Claims:
1. A pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients.
2. A pharmaceutical composition according to claim 1 wherein one or more pharmaceutically acceptable excipients areselected from the group comprising of one or more vehicles, one or more preservatives, one or more buffering agents, one or more sweetening agents, one or more flavoring agents or combination thereof.
3. A pharmaceutical composition according to claim 2 wherein one or more vehicle is selected from the group comprising of aqueous vehiclesand oily vehicles, wherein aqueous vehicles are selected from the group comprising purified water, hydro-alcoholic, polyhydric alcohols and buffers and oily vehicle is selected from the group comprising vegetable oils, mineral oils, organic oily bases or emulsified bases.
4. A pharmaceutical composition according to claim 2 wherein one or more preservative is selected from the group comprisingbenzyl alcohol, chloro-butanol, chloro-cresol, alkyl esters of paraben, phenol, phenyl ethanol, propylene glycol, chloroform, benzoic acid, potassium sorbate, sodium benzoate.
5. A pharmaceutical composition according to claim 2 wherein one or more buffering agent is selected from the group comprisingsodium acetate, sodium citrate, ammonium sulfate, sodium phosphate, disodium hydrogen phosphate, potassium citrate, citric acid monohydrate, trisodium citrate dihydrate.
6. A pharmaceutical composition according to claim 2 wherein one or more sweetening agent is selected from the group comprisingsucralose, sucrose, glycerol, liquid glucose, sorbitol, maltitol, saccharin sodium and aspartame.
7. A pharmaceutical composition according to claim2 wherein one or more flavoring agent is selected from the group comprisingof essential oils and fruit flavors, wherein essential oil is selected from the group comprisingpeppermint oil, orange oil, and lemon oil and fruit flavour comprising peppermint flavour, raspberry flavour, strawberry flavour and tutti-fruit flavour.
8. A pharmaceutical composition according to any one of claims 1 to 7 wherein the pharmaceutical composition is a liquid composition.
9. A pharmaceutical composition according to any one of claims 1 to 8 wherein the pharmaceutical composition is suitable for oral administration.
10. A process for the preparation of the pharmaceutical composition according to any one of claims 1 to 9, wherein the process comprising steps of,
(a) Add water and adjust desirable pH using pH adjusting agent
(b) Add melatonin and mix till it dissolves
(c) Add sweetening agent and flavouring agent
(d) Adjust volume to desirable batch size
, Description:FILED OF THE INVENTION
The present invention relates, in general, to the pharmaceutical field, and more precisely it relates to a pharmaceutical composition for the oral administration of Melatonin and to the process for the preparation thereof. In particular, the present invention relates to the oral liquid composition comprising Melatonin.

BACKGROUND OF THE INVENTION
Melatonin, chemically known as N-acetyl-5-methoxytryptamine having an empirical formula C13H16N2O2 and a molecular weight of 232.3 gm/mol has a following structural formula:

Melatoninis a natural substance produced in humans by a gland, named pineal gland or epiphysis, placed at the base of the brain. This substance 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.
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 2008/122104 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 1995/003043 and WO 2008/148015 describes a sustained release melatonin formulation. WO 2012/103411 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 of melatonin. 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 2010/062153 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 2012/156565 describes a stable and sterile pharmaceutical composition for the parenteral administration of melatonin in the form of an aqueous solution. WO 2015/135997 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 2016/058985 describes substantially water free composition consisting of liquid preparation of melatonin.WO 2016/139635 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 2008/127609 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 2016/131784 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 1999/047175 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 2014/044896 describes an orodispersible solid pharmaceutical composition comprising melatonin.CN 1348758 describes a composition comprising melatonin and ß-glucan.

From above mentioned prior art, it can be seen that currently available preparations of Melatonin are solid oral preparations e.g. tablets, capsules, powders 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 patients). Therefore, there is an existing need for oral liquid pharmaceutical composition comprising Melatonin having improved stability and palatability. 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 patientpopulations (e.g. pediatric patients) to take because of swallowing problems.Therefore it is preferable to administer active ingredient in pharmaceutical liquid dosage form.

OBJECT OF THE INVENTION
It has already been proposed that solid oral preparations as well as other route of administrations are not suitable for all types of patient populations. Therefore the principal object of the present invention is to provide oral liquid pharmaceutical preparation of Melatonin.

Another object of the present invention is to provide oral liquid pharmaceutical preparation of Melatonin without risk of over dosage of the drug.
A further object of the present invention is to provide oral liquid pharmaceutical preparation of Melatonin with sweetening agent and flavoring agent to mask the bitter taste of Melatonin and to provide pleasant taste.

