WO2019175830A1

WO2019175830A1 - Cholecalciferol nanoemulsion formulations and methods for producing same

Info

Publication number: WO2019175830A1
Application number: PCT/IB2019/052086
Authority: WO
Inventors: Srinivas Reddy MALE; Jaipal ARIKOTLA; Ajinkya Purushottam SUPEKAR; Shantaram Laxman PAWAR
Original assignee: Azista Industries Pvt Ltd
Priority date: 2018-03-14
Filing date: 2019-03-14
Publication date: 2019-09-19

Abstract

The present invention relates to stable oral nanoemulsion formulations. The present invention specifically relates to stable oral cholecalciferol nanoemulsion formulations and methods for producing same. The present invention specifically relates to methods for preparation of cholecalciferol nanoemulsion formulations using tocophersolon as a stabilizing agent.

Description

CHOLECALCIFEROL NANOEMULSION FORMULATIONS AND METHODS FOR PRODUCING SAME

FIELD OF INVENTION

The present invention relates to stable oral nanoemulsion formulations.

The present invention specifically relates to stable oral cholecalciferol nanoemulsion formulations and methods for producing same. The present invention specifically relates to methods for preparation of cholecalciferol nanoemulsion formulations using tocophersolon as a stabilizing agent.

BACKGROUND OF INVENTION

Poorly water soluble drugs or therapeutic agents are sometimes emulsified in oil-in-water or water-in-oil emulsions to improve solubility and bioavailability of the therapeutic agent. Conventional emulsions have droplet sizes larger than 1 pm. Not only are these droplet sizes susceptible to gravity forces, which causes the emulsion to be thermodynamically unstable (i.e., susceptible to sedimentation or creaming). Nanoemulsions due to their small droplet size, are more thermodynamically stable, are less susceptible to sedimentation or creaming, and may even appear transparent. Nanoemulsions, in contrast to conventional emulsions, are metastable and can be diluted with water without changing the droplet size distribution. While nanoemulsions are preferable in comparison to conventional emulsions, they require high energy input and or high surfactant (emulsifier) content to obtain the sub-micron droplet sizes and maintain the stability of the emulsion. The preparation of nanoemulsions is generally achieved by either high-shear stirring, high-pressure homogenizers, or ultrasound generators. The smaller the droplet size, the more energy and/or surfactant is required. The higher energy requirements make this preparation route unfavorable for industrial applications. Nanoemulsion based delivery systems have been found to be suitable for improving the oral administration of oil- soluble vitamins. Nanoemulsions are transparent or slightly turbid liquids consisting of emulsified oil and water systems with mean droplet diameters ranging from 20 to 1000 nm. Usually, the average droplet size is between 20 and 500 nm. These are thermodynamically unstable systems and therefore their stability depends on the method employed to produce them. The major advantages of nanoemulsions as drug delivery carriers include increased drug loading, enhanced drug solubility and bioavailability, and reduced patient variability. High energy and low energy methods were usually employed to produce stable nanoemulsions. High-pressure homogenizer or ultrasound generator can be used for the preparation of nanoemulsion by high-energy emulsification methods. Self emulsification and phase inversion methods (phase inversion temperature and phase inversion composition) are low-energy methods for the preparation of nanoemulsions. Low-energy emulsification methods depend on the phase behaviour and properties of the constituents, and they utilize the stored energy of the system to form nano-droplets or nanodispersions. The emulsification can be brought about by changing the parameters such as temperature and composition, which would affect the hydrophilic lipophilic balance of the system. Poor stability with respect to particle size, aggregation/flocculation, sedimentation, crystal growth and drug degradation in nanoformulation will impact the biological performance of the active ingredient.

