The present invention discloses a pharmaceutical formulation comprising Azelaic acid for the treatment of acne. The invention further describes the method of preparation of the formulation. The invention relates to a topical formulation containing Azelaic acid in micronized or nanonized form.
BACKGROUND OF THE INVENTION
IN 236117 relates to a composition with azelaic acid in a hydrogel. The invention furthermore includes the use of the azelaic acid hydrogel as medicinal product.
Indian Patent application 577/KOLNP/2013 discloses a combination of compounds for treating skin diseases and particularly rosacea and ocular rosacea. It is the combination of a compound selected from azelaic acid and salts thereof with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family. The invention also relates to a product in the form of a kit containing: (a) a first corn position comprising a compound selected from azelaic acid and salts thereof, and (b) a second composition different from the first one and comprising a compound of the alpha- 1 or alpha-2 adrenergic receptor agonist family, as a combination product for application thereof as a medicament for treating and/or preventing skin diseases and in particular rosacea and

ocular rosacea, wherein said first and second compositions can be applied simultaneously, separately or with a time delay.
US 20150119427 waterborne topical composition is designed specifically to address the treatment of acne vulgaris, rosacea, seborrheic dermatitis and other skin conditions. One composition contains effective amounts of essential components azelaic acid, niacinamide, and glycerin to create a rapidly penetrating and non-irritating compound. One composition contains effective amounts of essential components azelaic acid, niacinamide, and cyclodextran to create a rapidly penetrating and non-irritating compound.
US 20100004338 disclose a novel azelaic acid topical pharmaceutical gel composition that does not contain lecithin and a process for its preparation.
US 5925679 provides completely solubilized alcohol-free topical composition of azelaic acid in a glycol base which is stable at normal temperatures and which is useful as a commercial substitute for dispersed azelaic acid preparations. The composition has a pH of 4.0 or greater thereby substantially reducing irritation.
OBJECTIVE OF THE INVENTION
The object of the present invention is to provide a topical formulation comprising Azelaic acid for the management of acne and facial redness.

Another object of the present invention is to provide a pharmaceutical formulation comprising azelaic acid with lesser side effects.
Another object of the present invention is to provide the formulation with azelaic acid in nano-particulate form.
Another object of the present invention is to provide the formulation with azelaic acid in micro-particulate form.
Yet another object of the present invention is to provide a method of manufacturing a stable nanonized or micronized formulation of azelaic acid.
Another object of the present invention is to formulate a formulation of micronized and nanonized formulation of Azelaic acid along with other active ingredients used for acne management.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes the nanonized and micronized formulation of Azelaic acid and the process of its preparation.
The "Nanoparticles" "nanonized particles" according to the present invention are the particles having the particle size ranging from 10 nm to 800 nm.

The "micro particles" "micronized particles" according to the present invention are the particles having the particle size ranging from 1 micron to 150 micron.
The transport of the active ingredient through the skin is a very complex process. The actives are dissolved or dispersed in a solvent system in such a, manner that they can readily diffuses the drug to stratum corneum and then to the dermis.
The gel formulation comprises, along with azelaic acid, the other pharmaceutical excipients which aids in developing the formulation. The pharmaceutical excipients such as solvent, chelating agent, polymer, surfactant, antioxidant, emollient, gel base and polymer along with purified water are used in this formulation.
The solvent, according to the present invention, can be selected from Iso-propyl alcohol, Ethyl acetate, Chloroform, Acetone, Di chloromethane and Dimethyl sulphoxide or combinations thereof. The preferable solvent is dimethylsulphoxide.
The chelating agent can be selected from the group consisting Di-Sodium Edetate, Edetic acid, Dimercaprol, Diethylene trimine pentacetic acid (DPTA) and Desferrioxamine or combinations thereof. The preferable chelating agent according to the present invention may be disodium edetate.

The polymers used in the formulation according to the present invention can be selected from Polyvinylpyrrolidone, Poly methyl methacrylates , Alginates, Chitosan, and Dextran or the combinations thereof. The preferable polymer is polyvinyl pyrrolidone K-90.
The surfactants can be selected from Polysorbates, Polyoxy 60, Castor Oil, Caprylic Glyceride, Poloxamer, Polyoxyl 35 Castor oil and Polyoxyl 40 Castor oil or the combinations thereof. The preferable surfactant is polysorbate-80.
In the present invention, the antioxidant used, can be selected from the group consisting of Sodium Sulfite, Vitamin E acetate, Ascorbic acid, Butylated Hydroxy Toluene, Butylated Hydroxy Anisole and Sodium Metabisulphite or the combinations thereof. The preferable antioxidant may be Sodium metabisulphite.
Emollients used for formulating the product using the present invention can be selected from the group consisting Glycerin, Propylene Glycol, Polyethylene Glycol, Sorbitol, Aloe vera Gel and Honey or combinations thereof. The preferable emollient may be Glycerin.
The gel base plays an important part in the formulation of a dermal preparation for it provides the much needed consistency so that the application is uniform and with ease. The gel base used in the present invention may be selected from the group consisting Carbopol,

