Pharmaceutical Preparations Of Melatonin Suitable For Intranasal Administration

Abstract

A pharmaceutically acceptable intranasal spray formulation includes about 0.01% w/v to about 5% w/v melatonin, about 0% w/v to about 50% w/v liquid solvent selected from the group consisting of alcohol, polyethylene glycol, propylene glycol and combinations thereof, a pH system in an amount effective to maintain a pH of the formulation at about 4.5 to about 6.5, at least one preservative, and water. An aqueous formulation of melatonin for nasal administration as an in-situ gel includes melatonin, water, at least one organic solvent, and at least one gelling agent.

Claims

1. A pharmaceutically acceptable intranasal spray formulation comprising: about 0.01 % w/v to about 5% w/v melatonin; about 0% w/v to about 50% w/v liquid solvent selected from the group consisting of alcohol, polyethylene glycol, propylene glycol and combinations thereof; a pH system in an amount effective to maintain a pH of the formulation at about 4.5 to about 6.5; at least one preservative; and water.

2. The formulation of claim 1, further comprising a stabilizer.

3. The formulation of claim 2, wherein the stabilizer comprises sorbitol and/or glycerin.

4. The formulation of claim 2, comprising about 1% w/v to about 25% w/v of the stabilizer.

5. The formulation of claim 2, comprising about 0.1% w/v to about 20% w/v of the stabilizer.

6. The formulation of claim 1, further comprising a tonicity agent.

7. The formulation of claim 6, wherein the tonicity agent is selected from the group consisting of mannitol, dextrose, sucrose, and combinations thereof.

8. The formulation of claim 6, comprising about 1% w/v to about 20% w/v of the tonicity agent.

9. The formulation of claim 1, further comprising an antioxidant.

10. The formulation of claim 9, wherein the antioxidant comprises methionine.

11. The formulation of claim 9, comprising about 0.02% w/v to about 0.2% w/v of the antioxidant.

12. The formulation of claim 1, wherein the preservative is selected from benzyl alcohol, methyl paraben and propylparaben.

13. A melatonin nasal spray composition comprising: melatonin, water, and at least one organic solvent selected from propylene glycol, polyethylene glycol, ethanol, and glycerol.

14. The composition of claim 12, comprising about 0.01% w/v to about 5% w/v melatonin.

15. The composition of claim 12, comprising about 0.1% w/v to about 50% w/v of the at least one organic solvent.

16. The composition of claim 12, further comprising a preservative selected from benzyl alcohol, methyl paraben, and propylparaben.

17. A pharmaceutically acceptable intranasal spray formulation for a sustained release or immediate release with a sustained release effect of melatonin comprising: about 0.01 % w/v to about 5% w/v melatonin; about 10% w/v to about 50% w/v solvent comprising alcohol, polyethylene glycol, propylene glycol or combinations thereof; about 1 % w/v to about 25% w/v sorbitol or glycerin; about 1 % w/v to about 20% w/v mannitol, dextrose, or sucrose; about 0.01% w/v to about 10% w/v microcrystalline cellulose and/or carboxymethyl cellulose; at least one preservative selected from benzyl alcohol, methyl paraben and propylparaben; and about 0.02% w/v to about 0.25% w/v methionine.

18. An aqueous formulation of melatonin for nasal administration as an in-situ gel comprising: melatonin; water; at least one organic solvent; and at least one gelling agent.

19. The formulation of claim 18, wherein the at least one gelling agent comprises a thermoreversible polymer.

20. The formulation of claim 18, comprising from about 0.10% w/v to about 40% w/v of the at least one gelling agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention provides stable aqueous pharmaceutical solutions, suspensions or gels suitable for intranasal administration comprising melatonin in association with a pharmaceutically acceptable liquid carrier and viscosity enhancer.

[0040] The following detailed description is merely exemplary in nature and is not intended to limit the disclosed melatonin formulations, or any associated methods for producing or using the same described herein. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.

[0041] The term “about” as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. In general, such interval of accuracy is ±10%. Thus, “about ten” means 9 to 11. All numbers in this description indicating amounts, ratios of materials, physical properties of materials, and/or use are to be understood as modified by the word “about,” except as otherwise explicitly indicated.

[0042] The intranasal formulations described in the present invention are useful to significantly lower the dose burden of melatonin by circumventing first-pass hepatic metabolism that is associated with oral dosage administration. Moreover, the intranasal formulations are useful where another route is ineffective, invasive, or impractical.

