile of an extended release Melatonin powder (Batch No. MLTL1037)

Dissolution
condition Dosage
Form Stability
Condition Month 10
Mins 1
Hr 2
Hrs 3
Hrs 4
Hrs 6
Hrs 8
Hrs 10
Hrs 12
Hrs
Dissolution media-900 ml phosphate buffer of pH 6.8; Apparatus-Basket, 50 RPM Sachet (Extra Granular) Initial 1.1 13.3 36.9 58.1 76.6 87.5 92.9 95.6 95.3
40°C/75% RH 1 1.2 11.6 29.1 45.8 68.9 81.0 86.9 90.7 92.7
3 1.6 13.0 29.7 52.5 66.9 78.9 85.3 89.1 90.1
6 2.2 12.8 34.0 51.0 74.8 80.1 85.3 88.3 90.1
Active Pellets Initial 8.0 41.4 60.6 71.1 77.6 85.2 89.2 91.6 93.2
40°C/75% RH 1 11.1 43.1 62.0 72.3 78.8 86.2 90.6 93.0 94.4
2 10.6 41.6 59.9 70.6 76.3 83.7 87.7 90.2 91.8
3 10.6 40.7 58.5 68.9 75.5 83.4 87.4 90.0 91.8
6 10.3 43.0 61.3 71.4 77.6 85.1 89.0 91.3 93.2

Example-5: Dissolution profile of the extended release formulations prepared according to the present invention
Dissolution profile of the extended release Melatonin powder formulations were tested under different dissolution media using paddle and basket apparatus. It was surprisingly found that the extended release formulations according to the present invention show desired dissolution profile when tested under 0.1 N HCl, acetate buffer of pH 4.5 and phosphate buffer of pH 6.8. The comparison between the dissolution profiles of formulation of the present invention and Melatonin reference product (Circadin®) is provided in the table below.
Condition Batch No. 10 Mins 1
Hr 2
Hrs 3
Hrs 4 Hrs 6 Hrs 8 Hrs 10 Hrs 12 Hrs
% Cumulative drug dissolved
Dissolution media-900 ml 0.1 N HCl; Apparatus-Paddle, 50 RPM 40356-Lot 1-EU RLD 15.9 42.2 58.6 69.8 76.6 86.2 90.1 91.9 92.4
60254A-Lot 2-RLD Bio Lot 17.2 43.2 59.5 71.8 80.0 92.7 94.6 97.6 99.5
MLTL1048-Test Bio Lot 7.2 22.7 38.9 50.5 59.0 70.0 76.9 81.2 84.3
Dissolution media-900 ml pH 4.5 acetate buffer; Apparatus-Paddle, 50 RPM 40356-Lot 1-EU RLD 15.4 36.4 50.7 61.0 68.9 80.5 87.7 92.1 94.7
60254A-Lot 2-RLD Bio Lot 16.1 38.4 52.5 62.1 70.0 83.7 92.7 96.9 99.3
MLTL1048-Test Bio Lot 7.4 25.4 43.8 56.2 64.7 75.5 82.0 86.1 89.1
Dissolution media-900 ml pH 6.8 phosphate buffer; Apparatus-Paddle, 50 RPM 40356-Lot 1-EU RLD 14.9 38.2 52.8 - 70.6 81.0 88.2 92.3 94.8
60254A-Lot 2-RLD Bio Lot 17.2 40.1 53.1 - 69.4 79.9 85.7 88.8 90.8
MLTL1048-Test Bio Lot 7.5 27.2 44.3 - 64.7 76.0 83.0 87.0 90.0
Dissolution media-900 ml 0.1 N HCl; Apparatus-Basket, 50 RPM 40356-Lot 1-EU RLD 14.8 37.7 53.0 63.7 69.4 80.1 86.6 94.0 95.6
60254A-Lot 2-RLD Bio Lot 15.8 40.2 55.1 65.5 73.1 84.3 90.5 94.5 96.36
MLTL1048-Test Bio Lot 8.4 27.0 42.0 56.1 63.0 73.3 78.8 85.4 87.9

Example-6: Bioequivalence study of the extended release Melatonin powder prepared according to the present invention
A randomized, open label, balanced, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study of extended release Melatonin powder for oral suspension 2 mg/5 ml and Circadin® 2 mg prolonged-release tablets was conducted in normal, healthy, adult human subjects under fed conditions. The results are summarized in table below.
Sr No Parameter Ratio Lower Upper Power Intra_CV
1 Cmax 88.4944 76.6619 102.1532 83.3730 17.3891
2 AUCt 105.2130 96.1040 115.1853 98.6930 10.9215
3 AUCinf 103.1138 94.1703 112.9066 98.6753 10.9424

Above mentioned data shows that the extended release Melatonin preparation according to the present invention is suitable for the treatment of conditions where the Melatonin is an effective therapy and can be a better choice over existing Melatonin formulations where patients e.g. pediatric, geriatric and other patients who have problem of swallowing solid formulations (tablets, capsules etc.) can be benefited by the administration of extended release powder for oral suspension.

It should be understood that various changes and modifications to the presently preferred embodiments and examples described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.