Hydroxyethyl cellulose, Hydroxypropylmethyl cellulose, Xanthum gum, Carboxymethyl cellulose, Gelatin, Alginic acid and Pectin or combinations thereof. The preferable gel base is Hydroxyethyl cellulose.
The preservatives will preferably be Benzoic acid.
The present invention can be developed, but not limited to, in the following manner:
A) FORMULATION 1

S. No. Material Name Label Claim UOM Quantity Required
1. Azelaic acid 20% w/w Kg 20.00
2. Benzoic acid 0.2% w/w Kg 0.20
3. Dimethyl sulphoxide - Ltr. 20.0
4. Disodium edetate - Kg 0.05
5. Sodium metabisulphite - Kg 0.20
6. Hydroxy ethyl cellulose - Kg 2.0
7. Glycerin - Kg 1.0
8. Purified Water q.s Kg q.s to 100 kg
Process:

I
Take 50.0 Kg of purified water in SS vessel and add 0.05 Kg of
Disodium edetate and 0.2 Kg Sodium metabisulphite under
stirring at 500-600 RPM to get clear solution.
Add slowly 2.0 kg of Hydroxy ethyl cellulose into above solution
with stirring at 500-600 RPM for 1 hour and further stirring for
next 30 minute with heating up to 50°C"55°C to get uniform gel
formation.
Take 20 Liter of Dimethyl sulphoxide in another SS vessel and add
0.2 kg Benzoic acid with stirring at 500-600 RPM to get clear
solution.
Add 20kg of Azelaic acid into above Dimethyl sulphoxide solution
with stirring at 500-600 RPM and heating up to 45°C "50° C to get
clear solution.
Transfer above drug solution into gel base with stirring at 500-600
RPM for 1 hour to get uniform gel formation.
Add 1 kg of Glycerin into above gel formation with stirring at 500-
600 RPM for 30 minute.
Final weight makes up with purified water up to 100 kg with
stirring at 500-600 RPM for 15 minutes.
Check the pH of final formulation.
The particles of the final formulation are analyzed and are found in micro-particle range.

B) FORMULATION 2

S. No. Material Name Label Claim UOM Quantity Required
1. Azelaic acid 10%w/w Kg 10.00
2. Benzoic acid 0.2% w/w Kg 0.20
3. Dimethyl sulphoxide r Ltr. 20.0
4. Disodium edetate - Kg 0.05
5. Polyvinyl pyrrolidone K-90 ( PVPK-90) - Kg 10.0
6. Tween-80 - xKg 2.0
7. Sodium metabisulphite .- Kg 0.20
8. Hydroxy ethyl cellulose - Kg 1.5
9. Glycerin - Kg 1.0
V
10. Purified Water - Kg q.s to 100 kg
1. Take 50.0 Kg of purified water in SS vessel and add 0.05 Kg of Disodium edetate and 0.2 Kg Sodium metabisulphite under stirring at 500-600 RPM to get clear solution.
2. Add 2.0 Kg of tween-80 into above solution with stirring at 500-600 RPM and heating up to 50°C'55°C to get clear solution.

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3. Add slowly 10.0 kg of PVPK-90 into above solution with stirring at
500-600 RPM and heating up to 50oC~55°C.
4. Take 20 Liter of Dimethyl sulphoxide in another ss vessel and add
5 0.2 kg Benzoic acid with stirring at 500-600 RPM to get clear
solution.
5. Add 10kg of Azelaic acid into above DMSO solution with stirring at
500-600 RPM and heating up to 45°C -50°C to get clear solution.
6. Transfer above drug solution slowly into PVPK-90 polymer
10 solution under Homogenizer at 5000 RPM for 30 minute to get
nano dispersion.
7. Add slowly 1.5 kg of hydroxyethyl cellulose into above nano
dispersion with stirring at 500-600 RPM and heating up to 50°C
55°C for 1 hour to get uniform gel formation.
15 8. Add 1 kg of Glycerin into above gel formation with stirring at 500-
600 RPM for 30 minute.
9. Final weight makes up with purified water up to 100 kg with
stirring at 500-600 RPM for 15 minute.
10. Check the pH of final formulation.
20
The particles of the final formulation are analyzed and are found in nano-particle range.