[0043] The melatonin compositions may contain water, alcohol, polyethylene glycol, propylene glycol individually or combination as solvent. In some embodiments, a suspension is formed with the help of suspending agent.

[0044] Typically, the concentration of melatonin is 0.1 mg/ml to 50 mg/mL. Melatonin can be used as a free base or in any pharmaceutically acceptable form and/or solvate thereof.

[0045] A melatonin solution may contain water, polyethylene glycol, propylene glycol, alcohol as individual or a combination of the four. The solvent is studied as an important liquid carrier and its level was studied and optimized in the course of the development.

[0046] As used throughout the present description and claims, a concentration of polyethylene glycol in melatonin nasal compositions may correspond to the concentration of polyethylene glycol-400. The concentration of polyethylene glycol-400 may be within the range of 0 mg/mL to 500 mg/mL and/or the concentration of propylene glycol may be withing the range of 0 mg/mL to 500 mg/mL.

[0047] As used throughout the present description and claims, the concentration of alcohol in melatonin nasal compositions may correspond to a concentration of ethyl alcohol. A concentration of ethyl alcohol may be in the range of 0 mg/mL to 500 mg/mL.

[0048] In some embodiments of the invention, sorbitol is used a stabilizing agent. A concentration of sorbitol is preferably within the range from 10 mg/ml to 250 mg/ml.

[0049] As used throughout the present description and claims, a concentration of sorbitol in the intranasal preparation of melatonin refers to a concentration of anhydrous sorbitol.

[0050] In some embodiments, glycerin is used as an alternative for a stabilizing agent. A concentration of glycerin is preferably within the range from 1 mg/ml to 200 mg/ml.

[0051] Tonicity of intranasal compositions may be adjusted between 200-600 mOsmol/L by adding salts or other tonicity adjusting agents.

[0052] In some embodiments of the invention, a tonicity agent such as mannitol, dextrose, and/or sucrose is used for preparation of isotonic intranasal solution. A concentration of tonicity agent is preferably within the range from 10 mg/ml to 200 mg/ml.

[0053] In certain embodiments of the invention, preservatives such as propylparaben, methylparaben, benzyl alcohol, benzalkonium chloride, or in form of any pharmaceutically acceptable salt thereof are used as preservatives in the intranasal composition.

[0054] It is well known that low drug loading may cause homogeneity problems for suspension dosage form. Surprisingly, it has been found that by proper selection of suspending agent at optimized level, it is possible to achieve content uniformity.

[0055] Suitable suspending agents include microcrystalline cellulose, carboxymethyl cellulose sodium and mixtures thereof.

[0056] If used, a concentration of suspending agent is preferably within the range from 0.01% w/v to 10% w/v.

[0057] The compositions of the present invention may be prepared using methods well-known in the art. For example, they may be prepared using the following process: half of the specified amount of purified water is added to the main vessel. The amount of solvent is charged under continuous stirring. The specified quantity of melatonin is transferred to the above solution and mixed until complete dissolution. The quantities of stabilizing agent, tonicity agent, antioxidant and preservatives are added sequentially. The pH is checked and, if required, adjusted to 4.5 - 6.5 with sodium hydroxide or hydrochloric acid. The volume of the solution is adjusted to the desired batch volume by adding purified water. The solution is filled into the designated containers, preferably under nitrogen purging.

[0058] As another example, the inventive compositions may be prepared using the following process: half of the specified amount of purified water is added to the main vessel. The amount of solvent is charged under continuous stirring. The specified quantity of melatonin is transferred to the above solution and mixed until complete dissolution. The quantities of suspending agent with or without viscosity enhancer, tonicity agent, antioxidant and preservatives are added sequentially. The pH is checked and, if required, adjusted to 4.5 - 6.5 with sodium hydroxide 0.1 N or hydrochloric acid 0.1 N. The volume of the solution is adjusted to the desired batch volume by adding purified water. The solution is filled into the designated containers, preferably under nitrogen purging.

[0059] In a particular embodiment of the invention, the pharmaceutical formulation comprises melatonin suspension to be sprayed in one or both nostrils.

[0060] In certain embodiments of the invention, the pharmaceutical formulation comprises a melatonin solution suitable to be sprayed in one or both nostrils.

