WO2019186386A1

WO2019186386A1 - Melatonin oral dissolving film

Info

Publication number: WO2019186386A1
Application number: PCT/IB2019/052433
Authority: WO
Inventors: Srinivas Reddy MALE; Lakshman Rao SAKARE; Shantaram Laxman PAWAR
Original assignee: Azista Industries Pvt Ltd
Priority date: 2018-03-29
Filing date: 2019-03-26
Publication date: 2019-10-03

Abstract

The present invention relates to an oral dissolving film comprising melatonin or melatonin analogues. The present invention specifically relates to a composition of stable oral dissolving film comprising melatonin or melatonin analogues and one or more pharmaceutically acceptable excipients, wherein the melatonin in the film is in soluble form. The present invention more specifically relates to a process for the preparation of stable oral dissolving film comprising melatonin or melatonin analogues and one or more pharmaceutically acceptable excipients, wherein the melatonin is in the film is in soluble form.

Description

MELATONIN ORAL DISSOLVING FILM

FIELD OF INVENTION

The present invention relates to an oral dissolving film comprising melatonin or melatonin analogues.

The present invention specifically relates to a composition of stable oral dissolving film comprising melatonin or melatonin analogues and one or more pharmaceutically acceptable excipients, wherein the melatonin in the film is in soluble form.

The present invention more specifically relates to a process for the preparation of stable oral dissolving film comprising melatonin or melatonin analogues and one or more pharmaceutically acceptable excipients, wherein the melatonin is in the film is in soluble form.

BACKGROUND OF INVENTION

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from 5- hydroxytryptamine which is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident, regardless of whether the mammals are nocturnal or diurnal, and conversely, melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod and physiological processes, e.g. in animals which use changes in the photoperiod to time their thermoregulation, temporal signals to the thermoregulatory system are controlled by the daily rhythm in the duration of melatonin during the dark phase. Numerous studies have shown that melatonin has a potent influence on gonadal activity.

Melatonin has a chemical formula of C_l3H₁₆N₂O₂ and a molecular mass of 232.278 g/mol. It has a structural formula of;

Melatonin is synthesized mainly by the pineal gland and is suggested to have antioxidant and prophylactic properties. Melatonin possesses strong antioxidant activity by which it protects cells, tissues, and organs from the oxidative damage caused by ROS, especially the hydroxyl radical, which attacks DNA, proteins and lipids and causes pathogenesis.

Sleep is not a non-differentiated homogeneous process. In fact, it consists of different stages which in normal subjects have a precise temporal organization, which has to be respected, in order to grant a sleep as natural as possible; one complete cycle of such stages requires about 90 minutes.

Sleep structure is expressed by two basic situations: the NREM sleep (non rapid eye movements), subdivided into 4 different stages of increasing depth, and the REM sleep.

Exogenous melatonin, as both prescription and over the counter pills/tablets, has become one of the most frequently requested non -prescription sleep aids due to its regulator role in the internal timing of biological rhythms, including promotion/regulation of sleep. Melatonin is marketed to help promote total sleep time, aid with fatigue from jet lag, or balance circadian rhythms from jet lag and rotating shift work.

WO 94/007487 discloses method of inducing sleep in an individual, comprising administering to the individual a single, effective dose of melatonin.

U.S. Patent Nos. 7,407,669 and 7,025,983 disclose a fast-dissolving orally consumable film used to deliver breath deodorizing agents, antimicrobial agents and salivary stimulants to the oral cavity. The films can also be used to deliver pharmaceutically active agents.

U.S. Patent No. 8,691,275 discloses controlled release melatonin compositions and related methods and, more particularly, that include a controlled release pH environment around the melatonin in the composition.

U.S. Patent No. 8,962,024 discloses method for treating and improving the restorative quality of sleep in a patient suffering from non -restorative sleep as an element of primary insomnia by administering 0.0025 to 50 mg of melatonin.

U.S. Patent Application No. 2010/0256215 discloses fast dissolving film of melatonin and melatonin analogues with or without menthol that can absorb through oral mucosa into direct blood stream. From the strength 0.3 mg to 10 mg of melatonin. The film is thin and made from a low-moisture, non-tacky material that becomes dissolved when hydrated and that is sized so that the substrate can be placed in oral cavities of persons.

U.S. Patent Application No. 2014/0335153 discloses thin film comprising solvent, binder, flavoring agent, sweetener, lipid, emulsifier, dye or pigment, preservative, melatonin as active ingredient and powder coating.