Cholecalciferol or Vitamin D3 is a lipid soluble vitamin that is needed for the normal functioning of the body. It is highly sensitive to moisture, heat and light, leading to loss in biological activity or functionality. It is typically absorbed at particular locations in the small intestine by passive and active transport mechanisms and activated in the liver. It has poor water solubility and low oral bioavailability. Therefore, it is necessary to develop an alternative dosage forms other than tablets, capsules. Tocophersolan (Vit E TPGS) is an esterified Vitamin E with polyethylene glycol. It is water soluble, amphiphilic compound with melting point 37 to 4l°C. It is widely tested for its emulsifying, dispersing, gelling and solubilizing effects. It is also a P- glycoprotein inhibitor. Because of its amphiphilic nature, it forms micelles and stabili es the Nanodispersion at a concentration as low as 0.02%. It is one of the safe excipient and listed in US-FDA inactive ingredients database.

Some patent literature describe the formulation of nanoemulsions using high shear or energy input techniques such as high speed homogenizer, high pressure homogenizer, ultra- sonication, micro-fluidization etc.,. Use of organic solvents like ethanol, dichloro methane, isopropanol, acetone etc. are used to prepare nanoemulsions with high energy input techniques and spontaneous nanoemulsions called as self- emulsifying techniques have also been reported in literature. WO 2015/155703 A2 discloses nanoemulsions using stabilizing vehicle base containing viscosity forming agents like sucrose, glycerol, gums, polymers and proteins.

Food Chemistry 171 (2015) 117 122 discloses Formation of vitamin D nanoemulsion-based delivery systems by spontaneous emulsification process.

Asian Journal of Pharmaceutics · Jul-Sep 2016 (Suppl) · 10 (3) \ S359-S374 discloses a stable non-aqueous nanoemulsion (NANE) using cosmetically approved ingredients as a vehicle for the water sensitive active ingredients.

The inventors of the present invention have developed nanoemulsion formulation of cholecalciferol with improved long-term stability, there by retaining the most biological functionality of the active ingredient. The inventors of the present invention have used low energy technique to make the nanoemulsions using simple stirring and Tocophersolan to improve the stability of the nanoemulsion. OBJECTIVE OF INVENTION

The main objective of the present invention is to provide stable oral cholecalciferol nanoemulsion formulations and methods for preparation thereof. Another objective of the present invention is to provide a method of preparation of cholecalciferol nanoemulsion formulation using tocophersolon as stabilizer.

SUMMARY OF INVENTION

One embodiment of the present invention provides a stable cholecalciferol nanoemulsion formulation comprising tocophersolon as a stabili er.

Another embodiment of the present invention provides a stable cholecalciferol nanoemulsion formulation comprising tocophersolon, EDTA and optionally one or more other pharmaceutically acceptable excipients.

Another embodiment of the present invention provides a stable cholecalciferol nanoemulsion formulation further comprising one or more excipients selected from stabilizers, surfactants, emulsifying agents, solubilizers, antioxidants, preservatives, sweetners and flavouring agents.

Another embodiment of the present invention provides stable cholecalciferol nanoemulsion formulation comprising tocophersolon, EDTA, Oleic acid, Benzyl Alcohol, Butylated Hydroxyl Toluene, Sodium Benzoate and one or more other pharmaceutically acceptable excipients.

Another embodiment of the present invention provides a process for preparation of stable cholecalciferol nanoemulsion formulation comprising tocophersolon and one or more other pharmaceutically acceptable excipients Another embodiment of the present invention provides a process for preparation of stable cholecalciferol nanoemulsion formulation comprising tocophersolon, EDTA and optionally one or more other pharmaceutically acceptable excipients.

Yet another embodiment of the present invention provides a process for preparation of stable cholecalciferol nanoemulsion formulation comprising the steps of:

a) solubilizing the stabilizing agent in double distilled water with continuous stirring,

b) adding the sweetners and flavouring agents to the above solution and continue stirring for 15 minutes (Part A),

c) mixing surfactants, emulsifying agents, antioxidants and cholecalciferol, d) add double distilled water to the above solution (Part B), and

e) adding Part B to Part A under continuous stirring and adding preservatives and chelating agents to the emulsion.

