PHARMACEUTICAL FOAM COMPOSITION

PRIORITY DOCUMENT

This patent application claims priority to Indian Provisional Patent Application number 201621015520 (filed on May 04, 2016), the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present disclosure relates to azelaic acid foam compositions. BACKGROUND

Azelaic acid (1,7-heptanedicarboxylic acid) is a naturally occurring saturated dicarboxylic acid. Azelaic acid has many beneficial properties including anti-inflammatory, antibacterial, and antikeratinizing effects. It is a known inhibitor of tyrosinase, a vital constituent in the production of melanin, and it also has the ability to inhibit 5a-reductase, which is involved in androgenetic alopecia. It has been used in various formulations to treat rosacea, acne, and melasma. Azelaic acid 15% gel and azelaic acid 15% topical aerosol foam, is approved in USA for the topical treatment of inflammatory papules and pustules of mild to moderate rosacea, available under the trade name FINACEA. ^® United States patent No. 9,265,725 discloses azelaic acid foamable and cosmetic composition; the composition comprises an active agent; a beneficially or therapeutically effective concentration of at least one benefit agent, selected from the group consisting of a dicarboxylic acid and a dicarboxylic acid ester; stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof, a solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof.

According to the United States patent No. 9,265,725, the organic carrier does not contain petrolatum, which is also termed "white petrolatum" and "Vaseline". Petrolatum often forms an impermeable occlusive barrier, so that metabolic products and excreta from damaged tissue are not easily removed or drained away. Furthermore, it is difficult for the active drug dissolved in the carrier to pass through the white petrolatum barrier layer into the treated tissue, so the efficacy of the drug is reduced. According to said prior art, an additional disadvantage of petroleum jelly- based products relates to the greasy feeling left following their topical application onto the skin, mucosal membranes and wounds causing inconvenience to the user, thereby decreasing treatment compliance. Foamable composition disclosed in the U.S. Patent No. 9,265,725 is substantially alcohol-free, i.e., free of short chain alcohols. According to the United States patent No. 9,265,725, Short chain alcohols, such as ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol, are considered less desirable solvents or polar solvents due to their skin -irritating effect. Thus, the composition disclosed in U.S. Patent No. 9,265,725 is substantially alcohol-free and includes less than about 5% final concentration of lower alcohols, preferably less than about 2%, more preferably less than about 1 %.

There is a need to develop stable foam composition of azelaic acid which are stable at skin temperature, easy to apply on skin or mucosal surface and provide therapeutic benefits in treating dermatological disorders preferably in treating rosacea. Accordingly, it is an object of the present invention to provide stable azelaic acid foam compositions comprising, surface-active agent, short chain alcohol, white petrolatum and solvents. Such a composition creates an oil-in-water emulsion that is stable and upon release from the aerosol container, forms a stable foam product, which is suitable for topical or mucosal administration. OBJECTS OF THE INVENTION

An object of the present disclosure is to provide alternative azelaic acid foam compositions which are stable having an acceptable shelf-life over period of times and demonstrate desirable physicochemical properties.

SUMMARY OF THE INVENTION In one aspect of the present invention, stable foamable composition of azelaic acid is provided, which upon admixing with a liquefied gas propellant in an aerosol container releases stable foam that is suitable for topical administration. In one or more embodiment of the invention, there is provided a pharmaceutical or cosmetic composition comprising: a. therapeutically effective amount of azelaic acid;

b. a surface active agent;

c. a short chain alcohol selected from ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol;

d. hydrophobic base comprising white petrolatum, fatty alcohol, fatty acid, or mixtures thereof;

e. solvent;

f. liquefied hydrocarbon gas propellant such as butane, propane, isobutane, or mixtures thereof;

g. optional ingredients such as preservatives, pH adjusting agents and humectants.

In one or more embodiments, there is provided a foamable composition which produces a stable foam upon release and wherein surfactant, short chain alcohol, hydrophobic base and solvents are selected to generate a stable foam.