U.S. Patent Application No. 2017/0239217 Al discloses anhydrous melatonin composition, where in melatonin present in a quantity of 10% or higher in a substantially water free carrier mixture of ethanol and polyethoxylated derivative. The concentrated solution is free from preservatives. The invention also encompasses a method of the preparation and high levels of melatonin as adjuvant therapy in Ebola or dengu hemmorhagic fever (DHF) or as an antioxidant/antiaging treatment. Oral dissolving films major drawback is loading capacity which will affect its film forming nature and dissolving efficiency. Inventors of the present invention have developed high load films by using solubilising or partial solubilising methods which reduce loading problem in film forming agent. The present invention is an improvement over the prior art in that it delivers melatonin or melatonin analogues in a fast dissolving film with melatonin in soluble form and with higher strength. The present invention relates to the oral dissolving film of melatonin or their analogues where melatonin is in soluble form which causes rapid absorption of melatonin in oral cavity utilizing existing dissolving film technologies and to a product that act as a natural aid in the treatment of age-related sleeplessness or other disorders related to sleep.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a composition of oral dissolving film comprising melatonin or melatonin analogues, wherein the melatonin is in soluble form.

Another objective of the present invention is to provide a process for the preparation of stable melatonin or melatonin analogues oral dissolving film by using solubilising agents or solvent system or combination of thereof.

SUMMARY OF INVENTION

Accordingly, the present invention provides preparation of oral dissolving film with high drug loading capacity in soluble form of melatonin to enhance absorption in oral cavity.

One embodiment of the present invention provides a composition of oral dissolving film comprising melatonin or melatonin analogues, wherein the melatonin is in soluble form. One embodiment of the present invention provides a composition of oral dissolving film comprising melatonin or melatonin analogues and one or more pharmaceutically acceptable excipients, wherein the melatonin present in the film is in soluble form.

Another embodiment of the present invention provides a composition of melatonin oral dissolving film comprising one or more solubilizing agents, one or more stabilizing agents and one or more film-forming agents, wherein the melatonin present in the film is in soluble form.

Another embodiment of the present invention provides a composition of melatonin oral dissolving film comprising one or more solubilizing agents, one or more stabilizing agents, one or more chelating agents and one or more film -forming agents, wherein the melatonin present in the film is in soluble form.

Another embodiment of the present invention provides a composition of high drug load oral dissolving film comprising melatonin or its analogues, one or more solubilizing agents, one or more stabilizing agents, one or more film-forming agents, one or more sweetening agents, one or more plasticizing agents and optionally anti- adsorbent agents, wherein the melatonin present in the film is in soluble form.

Another embodiment of the present invention provides a composition of high drug load oral dissolving film comprising melatonin or its analogues, one or more solubilizing agents, one or more stabilizing agents, one or more binding agents, one or more chelating agents, one or more film-forming agents, one or more sweetening agents, one or more plasticizing agents and optionally anti-adsorbent agents, wherein the melatonin present in the film is in soluble form.

Another embodiment of the present invention provides a composition of melatonin oral dissolving film may further comprise one or more pharmaceutically acceptable excipients selected from acidifying agents, binding agents, cooling agents, antioxidants, viscosity-increasing agents, sweetening agents, colouring agents, opacifiers, plasticizing agents, humectants, flavouring agents, buffering agents, solvents and optionally anti- adsorbent agents.

Yet another embodiment of the present invention provides a composition of oral dissolving film comprising:

1 to 50 wt % of melatonin or melatonin analogues,

0.1 to 60 wt % of solubilising agents,

0.01 to 5 wt % of stabilizing agents,

0.1 to 70 wt % of film forming agents

0.1 to 30 wt % of sweetening agents

0.1 to 50 wt % of plasticizing agents,

optionally 0.1 to 30 wt % of anti- adsorbent agents, and

0.1 to 90% of one or more other excipients.

1 to 50 wt % of melatonin or melatonin analogues,

0.1 to 60 wt % of solubilising agents,

0.01 to 5 wt % of stabilizing agents,

0.1 to 70 wt % of film forming agents,

0.1 to 30 wt % of sweetening agents

0.1 to 50 wt % of plasticizing agents,

0.01 to 5 wt % of chelating agents,

optionally 0.1 to 30 wt % of anti- adsorbent agents, and

0.1 to 90% of one or more other excipients.