Still yet another embodiment of the present invention provides a process for preparation of stable cholecalciferol nanoemulsion formulation comprising the steps of:

a) solubilizing the tocophersolon in double distilled water with continuous stirring,

b) adding sucrose and vanilla flavour to the above solution and continue stirring for 15 minutes (Part A),

c) mixing polysorbate 80, oleic acid, butylated hydroxyl toluene and cholecalciferol,

d) add double distilled water to the above mixture (Part B), and

e) adding Part B to Part A under continuous stirring and adding sodium benzoate and EDTA to the emulsion. BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Effect of concentration of the particle size of the globules.

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 disclosure was aimed to develop a nanodispersion comprising an aqueous dispersion and dispersed phase. The nanodispersion containing a pharmaceutically active ingredient in the dispersed phase. The hydrophilic or lipophilic biologic active ingredient is either dissolved or dispersed in the dispersed phase. The stabilization of nanodispersion is achieved by using tocophersolan excipient, this excipient improves long-term stabilization. The nanodispersion also contains other excipients used as surfactants, solubilizers of lipophilic or hydrophilic biologically active ingredient, preservative, sweetener and flavouring agent.

The particle of the globules in the nanodispersion ranges from 15 to 1000 nm, preferably in the range of 15 and 500 nm, more preferably 20 to 100 nm. Further, the particle size decreased as the concentartion of Tocophersolan is increased, as can be shown in Figure 1.

This invention also used a simple method of stirring for manufacturing nanodispersion, compared to that of any sophisticated methods used to manufacturing nanodispersions, i.e this method does not use high speed homogenizers, high pressure homogenizer, micro-fluidizers/ultrasound generator. As the surfactant concentrations will be optimized in such a way that the simple agitation or stirring or low energy mixing will generate nanodispersions. The size range of the dispersed phase can be tailored with help of surfactants concentration or proportion of combination surfactants concentration.

Other additives used in the preparations to the compositions of this invention, the following can be used and there were no limitations: reducing agent, buffer agent, base, suspending agent, wetting agent, coloring matter, perfume, pH modifier, dispersing agent, fragrance, solvent, and the like.

Stabilizers used in the present invention are selected from group consisting of polyethylene glycol (PEG) -derivatives of Vitamin E, for example, a tocopherol polyethylene glycol diester (TPGD). In one example, the TPGD is selected from among tocopherol sebacate polyethylene glycol, tocopherol dodecanedioate polyethylene glycol, tocopherol suberate polyethylene glycol, tocopherol azelaate polyethylene glycol, tocopherol citraconate polyethylene glycol, tocopherol methylcitraconate polyethylene glycol, tocopherol itaconate polyethylene glycol, tocopherol maleate polyethylene glycol, tocopherol glutarate polyethylene glycol, tocopherol glutaconate polyethylene glycol and tocopherol phthalate polyethylene glycol. In another example, the TPGD surfactant is a tocopherol polyethylene glycol succinate (TPGS) (Tocophersolon), such as a TPGS-1000 and/or a d-a TPGS. In another example, the surfactant is a TPGS analog. In one aspect, the surfactant is a TPGS homolog, such as, for example, a TPGS homolog that differs from a TPGS parent compound by the addition or removal of one or more methylene unit(s), e.g.,— (CH₂)_n— · Preferably, the stabilizer is Vitamin E (TPGS). Chelating agents used in the present invention are selected from the group consisting of ethylene diaminetetraacetic acid (EDTA), deferoxannine, desferrioxannine B, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), dihydroethylglycine, bis(anninoethyl)glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, poly (aspartic acid), citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, oxalic acid, malic acid, lecithin or any salt thereof, and the like or a combination thereof may be employed. Preferably, the chelating agent comprises EDTA.