In one or more embodiment of the invention, there is provided a method of treating a disorder of a mammalian subject, comprising: administering a foamable therapeutic composition to a target site, the composition comprising: a. therapeutically effective amount of azelaic acid;

b. a surface active agent;

c. a short chain alcohol, selected from ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol;

h. hydrophobic base comprising white petrolatum, fatty alcohol, fatty acid, or mixtures thereof;

d. solvent;

e. liquefied hydrocarbon gas propellant such as butane, propane, isobutane, or mixtures thereof;

f. optional ingredients such as preservatives, pH adjusting agents and humectants. In one or more embodiment of the invention, there is also provided a process for preparing the foamable composition, comprising: a. therapeutically effective amount of azelaic acid;

b. a surface active agent;

c. a short chain alcohol selected form ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol;

d. hydrophobic base comprising white petrolatum, fatty alcohol, fatty acid, or mixtures thereof;

e. solvent;

f. liquefied hydrocarbon gas propellant such as butane, propane, isobutane, or mixtures thereof;

g. optional ingredients such as preservatives, pH adjusting agents and humectants.

Unexpectedly it was found that stable azelaic acid foam compositions can be prepared using surface active agents, short chain alcohols and a hydrophobic base comprising white petrolatum, fatty acid, and fatty alcohols or mixtures thereof. Such compositions are "stable foam compositions", having an acceptable shelf-life over period of times and demonstrate desirable physicochemical properties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to stable foam compositions of azelaic acid, which are suitable for topical, dermal or transdermal delivery and can be administered by direct application to the skin, for the treatment of rosacea.

According to one or more embodiments of the present invention, the foamable composition includes:

a. therapeutically effective amount of azelaic acid;

b. a surface active agent;

c. a short chain alcohol, selected form ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol;

d. hydrophobic base comprising white petrolatum, fatty alcohol, fatty acid, or mixtures thereof; e. solvent comprising a hydrophilic component;

f. liquefied hydrocarbon gas propellant such as butane, propane, isobutane, or mixtures thereof;

g. optional ingredients such as preservatives, pH adjusting agents and humectants.

Wherein the surfactant, short chain alcohol, hydrophobic base, solvent are selected to provide a foam composition that is stable and suitable for topical, dermal or transdermal delivery and can be administered by direct application to the skin.

In an embodiment of the present invention stable foam compositions are provided. By "stable foam compositions" means foam compositions which are stable over period of time, having an acceptable shelf-life of at least one year, or preferably, at least two years at ambient temperature, as revealed in stability tests. In one or more embodiments, the term "stable foam composition" means foam compositions which demonstrates desirable physicochemical properties such as foam volume, foam density, foam feel, easily spreadable over application site, and such properties do not change over period of time.

In an embodiment of the present invention, the azelaic acid is incorporated in the foamable composition in therapeutically effective amount. The term "therapeutically effective" means an amount of an active agent that exerts a therapeutic effect on a specific disorder, without causing adverse effects that may prohibit the use of said active agent in the treatment of said disorder. Azelaic acid can be incorporated in the foamable composition of the present invention in a concentration from about 5% to about 25%, preferably from about 10% to about 20%, or more preferably from about 10 to about 15%.

The term "about" has its usual meaning in the context of pharmaceutical formulations to allow for reasonable variations in amounts that can achieve the same effect. As used herein, the term "about" when used to refer to weight % in a composition means plus or minus up to 30% of the reported weight %.

In one or more embodiment there is provided a foamable composition of azelaic acid which produces stable foam upon release and wherein surfactant, polar solvent, hydrophobic organic carrier are selected to generate a stable foam. In one or more embodiment there is provided a foamable composition comprising a surfactant wherein surfactant is selected from the group consisting of a non-ionic surfactant, anionic surfactant and cationic surfactants and mixtures thereof.

In one or more embodiment there is provided a foamable composition wherein surfactant is selected from non-ionic surfactants such as glycerol fatty acid esters such as glycerol monostearate, glycol fatty acid esters such as propylene glycol monostearate, polyhydric alcohol fatty acid esters such as polyethylene glycol (400) monooleate, polyoxyethylene fatty acid esters such as polyoxyethylene (40) stearate, polyoxyethylene fatty alcohol ethers such as polyoxyethylene (20) stearyl ether, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate, sorbitan esters such as sorbitan monostearate, alkyl glycosides such as cetearyl glucoside, fatty acid ethanolamides and their derivatives such as the diethanolamide of stearic acid, and the like.