Yet another embodiment of the present invention provides a composition of oral dissolving film comprising: 1 to 50 wt % of melatonin or melatonin analogues,

0.1 to 60 wt % of cyclodextrins,

0.01 to 5 wt % of xanthan gum,

0.1 to 70 wt % of hydroxypropyl methylcellulose,

0.1 to 30 wt % of sucralose,

0.1 to 50 wt % of propylene glycol,

optionally 0.1 to 30 wt % of calcium carbonate, and

0.1 to 90% of one or more other excipients. Yet another embodiment of the present invention provides a composition of oral dissolving film comprising:

1 to 50 wt % of melatonin or melatonin analogues,

0.1 to 60 wt % of cyclodextrins,

0.01 to 5 wt % of xanthan gum,

0.1 to 70 wt % of hydroxypropyl methylcellulose,

0.1 to 30 wt % of sucralose,

0.1 to 50 wt % of propylene glycol,

0.01 to 5 wt % of EDTA,

optionally 0.1 to 30 wt % of calcium carbonate, and

0.1 to 90% of one or more other excipients.

Yet another embodiment of the present invention provides a process for the preparation of stable oral dissolving film, wherein the process comprising steps of: a) dissolving the solubilizing agents in purified water,

b) adding melatonin to the above solution and heating upto 45 °C under stirring upto get clear solution,

c) adding stabilizing agents and film-forming agents, sweetening agents, plasticizing agents and optionally anti- adsorbent agents to the above solution and stirring to get clear solution,

d) adding flavouring agents to the above solution, and e) coating the above dispersion on PET liner and drying in hot air chambers at

80 °C.

b) adding melatonin to the above solution and heating up to 45 °C under stirring upto get clear solution,

c) adding stabilizing agents, chelating agents, film-forming agents, sweetening agents, plasticizing agents and optionally anti- adsorbent agents to the above solution and stirring to get clear solution,

d) adding flavouring agents to the above solution, and

e) coating the above dispersion on PET liner and drying in hot air chambers at 80 °C.

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The present invention provides preparation oral dissolving film with high drug loading capacity in soluble form of melatonin to enhance absorption in oral cavity. The term“sleeping aid” of the present invention is used to treat insomnia and sleeplessness. Preferably used sleeping aid is melatonin or melatonin analogues.

Suitable solubilising agents used alone or in combination in the compositions of the present invention include, but are not limited to cyclodextrins or their analogues, poloxamers or their analogues, propylene glycol or their analogues, polyethylene glycols or their analogues, medium chain triglycerides, povidone or their analogues and polysorbate or their analogues, cremophor, glycerol, benzalkonium chloride, benzyl benzoate, sorbitan esters, stearic acids. Solvent system used alone or in combination in the compositions of the present invention include, but are not limited to alcohols, carboxylic acids, ketones, ethers, esters and/or their derivatives or from aqueous solvent or a combination of aqueous and organic solvents. Film forming agents used alone or in combination in the compositions of the present invention include, but are not limited to one or more water soluble polymers selected from the group consisting of pullulan, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, high amylase starch, hydroxypropylated high amylase starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and maltodextrin. Said starch in the present invention can be used as disintegrating agent and film forming agent to enhance faster drug release in case of higher strengths of melatonin and their analogues.

Stabilizing agents used in the compositions of the present invention include, but are not limited to xanthan gum, carrageenan, locust bean gum, guar gum and mixtures thereof, preferably used stabilizing agent include xanthan gum, carrageenan and mixtures thereof. Acidifying agents used in the compositions of the present invention include, but are not limited to tartaric acid, ascorbic acid, malic acid, phosphoric acid, lactic acid and citric acid, preferably used acidifying agent includes citric acid.

Chelating agents used in the compositions of the present invention includes, but are not limited to disodium ethylenediaminetetraacetic acid or ethylene glycol tetraacetic acid, citric and tartaric acids and alkali metal salts thereof.

Buffering agents used in the compositions of the present invention includes, but are not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate dibasic, potassium phosphate tribasic, calcium carbonate, magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassium hydroxide, aluminium hydroxide, and combinations thereof.

Plasticizing agents or humectants used alone or in combination in the compositions of the present invention include, but are not limited to glycerols, glycerine, sorbitol, propylene glycol, polyethylene glycol, acetylated monoglycerides and alkyl citrates.

Viscosity increasing agents used in the compositions of the present invention includes, but is not limited to gellan gum, xanthan gum and carrageenan.

Colouring agents used in the compositions of the present invention includes, but are not limited to FD&C dyes and pigments, talc, mica, magnesium carbonate, calcium carbonate, magnesium silicate, magnesium aluminum silicate, silica, titanium dioxide, zinc oxide, red, yellow, brown and black iron oxides, ferric ammonium ferrocyanide, manganese violet, ultramarine, titaniated mica, bismuth oxychloride, and mixtures thereof. Sweetening agents used in the compositions of the present invention includes, but are not limited to saccharin, aspartame, sucralose, thaumatin, acesulfame potassium, stevioside, stevia extract, paramethoxy cinnamic aldehyde, neohesperidyl dihydrochalcone and perillartine.