A further object of the present invention is to provide process for the preparation of the oral liquid pharmaceutical preparation of Melatonin of the present invention.

A further object of the present invention is to provide use of the composition of the invention in the manufacture of a medicament.

A further object of the present invention is to provide composition of the invention for use as a medicament.

A further object of the present invention is to provide composition for use in the manufacture of a medicament for regulating circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), treatment the multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of sepsis in adults, the treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment failure kidney or liver, or treating oxidative stress situation generated during surgery, and particularly during abdominal surgery. Therefore, the present invention relates to a method for regulating the circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment of kidney or liver failure, or treatment of the situation of oxidative stress caused by surgery.

STATEMENT OF THE INVENTION
Accordingly, the present invention provides a liquid pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, preservatives, buffering agents, sweetening agents, flavoring agentsor combinations thereof with improved stability and palatability.

There is also provided a method of preparing the liquid pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, preservatives, buffering agents, sweetening agents, flavoring agents or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION
Melatonin, chemically known as N-acetyl-5-methoxytryptamine having an empirical formula C13H16N2O2 and a molecular weight of 232.3 gm/mol has a following structural formula:

Melatonin is a natural substance produced in humans by a gland, named pineal gland or epiphysis, placed at the base of the brain. This substance 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.

Melatonin is known to administer through several routes of administration e.g. oral, nasal, intranasal, parenteral, transdermal, buccal, sublingual etc. Oral dosage forms include solid preparations (e.g. tablets, capsules, and powders etc.) and liquid preparations (e.g. solutions, suspensions etc.). Solid dosage forms include sustained release, prolonged release and extended release dosage forms. 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 patients) to take because of swallowing problems. Therefore it is preferable to administer active ingredient in pharmaceutical liquid dosage form. Further, pharmaceutical agents are known to have strong bitterness which results into a bitter taste and a feeling of numbness in the mouth. Therefore oral solid dosage forms are not preferred for some types of patient population especially pediatric patient population.

Therefore in one of the embodiments, the present invention provides a pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients.

In one of the further embodiments, the pharmaceutical composition comprises Melatonin and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, preservatives, buffering agents, sweetening agents and flavouring agents or combination thereof.

In one of the further embodiments, the pharmaceutical composition comprises Melatonin and one or more vehicles, one or more preservatives, one or more buffering agents, one or more sweetening agents and one or more flavouring agents or combination thereof.

In one of the preferred embodiments, the pharmaceutical composition comprises Melatonin, a vehicle, a preservative, a buffering agent, a sweetening agent and a flavouring agent or combination thereof.

In one of the preferred embodiments, the pharmaceutical composition is a liquid pharmaceutical composition.

In one of the preferred embodiments, the liquid pharmaceutical composition is suitable for oral administration.

In one of the preferred embodiments, the liquid pharmaceutical composition has pH in between 3.0 and 7.0.

In one of the further embodiments, the pharmaceutical composition is useful for the manufacture of a medicament.

In one of the further embodiments, the pharmaceutical composition is useful as a medicament.

In one of the further embodiments, the pharmaceutical composition is useful for the manufacture of a medicament for regulating circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), treatment the multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of sepsis in adults, the treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment failure kidney or liver, or treating oxidative stress situation generated during surgery, and particularly during abdominal surgery. Therefore, the present invention relates to a method for regulating the circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment of kidney or liver failure, or treatment of the situation of oxidative stress caused by surgery.

Vehicles referred in the present invention are the liquid bases which carry drug and other excipients in dissolved or dispersed state and can be selected from either aqueous vehicles or oily vehicles. Examples of suitable aqueous vehicles are but not limited to purified water, hydro-alcoholic, polyhydric alcohols and buffers, while suitable examples of oily vehicles are but not limited to vegetable oils, mineral oils, organic oily bases or emulsified bases. The preferred vehicle is purified water.

Preservatives referred in the present invention are the compounds which are included in pharmaceutical dosage form to prevent the growth of microorganisms during the product’s manufacture and shelf life. Examples of the suitable preservatives are but not limited to benzyl alcohol, chloro-butanol, chloro-cresol, alkyl esters of paraben, phenol, phenyl ethanol, benzoic acid, potassium sorbate, sodium benzoate, chlorobutanol etc. and antimicrobial solvents likepropylene glycol, chloroform etc.The preferredpreservative is sodium benzoate.