[0061] In a preferred embodiment, a droplet particle size is 10 to 200 microns in diameter, as such size is appropriate for intranasal administration.

[0062] In a particular embodiment, an intranasal pharmaceutical preparation of melatonin solution includes melatonin as active ingredient, ethyl alcohol, propylene glycol, polyethylene glycol-400, water and optionally one or more tonicity adjusting agent, one or more stabilizer, antioxidant, and preservatives, wherein the pH of the intranasal solution is from 4.5 to 6.5.

[0063] In a particular embodiment of the invention, the intranasal pharmaceutical suspension includes melatonin as active ingredient, with or without propylene glycol, polyethylene glycol-400, one or more suspending agent, viscosity enhancer, one or more tonicity agent, antioxidant, and preservatives, wherein the pH of the intranasal solution is from 4.5 to 6.5.

[0064] In a particular embodiment of the invention, cellulose is used a suspending agent. The concentration is preferably within the range from 0.01% w/v to 10% w/v.

[0065] In a particular embodiment of the invention where cellulose is used a suspending agent, the cellulose is selected from the group consisting of microcrystalline cellulose and carboxymethyl cellulose.

[0066] In a particular embodiment of the invention, polymer (mucoadhesive polymer) is used as viscosity enhancer. A concentration of the polymer viscosity enhancer is preferably within the range from 0.01% w/v to 5% w/v. In some of those embodiments, the polymer is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), Pectin, Polyvinyl pyrrolidine (PVP).

[0067] In a particular embodiment of the invention, a tonicity agent is included, such as mannitol, dextrose, sucrose, for preparation of isotonic or hypertonic intranasal solution. A concentration of the tonicity agent is preferably within the range from 10 mg/ml to 200 mg/ml.

[0068] In a particular embodiment of the invention, preservatives such as propylparaben, methylparaben or in form of any pharmaceutically acceptable salts thereof are used as preservatives in the intranasal composition.

[0069] Also provided are melatonin thermo-reversible in-situ gel compositions to be administrated as drop in one or both nostrils. In addition to any of the above-described ingredients and combinations of ingredients and their respective amounts, the gel compositions comprise a thermo-reversible polymer.

[0070] A concentration of the thermo-reversible polymer is preferably within the range from 0.10% w/v to 40% w/v.

[0071] In a particular embodiment of the invention, poloxamer is used as the thermo-reversible polymer. In some embodiments, the grades of poloxamer are poloxamer 188 and poloxamer 407.

[0072] Polymer may also be used for a mucoadhesive effect. A concentration of the mucoadhesive polymer is preferably within the range from 0.01% w/v to 5% w/v.

[0073] In a particular embodiment of the invention, where a mucoadhesive polymer is used, the polymer is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC).

[0074] In a particular embodiment of the invention, a tonicity agent such as mannitol, dextrose, or sucrose is used for preparation of an isotonic intranasal gel. A concentration of the tonicity agent is preferably within the range from 10 mg/ml to 200 mg/ml.

[0075] In a particular embodiment of the invention, preservatives such as propylparaben, methylparaben or in form of any pharmaceutically acceptable salt thereof are used in the intranasal gel composition.

[0076] The gel compositions of the present invention may be prepared using methods well-known in the art. For example, they may be prepared using the following process: half of the specified amount of purified water is added to the main vessel. The amount of poloxamer and solvent is charged under continuous stirring. The specified quantity of melatonin is transferred to the above solution and mixed until complete dissolution. The quantities of mucoadhesive polymer, tonicity agent, antioxidant and preservatives are added sequentially. The pH is checked and, if required, adjusted to 4.5 - 6.5 with sodium hydroxide 0.1 N or hydrochloric acid 0.1 N. The volume of the solution is adjusted to the desired batch volume by adding purified water. The solution is filled into the designated containers, preferably under nitrogen purging.

[0077] In a particular embodiment of the invention, the pharmaceutical formulation comprises melatonin gel to be administered as a drop in one or both nostrils.

Experimental

[0078] The pharmaceutical compositions of melatonin described in the below table were formulated. A detailed procedure for preparation of each individual type of a composition is described below.