Flavouring agents used in the compositions of the present invention includes, but are not limited to vanillin, sage, marjoram, parsley oil, spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, citrus oils, fruit oils and essences including those derived from lemon, orange, lime, grapefruit, apricot, banana, grape, apple, strawberry, cherry, pineapple, etc., bean- and nut-derived flavors such as coffee, cocoa, cola, peanut, almond, etc., adsorbed and encapsulated flavorants, and mixtures thereof.

Cooling agents used in the compositions of the present invention includes, but are not limited to N-ethyl-p-menthane-3-carboxamide, N,2,3 - trimethyl-2-isopropyl- butanamide, menthyl glutarate, menthyl succinate, menthol PG carbonate, menthol EG carbonate, menthyl lactate, menthone glyceryl ketal, menthol glyceryl ether, 3,3,5- trimethylcyclohexanol, isopulegol, menthol flavor and some polyol sugars , WS3, WS23, ultracoll II and thymol.

Opacifier used in the compositions of the present invention includes, but are not limited to titanium dioxide, zinc oxide, calcium carbonate, magnesium oxide and the like. Antioxidants used in the compositions of the present invention includes, but are not limited to citric acid, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, and butylhydroxyanisole and the like. Binding agents used in the compositions of the present invention includes, but are not limited to starch, maltodextrins, povidone, carboxymethyl cellulose and combinations thereof. Anti-adsorbent agents used in the compositions of the present invention includes calcium carbonate, colloidal silicone dioxide, microcrystalline cellulose, talc, kaolin, activated charcoal, dibasic calcium phosphate, Bentonite, natural clay, activated alumina, zeolites and the like. The present invention is illustrated in detail but not limiting to, the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Example 1

Manufacturing procedure:

1. Preparation of polymeric drug dispersion:

Dissolve cyclodextrin, poloxamer and citric acid in purified water. To this add melatonin and heat up to 45 °C under stirring up to get clear solution.

Then add Disodium EDTA, Titanium dioxide, apple green colour, Sucralose, calcium carbonate, propylene glycol, xanthan gum and HPMC above solution and stir up to get clear solution.

Then add flavour and stir well.

2. Coating & drying of polymeric drug dispersion:

Prepared dispersion coat on PET liner and dry in Hot air chambers at 80 °C.

Example 2

Manufacturing procedure:

1. Preparation of polymeric drug dispersion:

Then add flavour and stir well.

2. Coating & drying of polymeric drug dispersion:

Prepared dispersion coat on PET liner and dry in Hot air chambers at 80 °C.

Example 3

Manufacturing procedure:

1. Preparation of polymeric drug dispersion:

Add Polysorbate 80, Povidone, sucralose, melatonin, colour, propylene glycol, Glycerine, xanthan gum and Starch purified water and stir up to get uniform mixing. Then add flavour and stir well. 2. Coating & drying of polymeric drug dispersion:

Prepared dispersion coat on PET liner and dry in Hot air chambers at 80 °C.

Example 4

Manufacturing procedure:

1. Preparation of polymeric drug dispersion:

Add Polysorbate 80, Polyethylene glycol and disperse melatonin then add Organic solvent and stir up to form clear solution. Then add purified water and sucralose, colour, Titanium dioxide, silicon dioxide, Poloxamer, Maltodextrin, xanthan gum and HPMC to purified water and stir up to get uniform mixing.

Then add flavour and stir well.

2. Coating & drying of polymeric drug dispersion:

Prepared dispersion coat on PET liner and dry in Hot air chambers at 80 °C. Example 5

Manufacturing procedure:

1. Preparation of polymeric drug dispersion:

Add Medium chain triglycerides and disperse melatonin then add Purified water and stir up to get uniform dispersion. Then add sucralose, colour, Maltodextrin and HPMC to purified water and stir up to get uniform mixing.

Then add flavour and stir well.

2. Coating & drying of polymeric drug dispersion:

Prepared dispersion coat on PET liner and dry in Hot air chambers at 80 °C.

Example 6

Manufacturing procedure:

1. Preparation of polymeric drug dispersion:

Add medium chain triglycerides and disperse melatonin then add purified water and stir up to get uniform dispersion. Then add sucralose, colour, Maltodextrin, propylene glycol, carrageenan gum, Xanthan gum and Pullulan to purified water and stir up to get uniform mixing.