In one or more embodiment there is provided a foamable composition wherein surfactant is selected from anionic surfactants such as soaps including alkali soaps, such as sodium, potassium and ammonium salts of aliphatic carboxylic acids, usually fatty acids, such as sodium stearate. Organic amine soaps, also included, include organic amine salts of aliphatic carboxylic acids, usually fatty acids, such as triethanolamine stearate. Another class of suitable soaps is the metallic soaps, salts of polyvalent metals and aliphatic carboxylic acids, usually fatty acids, such as aluminium stearate. Other classes of suitable anionic surfactants include sulfated fatty acid alcohols such as sodium lauryl sulfate, alkyl sulfates such as Sodium Cetostearyl sulfate, sulfated oils such as the sulfuric ester of ricinoleic acid disodium salt, and sulfonated compounds such as alkyl sulfonates including sodium cetane sulfonate, amide sulfonates such as sodium N-methyl-N- oleyl laurate, sulfonated dibasic acid esters such as sodium dioctyl sulfosuccinate, alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate, alkyl naphthalene sulfonates such a sodium isopropyl naphthalene sulfonate, petroleum sulfonate such as aryl napthalene with alkyl substitutes.

In one or more embodiment there is provided a foamable composition wherein surfactant is selected from cationic surfactants include amine salts such as octadecyl ammonium chloride, quaternary ammonium compounds such as benzalkonium chloride. In one or more embodiment there is provided a foamable composition wherein surfactant is an anionic surfactants.

In one or more embodiment there is provided a foamable composition wherein surfactant is sodium lauryl sulfate. In one or more embodiment there is provided a foamable composition wherein surfactant is sodium cetostearyl sulfate.

In one or more embodiment there is provided a foamable composition wherein surfactant is a non- ionic surfactants such as glycerol fatty acid esters such as glycerol monostearate.

In one or more embodiment surfactant is a mixture of anionic and non-ionic surfactants such as sodium lauryl sulfate and glycerol monostearate respectively.

In one or more embodiment surfactant is a mixture of anionic and non-ionic surfactants such as sodium cetostearyl sulfate and glycerol monostearate respectively.

In one or more embodiment there is provided a foamable composition wherein surfactant is a combination product. This applies to for example Sepineo SE68, which is a mixture of cetearyl alcohol and cetearyl glucosid, Polawax NF, which is a mixture of cetearyl alcohol and polysorbate 60, and Crodafos CES, which is a mixture of cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate.

In one or more embodiment there is provided a foamable composition wherein the amount of the above mentioned surfactants used in the present invention is from about 0.1% to about 10%; preferably from about 1% to about 8% and most preferably from about 1.5% to about 5.0%.

In one or more embodiment there is provided a foamable composition which comprises short chain alcohol.

In one or more embodiment short chain alcohols are provided to facilitate or enhance the transdermal penetration or delivery of a drug. A short chain alcohol according to one or more certain other embodiments has up to 5 carbon atoms in their carbon chain skeleton and one hydroxy group, and are selected from ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol, pentanol. In one or more embodiments the short chain alcohol, is preferably isopropanol.

In one or more embodiments the short chain alcohol is present in amount from about 10% to about 40% by weight of the composition.

In one or more embodiments the short chain alcohol is present in amount from about 10% to about 30% by weight of the composition.

In one or more embodiments the short chain alcohol is present in amount from about 12% to about 25% by weight of the composition.

In one or more embodiment there is provided a foamable composition substantially free of short chain alcohols. In one or more embodiments compositions are formulated essentially free of alcohols. In one or more embodiment compositions are formulated with less than about 10% short chain alcohols or less than about 5% short chain alcohols or less than about 2% short chain alcohols; or less than about 1% short chain alcohols; or less than about 0.5% short chain alcohols.

In one or more embodiment there is provided a foamable composition comprising a hydrophobic base. In one or more embodiment hydrophobic base is included in the composition to facilitate or enhance the transdermal penetration or delivery of a drug. The hydrophobic base facilitates topical distribution and enhances the rate of penetration of drugs at the application site.