[0079] Compositions of Melatonin Formulation for Nasal Use:

TABLE-US-00001 Composition Code F0 F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 sr.no Material mg/ mL mg/ mL mg/ mL mg/ mL mg/ mL mg/ mL mg/ mL mg/ mL mg/ mL mg/ mL mg/ mL 1 Melatonin 10 10 10 10 10 10 10 10 10 10 10 2 Ethyl Alcohol ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- 50 3 Polyethylene Glycol 200 200 200 200 ---- ---- ---- ---- 200 ---- ---- 4 Propylene glycol ---- ---- ---- ---- 150 150 150 150 150 150 ---- 5 HPMC K4M ---- 1 ---- 1 ---- 1 ---- 1 0 ---- 1 6 VIVAPUR® MCG* ---- 12.5 12.5 ---- ---- 12.5 12.5 ---- 0 ---- ---- 7 Pectin ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- 10 8 Sorbitol, Liquid 70 70 70 70 70 70 70 70 70 70 9 Poloxamer 407 +188 (93:7) ---- ---- ---- ---- ---- ---- ---- ---- ---- 160 --- 10 Mannitol 42 42 42 42 42 42 42 42 0 42 --- 11 Dextrose ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- 50 12 Benzyl Alcohol 9 9 9 9 9 9 9 9 9 9 9 13 Methionine 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0 0.1 0.1 14 HCl/NaOH QS to pH 4.5-6.5 15 Water (DI) QS to 1 mL *(VIVAPUR® MCG 811 P) Microcrystalline Cellulose and Carboxymethylcellulose Sodium.

Example 1: Melatonin Nasal Spray 10 mg/ml (Formulation F0)

[0080] 4.2 g of mannitol and 7 g of sorbitol were dissolved in 50 mL of purified water. After getting a clear solution, 0.01 g of methionine was added and stirred until clear solution was formed.

[0081] In another vessel, 1 g of melatonin was dissolved in 20 g of PEG-400 and 0.9 g of benzyl alcohol was added to it. The aqueous solution prepared above was added to this solution under continuous stirring. The pH was adjusted to 4.5 to 6.5 using 0.1N HCl solution. Water was added to the mixture to make the total volume of the formulation to 100 mL and the formulation was filled into a multidose nasal spray device with the deliverable volume of 100 microliter per spray.

Example 2 (Formulation F1): Melatonin Nasal Spray 10 mg/ml Suspension with Mucoadhesive Polymer

[0082] 4.2 g of mannitol and 7 g of sorbitol were dissolved in 50 mL of purified water. After getting clear solution, 0.01 g of methionine was added and stirred until a clear solution was obtained. To the clear solution, 1.25 g of VIVAPUR MCG was added and stirred to get a homogenous liquid.

[0083] In another vessel, 1 g of melatonin was dissolved in 20 g of PEG-400 and 0.9 g of benzyl alcohol was added to it. Further, 0.1 g of HPMC was added under continuous stirring.

[0084] The aqueous mixture was added to the solvent phase. pH was adjusted to 4.5 to 6.5 using 0.1N NaOH solution. Water was added to the mixture to make the total volume to 100 mL. The formulation was filled in a suitable multidose nasal spray device with the deliverable volume of 100 microliter.

[0085] Other compositions described in the table (F2-F8) were prepared by analogous methods.

Example 3 (Formulation F9): Melatonin Nasal Drop 10 mg/ml InSitu Thermo-Reversible Gel

[0086] In order to prepare a thermo-reversible gel, 15 g of Poloxamer 407 and 1 g of Poloxamer 188 were dissolved in 80 mL of cold water (temp 15-20° C.) and 0.9 g of benzyl alcohol was added to it. To this solution 4.2 g of mannitol and 7 g of sorbitol were added and stirred to dissolve. Melatonin solution was prepared by dissolving 1 g of melatonin in 15 g of PG.

[0087] The above aqueous solution was added to the solvent phase under continuous stirring. pH was adjusted to 4.5 to 6.5 using 0.1N HCl. Water was added to the mixture to make the total volume of the formulation to 100 mL. The formulation was filled into a suitable multidose nasal dropper device with the deliverable of 100 microliter per drop.

Example 4 (Formulation F10): Melatonin Nasal Spray 10 mg/ml, Suspension

[0088] Melatonin (1 g) was dissolved in 5 g of ethyl alcohol. To this solution, 0.9 g of benzyl alcohol and 100 mg of HPMC were added.

[0089] In a separate vessel, 50 mL water was filled and 100 mg of pectin was dissolved by stirring for 4-5 hours at high speed. In another vessel, 5 g of dextrose was dissolved along with 625 mg of microcrystalline cellulose in 20 ml of water (DI). Both aqueous phases were mixed and stirred for 30 minutes.