We claim
1) A topical pharmaceutical formulation comprising Azelaic acid or its
pharmaceutical^ acceptable salts along with at least one pharmaceutical
excipient for the management of acne and related symptoms.
2) The formulation claimed in claim 1 contains the Azelaic acid in nano-particle form.
3) The formulation claimed in claim 1 contains the Azelaic acid in micro-particle form.
4) The concentration of azelaic acid formulation claimed in claim 1 may be 5% w/w to 25 % w/w, preferably between 10% w/w to 20% w/w.
5) The pharmaceutical excipients claimed in claim 1 may be selected from the group comprising solvent, chelating agent, polymer, surfactant, antioxidant, emollient, gel base, polymer and purified water or the combinations thereof.
6) A process for manufacture of the pharmaceutical formulation claimed in claim 1.
7) Process of manufacturing a formulation containing nano-particle as claimed in claim 2 as described below:

S. No. Material Name Label Claim UOM Quantity Required
1. Azelaic acid 10% w/w Kg 10.00
2. Benzoic acid 0.2% w/w Kg 0.20
3. Dimethyl sulphoxide - Ltr. 20.0
4. Disodium edetate - Kg 0.05
5. Polyvinyl pyrrolidone K- - Kg 10.0

90 ( PVPK-90)
6. Tween-80 - Kg 2.0
7. Sodium metabisulphite - Kg 0.20
8. Hydroxy ethyl cellulose - Kg 1.5
9. Glycerin - Kg 1.0
10. Purified Water - Kg q.s to 100 kg
a) Take 50.0 Kg of purified water in SS vessel and add 0.05 Kg of Disodium edetate and 0.2 Kg Sodium metabisulphite under stirring at 500-600 RPM to get clear solution.
b) Add 2.0 Kg of tween-80 into above solution with stirring at 500-600 RPM and heating up to 50.°C"55°Ctoget clear solution.
c) Add slowly 10.0 kg of PVPK-90 into above solution with stirring at 500-600 RPM and heating up to 50°C"55°C.
d) Take 20 Liter of Dimethyl sulphoxide (DMSO) in another SS vessel and; add 0.2 kg Benzoic acid with stirring at 500-600 RPM to get clear solution.
e) Add 10kg of Azelaic acid into above DMSO solution with stirring at 500-600 RPM and heating up to 45°C -50°C to get clear solution.
f) Transfer above drug solution slowly into PVPK-90 polymer solution under Homogenizer at 5000 RPM for 30 minute to get nano dispersion.
g) Add slowly 1.5 kg of hydroxyethyl cellulose into above nano dispersion with stirring at 500-600 RPM and heating up to 50°C'55°C for 1 hour to get uniform gel formation.

h) Add 1 kg of Glycerin into above gel formation with stirring at 500-600 RPM for 30 minute.
i) Final weight makes up with purified water up to 100 kg with stirring at 500-600 RPM for 15 minute.
j) Check the pH of final formulation.
8) Process of manufacturing a formulation containing micro-particle as claimed in claim 3 as described below:

S. No. Material Name Label Claim UOM Quantity Required
1. Azelaic acid 20% w/w Kg 20.00
2. Benzoic acid 0.2% w/w Kg 0.20
3. Dimethyl sulphoxide - Ltr. 20.0
4. ' Disodium edetate - Kg 0.05
5. Sodium metabisulphite - Kg 0.20
6. Hydroxy ethyl cellulose - Kg 2.0
7. Glycerin - Kg 1.0
8. Purified Water q.s Kg q.s to 100 kg
Process:
a) Take 50.0 Kg of purified water in SS vessel and add 0.05 Kg of Disodium edetate and 0.2 Kg Sodium metabisulphite under stirring at 500-600 RPM to get clear solution.

b) Add slowly 2.0 kg of Hydroxy ethyl cellulose into above solution with stirring at 500-600 RPM for 1 hour and further stirring for next 30 minute with heating up to 50°C"55°Cto get uniform gel formation.
c) Take 20 Liter of Dimethyl sulphoxide in another SS vessel and add 0.2 kg Benzoic acid with stirring at 500-600 RPM to get clear solution.
d) Add 20kg of Azelaic acid into above Dimethyl sulphoxide solution with stirring at 500-600 RPM and heating up to 45°C"50°C to get clear solution.
e) Transfer above drug solution into gel base with stirring at 500-600 RPM for 1 hour to get uniform gel formation.
f) Add 1 kg of Glycerin into above gel formation with stirring at 500-600 RPM for 30 minute.
g) Final weight makes up with purified water up to 100 kg with stirring at 500-
600 RPM for 15 minutes.