Solubilizers used in the present invention are selected from the group consisting of benzyl alcohol, fatty acid monoesters or diesters or mixtures thereof of glycols such as ethylene glycols or propylene glycols or butylenes glycols; monoglycerides or diglycerides or mixtures thereof; polyglycerized fatty acids, polyethylene glycol fatty acid monoesters or diesters or mixtures thereof; POE-POP block copolymer fatty acid monoesters or diesters or mixtures thereof; polyethylene glycol sorbitan fatty acid esters; sorbitan fatty acid esters; ethylene glycol or diethylene glycol or triethylene glycol or polyethylene glycol alkyl ethers; phospholipids and derivatives thereof; PEG-phospholipids; PEGs; alcohols; fatty alcohols; fatty acids; propylene glycol dicaprylate/dicaprate (Captex 200), propylene glycol monocaprylate (Capmul PG-8), propylene glycol caprylate/caprate (Labrafac PG), propylene glycol dicaprylate (Captex 100), propylene glycol diethylhexanoate, propylene glycol monolaurate (Capmul PG-12), glyceryl caprylate/caprate (Capmul MCM), glyceryl monocaprylate (Capmul MCMC-8, Imwitor 308), glyceryl monooleate (Capmul GMO), capric acid monoglyceride (Imwitor 312), PEG-6 corn oil (Labrafil M 2125), sorbitan monooleate (Span 80); sodium lauryl sulfate, sodium taurocholate, lecithin, lyso-lecithin, phosphatidyl glycerol, polyethylene glycol-phosphatidyl ethanolamines, cetyl trimethyl ammonium bromide, lauryl betaine; acetyl triethylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, triacetin; tetrahydrofurfuryl alcohol PEG ether (glycofurol), m-PEG, diethylene glycol monoethyl ether (Transcutol), diethylene glycol monobutyl ether, ethylene glycol monoethyl ether; ethanol, isopropanol, ethylene glycol, propylene glycol, glycerol, sorbitol, mannitol, polyvinylalcohol, cellulose derivatives; polyethylene glycol (PEG 400 etc.), polypropylene glycol, POE- POP block polymers; pyrrolidones, N-alkylpyrrolidones, N-hydroxyalkylperrolidones, N-methylpyrrolidone, piperidones, N-alkylpiperidones, polyvinylpyrrolidones. Surfactant used in the present invention are selected from the group consisting of Polysorbate 20, 60 and 80; glyceryl monooleate/propylene glycol mixture; glyceryl monooleate; sorbitan monooleate; oleyl alcohol; and linoleic acid. Emulsifying agents used in the present invention are selected from the group consisting of oleic acid, gadoleic acid, erucic acid, n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid.

Antioxidants used in the present invention are selected from the group consisting of butylhydroxytoluene (BHT), benzotriazol, butylhydroxyanisole (BHA), ascorbyl palmitate, disodium calcium ethylenediaminetetraacetate, DL-alpha- tocopherol, disodium ethylenediaminetetraacetate, erythorbic acid, dithiothreitol, monothioglycerol, thioglycerol, propyl gallate, erythorbate, sodium thioglycolate, , a- thioglycerin, and/or salts thereof and combinations thereof.

Preservatives used in the present invention are selected from the group consisting of parabens, benzyl alcohol, sodium benzoate, phenol, benzalkonium chloride, thimerosal, chlorobutanol, benzoic acid, sodium bisulfite, and sodium proprionate.

Sweetners used in the present invention are selected from the group consisting of saccharin, saccharin sodium, sucrose, maltose, glucose, fructose, aspartame, potassium acesulfame, sucralose, neotame (not used in beverages), alitame, cyclamate, tagatose and trehalose.

Flavors used in the present invention are selected from the group consisting of synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits, and so forth and combinations thereof. Suitable oils include, for example, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, vanilla, citrus oil (e.g., lemon, orange, grape, lime, grapefruit), citric acid, menthol, glycine, orange powder, cream, chocolate, mocha, spearmint, cola, apple, apricot, banana, cherry, peach, pear, pineapple, plum, raspberry and strawberry

Preferred solvents used in the compositions of the present invention organic or inorganic solvent or mixtures thereof selected from isopropyl alcohol (IP A), acetone, ethanol, dichloromethane, water and mixtures thereof.