In one or more embodiment hydrophobic base comprises white petrolatum, fatty alcohol, fatty acid, or mixtures thereof. In one or more embodiments hydrophobic base includes white petrolatum. White petrolatum also termed as "Vaseline" possesses well known lubricating, softening and skin conditioning characteristics. Among the many attributes of petrolatum, which make its use in topical applications advantageous are its moisturizing efficacy, water barrier property, water repellency, resistance to being washed off by water, physiological inertness, and chemical inertness and stability.

In one or more embodiments, fatty alcohol is included in the foamable compositions to increase the foaming property of the composition and/or to stabilize the foam. Fatty alcohols are also useful in facilitating improved spreadability and absorption of the composition.

In one or more embodiments, the fatty alcohol is selected from the group consisting of fatty alcohols having 15 or more carbons in their carbon chain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof). Other examples of fatty alcohols are myristyl alcohol (C ₁₄ ), arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well as alcohols with longer carbon chains (up to C50). In one or more preferred embodiments, the fatty alcohol is cetyl alcohol, stearyl alcohol, behenyl alcohol or myristyl alcohol or mixtures thereof.

In one or more embodiment there is provided a foamable composition which comprises a fatty acid or a combination of different fatty acids.

In one or more embodiments the fatty acid can include medium-chain triglycerides. In one or more embodiments medium-chain triglycerides include capric/caprylic triglycerides commercially available under the trade name Miglyol® 812. Caprylic/capric triglyceride creates a barrier on the skin's surface, decreasing the amount of moisture lost through the skin, functioning not only to prevent dryness in skin, but also as a skin conditioning agent. Caprylic/capric triglyceride is an excellent emollient as well, improving both the aesthetics of the product, as well as working to soften and smooth the skin.

In one or more embodiments, the stable foamable composition includes a hydrophobic base which comprises white petrolatum, medium chain triglycerides and cetostearyl alcohol or mixtures thereof.

In one or more embodiments stable foam is obtained by combining white petrolatum, medium chain triglycerides and cetostearyl alcohol.

In one or more embodiment there is provided a foamable composition comprising hydrophobic base in amount from about 1% and about 50%, preferably between about 1% to about 35%, more preferably about 1% to about 10%. In one or more embodiments there is provided a stable foamable composition which further includes hydrophilic component selected from dimethyl isosorbide, water, glycerol, sorbitol, propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di- terpenes, tri-terpenes, limonene, terpene-ol, 1 -menthol, dioxolane, ethylene glycol, other glycols, oleyl alcohol, alpha-hydroxy acids, such as lactic acid and glycolic acid, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide, dimethylacetamide, azone (l-dodecylazacycloheptan-2-one), 2-(n-nonyl)-l,3-dioxolane, alkanols, such as dialkylamino acetates, or mixtures thereof.

In one or more embodiments there is provided a stable foamable composition which contains about 80% hydrophilic component, preferably about hydrophilic component 70%, more preferably about hydrophilic component 50%.

In one or more embodiments there is provided a stable foamable composition which further comprises a propellant.

In one or more embodiments, hydrocarbon propellants are preferred in the present invention. Hydrocarbon propellants are selected from the group consisting of butane, iso-butane, propane, pentane, and mixtures thereof.

In one or more embodiments propellants or mixtures are present in amount from about 2% to about 10%, preferably from about 6.5% to about 8.5%.

In one or more embodiments stable foamable compositions of azelaic acid further comprise optional ingredients such as pH adjusting agents, preservatives or humectants. Any pH adjusting agents, preservatives or humectants suitable for pharmaceutical composition may be used.

In one or more embodiments, the pH of the composition is adjusted to a value between from about 4.0 to about 6.0, preferably in the range from about 4.6 to about 5.0. In one or more embodiments pH adjusting agent is selected form acetic acid, citric acid, tartaric acid, fumaric acid, lactic acid, malic acid, ammonium carbonate, calcium acetate, calcium carbonate, magnesium carbonate, magnesium sulfate, potassium sulfate, sodium bicarbonate, sodium citrate, sodium lactate, sodium hydroxide. In one or more embodiments pH adjusting agent is sodium hydroxide. In one or more embodiments foamable composition includes a preservative. In one or more embodiments preservative is selected form ascorbic acid, benzoic acid, citric acid, lecithin, methyl paraben, propyl paraben, sodium acetate, sodium benzoate, sodium bisulphite, sodium lactate, sodium metabisulphite, sorbic acid, tartaric acid. In one or more embodiments preservative is benzoic acid.