Buffering agents referred in the present invention are the compounds which provide stability and pH control to the pharmaceutical formulations. Examples of suitable buffering agents are but not limited to sodium acetate, sodium citrate, ammonium sulfate, sodium phosphate, disodium hydrogen phosphate, potassium citrate, citric acid monohydrate, trisodium citrate dihydrate. The preferred buffering agent is citric acid monohydrate.

Sweetening agentsreferred in the present invention are the compounds that impart sweetness and improve patient compliance through taste masking. Examples of the suitable sweetening agents are but not limited to sucralose, sucrose, liquid glucose, glycerol, sorbitol, maltitol, saccharin sodium and aspartame.The preferredsweetening agent is sucralose.

Flavouring agents referred in the present invention are the compounds which are added to increase patient acceptance of the drug by masking the specific taste sensations. Examples of suitable flavouring agent are but not limited to essential oilsincluding peppermint oil, orange oil, and lemon oil etc. or can be selected from fruit flavour, e.g. peppermint flavour, strawberry flavour, tutti fruit flavour etc. The preferred flavouring agent is strawberry flavour.

The composition of the oral liquid formulation according to the present invention can be described in following general formula.

Table-1: General formula of the composition of the invention
Ingredient Quantity (mg/mL)
Melatonin 0.1-10
Preservative 0.01-10
Buffering agent Q.S to pH 3-7
Sweetening agent 0.1-100
Flavouring agent 0.001-10
Vehicle Q.S to 1 ml

In one of the further embodiments, the present invention provides process for the preparation of the pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, preservatives, buffering agents, sweetening agents and flavouring agents or combination thereof as described herein above.A general process for the preparation of the pharmaceutical composition according to the present invention is described below.
(a) Add water and adjust desirable pH using pH adjusting agent;
(b) Add Melatonin and mix till it dissolves;
(c) Add sweetening agent and flavouring agent; and
(d) Adjust volume to desirable batch size.
BEST MODE OF CARRYING OUT THE INVENTION
EXAMPLES
The pharmaceutical composition of the present invention is 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 limit to the scope of the claims in any manner.

Example-1: A liquid oral pharmaceutical composition comprising Melatonin
Table-2: Melatonin liquid composition
Ingredient Quantity (mg/mL)
Melatonin 1.0
Sodium benzoate 0.625
Citric acid monohydrate Q.S. to pH 3-7
Sucralose 0.1-100
Strawberry flavour 0.001-10
Purified water Q.S. to 1 ml

Method of Preparation: A liquid oral pharmaceutical composition comprising Melatonin as active ingredient and Sodium benzoate, Citric acid monohydrate, Sucralose, Strawberry flavour and Purified water was prepared following below mentioned process comprising steps of:
(a) Add required quantity of Purified water and adjust desirable pH using required quantity of Citric acid monohydrate;
(b) Add required quantity of Melatonin into the mixture obtained in step (a) and mix till it dissolves;
(c) Add required quantity of Sucralose and Strawberry flavor into the mixture obtained in Step (b); and
(d) Adjust volume to desirable batch size with Purified water.

Those who are skilled in the art can understand that variations in the above described process for the preparation of liquid compositions of the present invention can be adopted which are well within the skills of the skilled artisan. One can change sequences of the steps in the above mentioned process for the purposes of suitability and convenience without affecting the quality and characteristics of the resulting product.

Those who are reasonably skilled in the art can easily understand that similar liquid formulations using Melatonin with other suitable excipients, mentioned in the foregoing paragraphs may be prepared in the above mentioned formulas using above mentioned processes for the preparation. Such other examples of compositions and processes of preparation thereof are also within the ambit of the invention disclosed and claimed in the present application.

Example 2: Stability studies of the pharmaceutical composition prepared in Example 1
The oral liquid pharmaceutical composition prepared according to Example 1 exhibits unexpected stability profile when tested after three (3) months under the conditions 40 ± 2°C/25% RH and 25 ± 2°C/60% RH. The liquid composition according to the present invention possess very less amount of impurities and highest degree of purity. The results of the stability tests conducted are summarized in the table below.

Table-3: Stability study results of Melatonin liquid composition of Example-1
TESTS RESULTS
INITIAL 40±2°C/25% RH 25±2°C/60% RH
3 months ? 3 months ?
Description Clear Colorless Solution Clear Colorless Solution Clear Colorless Solution
pH 4.32 4.31 4.29
Assay of Melatonin (%) 99.6 97.8 98.3
Any Individual Impurity (%) BQL 0.06 BQL
Total Impurities (%) 0.06 0.13 BQL
BQL = Below Quantitation Limit

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.