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

Example 2

Example 3

Example 4

Example 5

Procedure

Preparation of Aqueous Phase (Part A): Solubilize Vitamin E-TPGS in 381.627 kg of double distilled water a stirrer at 400 to 600 RPM. After complete solubilization of Vitamin E-TPGS, add sucralose and vanilla flavour and continue stirring for 15 minutes at 400 to 600 RPM.

Preparation of Organic Phase (Part B): Mix polysorbate 80, oleic acid, butylated hydroxyl toluene, benzyl alcohol and cholecalciferol 40,000 IU/mg at 400 to 600 RPM.

Preparation of Primary Emulsion: After preparation of clear organic phase (Part B), add double distilled water to the organic phase (Part B).

The Primary emulsion formed will be added to aqueous Phase (Part A) under continuous stirring After complete addition of primary emulsion to part A, dissolve sodium benzoate and disodium EDTA under continuous stirring at 500 RPM. Particle size determination

The formulations of present invention are worked in bench scale and its particle size is measured by using Malvern Zetasizer, its Average Globule Size (nm)# and Average PDI data generated is given below:

#Particle size of the formulation was measured using Malvern Zetasizer.

Assay: The formulation of the present invention cholecalciferol Assay was determined by using HPLC and data generated is given below:

*Assay of cholecalciferol was performed using HPLC pH of Nanoemulsion formulation

The formulation of the present invention having pH of nanoemulsion was determined and the data obtained is given below:

Claims

We Claim:

1. Stable cholecalciferol nanoemulsion formulation comprising a stabilizer and one or more pharmaceutically acceptable excipients.

2. The stable cholecalciferol nanoemulsion formulation as claimed in claim 1, wherein the stabilizer is selected from group consisting of polyethylene glycol (PEG)-derivatives of Vitamin E, a tocopherol polyethylene glycol diester (TPGD).

3. The stable cholecalciferol nanoemulsion formulation as claimed in claim 2, wherein the TPGD is selected from among tocopherol sebacate polyethylene glycol, tocopherol dodecanedioate polyethylene glycol, tocopherol suberate polyethylene glycol, tocopherol azelaate polyethylene glycol, tocopherol citraconate polyethylene glycol, tocopherol methylcitraconate polyethylene glycol, tocopherol polyethylene glycol succinate (TPGS), tocopherol itaconate polyethylene glycol, tocopherol maleate polyethylene glycol, tocopherol glutarate polyethylene glycol, tocopherol glutaconate polyethylene glycol and tocopherol phthalate polyethylene glycol.

4. The stable cholecalciferol nanoemulsion formulation as claimed in claim 3, wherein the TPGS is a tocopherol polyethylene glycol succinate (Tocophersolon), such as a TPGS-1000 and/or a d-a TPGS.

5. The stable cholecalciferol nanoemulsion formulation as claimed in claim 1, wherein the particle/droplet size of nanoemulsion ranges from 15 to 1000 nm, preferably, 15 to 500 nm, more preferably, 20 to 100 nm.

6. The stable cholecalciferol nanoemulsion formulation as claimed in claim 1, wherein the formulation further comprising one or more pharmaceutically acceptable excipients selected from surfactants, chelating agents, emulsifying agents, solubilizers, antioxidants, preservatives, sweeteners and flavouring agents.

7. The stable cholecalciferol nanoemulsion formulation as claimed in claim 6, wherein the surfactant is selected from the group consisting of Polysorbate 20, 60 and 80; glyceryl monooleate/propylene glycol mixture, glyceryl monooleate, sorbitan monooleate, oleyl alcohol, and linoleic acid.