[0090] The above aqueous phase was added into the solvent phase under continuous stirring. pH was adjusted between 4.5 to 6.5 using 0.1N NaOH solution. Volume was made up to 100 mL and the formulation was filled into a suitable multidose nasal dropper device with the deliverable of 100 microliter per drop.

Example 5: Melatonin Nasal Spray 10 mg/ml, Solution

[0091] The solution compositions F11-F13 described in the table below were prepared according to the procedure of Example 1.

TABLE-US-00002 Solution Composition F11 F12 F13 Sr. No Name of material mg/mL mg/mL mg/mL 1 Melatonin 10 10 10 2 Propylene glycol 120 120 120 3 PEG 200 200 150 200 4 Cellulose microcrystalline/ carboxymethyl cellulose sodium 15 --- --- 5 PEG 4000 -- 100 6 Citric acid, -- 0.2 0.2 monohydrate 7 Glycerin 25 25 25 8 Dextrose 50 50 50 9 Polysorbate 80 0.1 0.1 0.1 10 Benzyl alcohol 5 2 2.5 11 HCl/NaOH QS to pH QS to pH QS to pH 12 Purified Water QS QS QS

Example 6: Melatonin Nasal Spray, a Suspension Formulation (Formulation: F14-F16)

[0092] The suspension formulations F14-F16 shown in the table below were prepared by the procedure of Example 4.

TABLE-US-00003 Suspension composition F14 F15 F16 Sr. No Name of material mg/g mg/g mg/g 1 Melatonin 1 10 10 2 Cellulose microcrystalline/ carboxymethylcellulose sodium 20 20 20 3 PEG 200 --- --- 25 4 Dextrose, Anhydrous 50 50 50 5 Benzalkonium Chloride 0.3 0.3 0.3 6 Polysorbate 80 0.08 0.08 0.08 7 EDTA sodium 0.1 0.1 0.1 8 HCl/NaOH QS to pH QS to pH QS to pH 9 DI water QS to 1 g QS to 1 g QS to 1 g

Example 7: Animal Study

[0093] Test formulations F11 - F16 were used in an animal study to evaluate bioavailability of melatonin. Six New Zealand White Rabbits (3 male, 3 female) were used in each group, with a weight range between 1.8 to 2.5 kg in each study. All rabbits were dosed with 0.1 ml of melatonin test product intranasally using a plastic syringe in each nostril. Approximately 0.5-1 mL of blood was collected through marginal ear vein/central ear artery from each animal before dosing (pre dose) and at 0.083, 0.168, 0.25, 0.50, 0.75, 1, 2, 3, 4 & 6 hrs post dosing, in tubes containing K2/K3-EDTA. Plasma was separated using refrigerated centrifuge at 5000 rpm for 10 min and stored in -80° C. (±10° C.). The concentration of melatonin in collected rabbit plasma was determined by LC-MS/MS.

[0094] Concentration of Melatonin in Rabbit plasma after nasal administration:

TABLE-US-00004 Group Tmax Cmax AUC (hr) (ng/mL) (hr*ng/mL) F11 0.168 543±195 205±57 F12 0.083 461±191 186±74 F13 0.083 411±155 202±70 F14 0.095 124±33 40±6 F15 0.11 1126±553 415±151 F16 0.08 1163±302 373±84

[0095] The bioavailability of melatonin in rabbits after nasal administration of six formulations has been studied. In five out of six cases (F11, F12, F13, F15 and F16), a total amount of 2 mg/animal melatonin was administered and in formulation F14, a total amount of 0.2 mg/animal melatonin was administered. The results are reported in the above table. In each case, significant melatonin was found in rabbit’s plasma after administration via nasal route.

[0096] While at least one exemplary embodiment has been presented in the foregoing detailed description, it should be appreciated that a vast number of variations exist. It should also be appreciated that the exemplary embodiment or exemplary embodiments are only examples, and are not intended to limit the scope, applicability, or configuration of the subject matter in any way. Rather, the foregoing detailed description will provide those skilled in the art with a convenient road map for implementing an exemplary embodiment, it being understood that various changes may be made in the function and arrangement of elements described in an exemplary embodiment without departing from the scope as set forth in the appended claims and their legal equivalents.