In one or more embodiments foamable composition further includes at least one humectant that helps retain moisture and also prevents rapid evaporation. Non limiting examples are propylene glycol, propylene glycol derivatives, glycerin, hydrogenated starch hydrosylate, hydrogenated lanolin, lanolin wax, D mannitol, sorbitol, sodium 2-pyrrolidone-5-carboxylate, sodium lactate, sodium PCA, soluble collagen, dibutyl phthalate, and gelatin or mixtures thereof. In one or more embodiment humectant is sorbitol. In one or more embodiment humectant is glycerin.

A specific embodiment according to the present invention comprises azelaic acid, a surfactant or mixture of anionic and nonionic surfactants, a hydrophobic base, hydrophilic components, optional ingredients and a propellant. In another embodiment, foambale compositions according to the present invention comprises about 15% azelaic acid, about 0.1% to about 10% by weight of a surface active agent, about 10% to about 40% by weight of a short chain alcohol, about 1% to about 50% by weight of a hydrophobic base, solvent and 2% to about 10% of propellant comprising mixture of isobutane, butane and propane. In one or more embodiments oil in water foamable compositions of present invention comprises about 15% azelaic acid, about 0.1% to about 10% by weight of a surface active agent, about 5% to about 10% by weight of a short chain alcohol, about 1% to about 10% by weight of a hydrophobic base, solvent and a propellant wherein composition has a pH of about 4.0-6.0.

In another embodiment of the invention oil in water foamable compositions of present invention comprises about 15% azelaic acid, about 1.5% to about 5% by weight of a surface active agent, bout 1% to about 10% by weight of a hydrophobic base, solvent and a propellant, wherein compositions are substantially free of short chain alcohols or comprises less than about 1% of short chain alcohols. A further embodiment of the invention provides a foam composition which comprises azelaic acid, a mixture of surfactants comprising sodium lauryl sulfate and glyceryl monostearate, a hydrophobic base comprising white petrolatum, medium chain triglycerides and cetostearyl alcohol, hydrophilic components comprising water and dimethyl isosorbide, a preservative comprising benzoic acid, pH adjusting agent such as sodium hydroxide solution, a humectant such as sorbitol and a propellant comprising mixture of isobutane, butane and propane.

A specific embodiment according to the present invention comprises about 15% azelaic acid, from about 1% to about 10% of mixture of anionic and nonionic surfactants comprising sodium lauryl sulfate and glyceryl monostearate, about 1% to about 10% of hydrophobic base comprising white petrolatum, medium chain triglycerides and cetostearyl alcohol, about 60% -80% of hydrophilic components comprising water and dimethyl isosorbide, about 6.5% to about 8.5% of propellant comprising mixture of isobutane, butane and propane, sodium hydroxide solution is added to adjust the pH of composition to about 4.6 to about 6.0. All % values are provided on a weight (w/w) basis.

A further embodiment of the invention provides a process for manufacturing stable foam composition. The process involves following steps:

1. Preparation of aqueous phase

2. Preparation of non-aqueous phase

3. Emulsification involving homogenization of aqueous and non-aqueous phases

4. Addition of drug to the emulsion Base

5. Addition of alcohol to the emulsion Base

6. pH adjustment using pH adjusting agents

7. Cooling of the emulsion, and,

8. Filling and packing in aluminum cans

9. Propellant filling

In one or more embodiments there is provided a method of producing a foam from aerosol dispenser which comprises dispensing the oil-in-water emulsion described above with a propellant, thereby producing a foam having a consistent foam density from first dispensing to last dispensing. In one or more embodiments there is provided a foamable composition of azelaic acid suitable for treating skin condition, preferably for treating rosacea, more preferably for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.

According to additional embodiments there is provided a method of skin or mucosal surface application comprising spreading or collapsing a stable foam by mechanical force at the target site of a subject.

In one or more embodiments there is provided an aerosol spray device for dispensing a metered amount of foamable compositions of present invention.