8. The stable cholecalciferol nanoemulsion formulation as claimed in claim 6, wherein the emulsifying agent is selected from the group consisting of oleic acid, gadoleic acid, erucic acid, n-dodecanoic acid, n-tetradecanoic acid, n- hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid.

9. The stable cholecalciferol nanoemulsion formulation as claimed in claim 6, wherein the chelating agent is selected from the group consisting of ethylene diaminetetraacetic acid (EDTA), deferoxannine, desferrioxannine B, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), dihydroethylglycine, bis(anninoethyl)glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, poly (aspartic acid), citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, oxalic acid, malic acid, lecithin or any salt thereof or combinations thereof.

10. The stable cholecalciferol nanoemulsion formulation as claimed in claim 6, wherein the solubilizer is selected from the group consisting of benzyl alcohol, fatty acid monoesters or diesters or mixtures thereof of glycols such as ethylene glycols or propylene glycols or butylenes glycols, monoglycerides or diglycerides or mixtures thereof; polyglycerized fatty acids, polyethylene glycol fatty acid monoesters or diesters or mixtures thereof, POE-POP block copolymer fatty acid monoesters or diesters or mixtures thereof, polyethylene glycol sorbitan fatty acid esters, sorbitan fatty acid esters, ethylene glycol or diethylene glycol or triethylene glycol or polyethylene glycol alkyl ethers, phospholipids and derivatives thereof, PEG-phospholipids, PEGs, alcohols, fatty alcohols, fatty acids, propylene glycol dicaprylate/dicaprate (Captex 200), propylene glycol monocaprylate (Capmul PG-8), propylene glycol caprylate/caprate (Labrafac PG), propylene glycol dicaprylate (Captex 100), propylene glycol diethylhexanoate, propylene glycol monolaurate (Capmul PG- 12), glyceryl caprylate/caprate (Capmul MCM), glyceryl monocaprylate (Capmul MCMC-8, Imwitor 308), glyceryl monooleate (Capmul GMO), capric acid monoglyceride (Imwitor 312), PEG-6 corn oil (Labrafil M 2125), sorbitan monooleate (Span 80), sodium lauryl sulfate, sodium taurocholate, lecithin, lyso-lecithin, phosphatidyl glycerol, polyethylene glycol-phosphatidyl ethanolamines, cetyl trimethyl ammonium bromide, lauryl betaine, acetyl triethylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, triacetin; tetrahydrofurfuryl alcohol PEG ether (glycofurol), m-PEG, diethylene glycol monoethyl ether (Transcutol), diethylene glycol monobutyl ether, ethylene glycol monoethyl ether, ethanol, isopropanol, ethylene glycol, propylene glycol, glycerol, sorbitol, mannitol, polyvinylalcohol, cellulose derivatives; polyethylene glycol (PEG 400 etc.), polypropylene glycol, POE-POP block polymers; pyrrolidones, N-alkylpyrrolidones, N-hydroxyalkylperrolidones, N- methylpyrrolidone, piperidones, N-alkylpiperidones, polyvinylpyrrolidones.

11. The stable cholecalciferol nanoemulsion formulation as claimed in claim 6, wherein the antioxidant is selected from the group consisting of butylhydroxytoluene (BHT), benzotriazol, butylhydroxyanisole (BHA), ascorbyl palmitate, disodium calcium ethylenediaminetetraacetate, DL-alpha- tocopherol, disodium ethylenediaminetetraacetate, erythorbic acid, dithiothreitol, monothioglycerol, thioglycerol, propyl gallate, erythorbate, sodium thioglycolate, a-thioglycerin, and/or salts thereof and combinations thereof.

12. A process for preparation of stable cholecalciferol nanoemulsion formulation comprising a stabilizer and one or more other pharmaceutically acceptable excipients, wherein the process comprising the steps of:

a) solubilizing the stabilizing agent in double distilled water with continuous stirring, b) adding the sweetners and flavouring agents to the above solution and continue stirring for 15 minutes (Part A),