Then add flavour and stir well.

2. Coating & drying of polymeric drug dispersion:

Prepared dispersion coat on PET liner and dry in Hot air chambers at 80 °C.

Example 7

Manufacturing procedure:

1. Preparation of polymeric drug dispersion:

Add Polysorbate 80, Povidone, sucralose, melatonin, colour, propylene glycol, Glycerine, xanthan gum and Starch to purified water and stir up to get uniform mixing. Then add flavour and stir well.

2. Coating & drying of polymeric drug dispersion:

Prepared dispersion coat on PET liner and dry in Hot air chambers at 80 °C.

Claims

We Claim:

1. High drug load oral dissolving film composition comprising melatonin or its analogues and one or more pharmaceutically acceptable excipients.

2. The high drug load oral dissolving film composition as claimed in claim 1, wherein the melatonin or its analogues present in the film is in soluble form.

3. The high drug load oral dissolving film composition as claimed in claim 1, wherein composition comprising one or more solubilizing agents, one or more stabilizing agents, one or more binding agents, one or more chelating agents one or more film-forming agents, one or more sweetening agents, one or more plasticizing agents and optionally anti-adsorbent agents.

4. The high drug load oral dissolving film composition as claimed in claim 3, wherein, solubilising agents used alone or in combination are selected from cyclodextrins or their analogues, poloxamers or their analogues, propylene glycol or their analogues, polyethylene glycols or their analogues, medium chain triglycerides, povidone or their analogues and polysorbate or their analogues, cremophor, glycerol, benzalkonium chloride, benzyl benzoate, sorbitan esters, stearic acids.

5. The high drug load oral dissolving film composition as claimed in claim 3, wherein stabilizing agent is selected from xanthan gum, carrageenan, locust bean gum, guar gum and mixtures thereof, preferably xanthan gum, carrageenan and mixtures thereof.

6. The high drug load oral dissolving film composition as claimed in claim 3, wherein film forming agent is selected from one or more water soluble polymers selected from the group consisting of pullulan, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, high amylase starch, hydroxypropylated high amylase starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and maltodextrin.

7. The high drug load oral dissolving film composition as claimed in claim 3, wherein binding agent is selected from starch, maltodextrins, povidone, carboxymethyl cellulose and combinations thereof.

8. The high drug load oral dissolving film composition as claimed in claim 3, wherein chelating agent is selected from disodium ethylenediaminetetraacetic acid or ethylene glycol tetraacetic acid, citric and tartaric acids and alkali metal salts thereof.

9. The high drug load oral dissolving film composition as claimed in claim 3, wherein sweetening agent is selected from saccharin, aspartame, sucralose, thaumatin, acesulfame potassium, stevioside, stevia extract, paramethoxy cinnamic aldehyde, neohesperidyl dihydrochalcone and perillartine.

10. The high drug load oral dissolving film composition as claimed in claim 3, wherein plasticizing agent is selected from glycerols, glycerine, sorbitol, propylene glycol, polyethylene glycol, acetylated monoglycerides and alkyl citrates.

11. The high drug load oral dissolving film composition as claimed in claim 3, wherein anti-adsorbent agent is selected from calcium carbonate, colloidal silicone dioxide, microcrystalline cellulose, talc, kaolin, activated charcoal, dibasic calcium phosphate, Bentonite, natural clay, activated alumina, zeolites.

12. The high drug load oral dissolving film composition as claimed in claim 3, wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from acidifying agents, cooling agents, antioxidants, viscosity-increasing agents, sweetening agents, colouring agents, opacifiers, plasticizing agents, humectants, flavouring agents, buffering agents solvents and optionally anti- adsorbent agents.

13. The high drug load oral dissolving film composition as claimed in claim 1, composition of oral dissolving film comprising:

1 to 50 wt % of melatonin or melatonin analogues,

0.1 to 60 wt % of solubilising agents,

0.01 to 5 wt % of stabilizing agents,

0.1 to 70 wt % of film forming agents,

0.1 to 30 wt % of sweetening agents,

0.1 to 50 wt % of plasticizing agents,

optionally, 0.1 to 30 wt % of anti-adsorbent agent, and

0.1 to 90% of one or more other excipients.

14. A process for the preparation of stable melatonin or melatonin analogues oral dissolving film, wherein the process comprising the steps of:

a) dissolving the solubilizing agents in purified water,

c) adding stabilizing agents, film-forming agents, chelating agents, sweetening agents, plasticizing agents and optionally anti- adsorbent agents to the above solution and stirring to get clear solution,

d) adding flavouring agents to the above solution, and