In one or more embodiments an aerosol spray device comprises a container suitable for accommodating the composition and a valve for releasing a foam. The valve is selected to release a foam in a volume that provides an adequate therapeutic dose to the target site of the skin. The valve is made up of the valve cup typically constructed from tinplated steel, or aluminum, an outer gasket, a valve housing, which contains the valve stem, spring and inner gasket, and a dip tube, which allows the liquid to enter valve. The inner gasket covers the aperture in the valve stem. Valves may contain one, two, three, four or more apertures, depending on the nature of the product to be dispensed.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE

Example 1 Formulation:

Ingredients %

Azelaic acid 15

Iso propyl alcohol 12

Benzoic acid USP 0.1 Dimethyl isosorbide 5.44

Sodium lauryl sulfate 0.3

Glyceryl mono stearate 6.2

Medium chain triglycerides 2.0

White petrolatum 3.0

Cetostearyl alcohol 3.0

Sodium hydroxide q.s. to adjust pH 4.6-5.2

Propylene glycol 12

Purified water q.s to 100.0

Propellants Isobutane 8.0

Butane

Propane

According to additional embodiments there is provided a method of producing a foamable composition. The process of manufacturing includes following steps:

Brief Manufacturing process:

1. Preparation of aqueous phase (Phase A):

1.1 Dimethyl Isosorbide was charged in an aqueous phase vessel. Benzoic acid was added into the aqueous phase vessel under continuous stirring. Solution was stirred to form a clear solution for about 10-20 minutes.

1.2 Purified water was added to the above step 1.1 and stirred continuously for about 5-10 minutes.

1.3 Propylene glycol was added to the above step 1.2 and stirred continuously for about 5-10 minutes.

1.4 Sodium lauryl sulfate was added to the above mixture and stirred continuously for about 5- 10 minutes.

1.5 Aqueous phase formed in above steps was heated up to 60°C-70°C under continuous stirring. Preparation of non-aqueous phase (Phase B) :

White petrolatum, cetostearyl alcohol, medium chain triglycerides, and mono- and di- glycerides were added in a vessel and heated up to 60-70 °C under continuous stirring to ensure complete mixing of the oil phase ingredients to form non-aqueous phase. The temperature was maintained at 60-70 °C. Emulsification:

1 Aqueous phase (Phase A) and non aqueous phase (Phase B) were transferred into the main manufacturing vessel and the mixture was homogenized for about 30 minutes at 60-70 °C to form an emulsion.

2 Emulsion formed in above step was cooled to the temperature of about 50-55 °C. ddition of the drug to the emulsion base :

Azelaic acid was added slowly to the emulsion base and the mixture was homogenized for 10-30 minutes under continuous stirring at about 45-50 °C.

Mixture was cooled to the temperature of about 35-40 °C.

Iso propyl alcohol was added and the mixture was homogenized for about 10-15 minutes at about 35°C - 40 °C. pH adjustment:

The pH of emulsion was adjusted to pH 4.8 (4.60 - 5.00) with 10 % sodium hydroxide under stirring. Cooling:

Emulsion was cooled to the temperature of about 28°C -30°C under stirring illing and Packing:

Weighed quantity of emulsion were filled into 50g aluminium cans at room temperature separately.

Filled aluminum can were crimped with crimping machine. 8. Propellant filling:

8.1 Required quantity of propellants were filled up into step 7.2 aluminum cans.

8.2 Leak testing was performed on final filled container. Example 2 Formulation:

Brief Manufacturing process: 1. Preparation of aqueous phase (Phase A):

1.1 Dimethyl Isosorbide was charged in an aqueous phase vessel. Benzoic acid was added into the aqueous phase vessel under continuous stirring. Solution was stirred to form a clear solution for about 10-20 minutes. Purified water was added to the above step 1.1 and stirred continuously for about 5-10 minutes.

Propylene glycol was added to the above step 1.2 and stirred continuously for about 5-10 minutes.

Sodium lauryl sulfate was added to the above mixture and stirred continuously for about 5- 10 minutes.

Aqueous phase formed in above steps was heated up to 60°C-70°C under continuous stirring.

reparation of non -aqueous phase (Phase B):

White petrolatum, cetostearyl alcohol, medium chain triglycerides, and glyceryl mono stearate, and sepineo SE-68 were added in a vessel and heated up to 60-70 °C, under continuous stirring to ensure complete mixing of the oil phase ingredients to form nonaqueous phase. The temperature of vessel was maintained at 60-70 °C. Emulsification:

.1 Aqueous phase (Phase A) and non aqueous phase (Phase B) were transferred into the main manufacturing vessel and the mixture was homogenized for about 30 minutes at 60- 70 °C to form an emulsion.

.2 Emulsion formed in above step was cooled to the temperature of about 50-55 °C. Addition of Drug to the Emulsion Base :

Azelaic acid was added slowly to the emulsion base and the mixture was homogenized for 10-30 minutes under continuous stirring at about 45-50 °C.

Mixture was cooled to the temperature of about 35-40 °C.

Iso propyl alcohol was added and the mixture was homogenized for about 10-15 minutes at about 35°C - 40 °C.

pH adjustment:

The pH of emulsion was adjusted to pH 4.8 (4.60 - 5.00) with 10 % sodium hydroxide under stirring. Cooling:

Emulsion was cooled to the temperature of about 28°C -30°C under stirring . Filling and Packing:

.1 Weighed quantity of emulsion were filled into 50g aluminium cans at room temperature separately.

.2 Filled aluminum cans were crimped with crimping machine. . Propellant filling:

8.1 Required quantity of propellants were filled up into step 7.2 aluminum cans.

8.2 Leak testing was performed on final filled container. Example 3 Formulation:

Ingredients %

Azelaic acid 15

Benzoic acid USP 0.1

Dimethyl isosorbide 5.44

Sodium lauryl sulfate 0.3

Glyceryl mono stearate 2.0

Medium chain triglycerides 2.0

White petrolatum 3.0

Cetearyl alcohol and cetearyl 4.5

glucosid (Sepineo SE 68)

Cetostearyl alcohol 2.0

Sodium hydroxide q.s. to adjust pH 4.6-5.2

Propylene glycol 12.0

Purified water q.s to 100.0

Propellants Isobutane 8.0

Butane

Propane Brief Manufacturing process:

1. Preparation of aqueous phase (Phase A):

1.1 Dimethyl Isosorbide was charged in an aqueous phase vessel. Benzoic acid was added into the aqueous phase vessel under continuous stirring. Solution was stirred to form a clear solution for about 10-20 minutes.

1.2 Purified water was added to the above step 1.1 and stirred continuously for about 5-10 minutes.

1.3 Propylene glycol was added to the above step 1.2 and stirred continuously for about 5-10 minutes.

1.4 Sodium lauryl sulfate was added to the mixture of above step and stirred continuously for about 5-10 minutes.

1.5 Aqueous phase formed in above steps was heated up to 60°C-70°C under continuous stirring.

2. Preparation of non-aqueous phase (Phase B):

White petrolatum, cetostearyl alcohol, medium chain triglycerides, and glyceryl mono stearate, and sepineo SE-68, were added in a vessel and heated up to 60-70 °C, under continuous stirring to ensure complete mixing of the oil phase ingredients to form nonaqueous phase. The temperature of vessel was maintained at 60-70 °C. 3. Emulsification:

3.1 Aqueous phase (Phase A) and non aqueous phase (Phase B) were transferred into the main manufacturing vessel and the mixture was homogenized for about 30 minutes at 60-70 °C to form an emulsion.

3.3 Emulsion formed in above step was cooled to the temperature of about 50-55 °C.

4. Addition of Drug to the Emulsion Base:

4.1 Azelaic acid was added slowly to the emulsion base and the mixture was homogenized for 10-30 minutes under continuous stirring at about 45-50 °C.

4.2 Mixture was cooled to the temperature of about 35-40 °C. pH adjustment:

The pH of emulsion was adjusted to pH 4.8 (4.60 - 5.00) with 10 % sodium hydroxide under stirring. Cooling:

Emulsion was cooled to the temperature of about 28°C -30°C under stirring Filling and Packing:

Weighed quantity of emulsion were filled into 50g aluminium cans at room temperature separately.

Filled aluminum cans were crimped with crimping machine. pellant filling:

Required quantity of propellants were filled up into step 7.2 aluminum cans.

Leak testing was performed on final filled container.