FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"TOPICAL FORMULATION CONTAINING SERTACONAZOLE NITRATE WITH HALOBETASOL PROPIONATE / ALCLOMETASONE
DIPROPIONATE"
2. APPLICANT:
(a) NAME: Lyka Labs Limited,
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri-Kurla Road,
Andheri (East), Mumbai - 400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed,

TECHNICAL FIELD OF INVENTION:
The present invention relates to a topical pharmaceutical formulation comprising therapeutically effective amount of antifungal drug such as Sertaconazole nitrate along with at least one synthetic corticosteroid selected from Halobetasol propionate or Alclometasone dipropionate, useful for controlling eczema and eradicating fungal infection. The invention further relates to the process for preparation thereof.
BACKGROUND OF THE INVENTION:
Sertaconazole nitrate is an antifungal medication of the imidazole class used topically in the form of cream, gel, solution or powder for the treatment of superficial candidiasis, dermatophytes is, seborrhoeic dermatitis, and pityriasis versicolor.
Chemically, Sertaconazole nitrate is l-{2-[(7-chloro-l-benzothiophen-3-yl)methoxy]-2-(2,4-dichIorophenyl)ethyl}-lH-imidazole. It has the following structural formula:

The most widely prescribed drugs to treat dermatological diseases are corticosteroids (glucocorticosteroids or glucocorticoids). These corticosteroids constitute a class of primarily synthetic steroids used topically as anti-inflammatory and antipruritic agents.
Halobetasol is a known synthetic corticosteroid for topical dermatological use. It is used to treat swelling, inflammation, and itching associated with skin conditions such as eczema, dermatitis, rashes, insect bites, poison ivy, and allergies. Halobetasol propionate reduces the swelling, itching and redness that can occur in these types of conditions.

Chemically, Halobetasol propionate is 21-chloro-6α, 9-difluoro-l lβ, 17-dihydroxy-16β-methylpregna-1, 4-diene-3-20-dione, 17-propionate, C25H31C1F2O5. It has the following structural formula:

Alclometasone dipropionate is a synthetic medium-strength glucocorticosteroid used for topical dermatological treatment such as eczema, dermatitis, allergies, and rash. Alclometasone dipropionate reduces the swelling, itching, and redness that can occur in these types of conditions.
Chemically, Alclometasone dipropionate is (7α-chloro-11β, 17, 21-trihydroxy-16α-methylpregna-l,4-diene-3,20-dione 17,21-dipropionate), C28H37CIO7. It has the following structural formula:

In clinical practice patients suffering from eczema, psoriasis or dermatitis have itching as a common symptom. Repeated itching and scratching of the skin leads to damage of the epidermis, a natural protective barrier which results into secondary fungal infections. Use of corticosteroid without anti-fungal drug not only delays therapeutic response but the immunosuppressive action of corticosteriod interferes in the body defense mechanism to tackle fungal infection.

Besides, those patients suffering from dermotophyte or Candida infection often get sensitized to fungal invasion and have secondary eczematous reaction. They are diagnosed as suffering from infective eczema. Thus, there is a need to control eczema and eradicate fungus in one topical formulation.
EP1698336 relates to topical formulations containing Sertaconazole such as Sertaconazole base, R-Sertaconazole base, Sertaconazole mononitrate and R-Sertaconazole mononitrate along with Hydrocortisone such as Hydrocortisone base, Hydrocortisone acetate, Hydrocortisone butyrate and Hydrocortisone valerate or an antibacterial agent, or a mixture thereof for treating dermal diseases caused by fungi and yeasts with inflammation and/or associated with a bacterial infection.
EP0471872 relates to a stable gel formulation for topical administration comprising (a) a therapeutically effective amount of a mixture of an imidazole antifungal agent and a 17-ester steroid anti-inflammatory agent, (b) a solvent system consisting essentially of a lower alkanol in combination with a dihydroxy alcohol or a trihydroxy alcohol or a mixture thereof and (c) an effective amount to cause gelling of hydroxypropyl cellulose or hydroxyethyl cellulose.
Lotrisone cream or lotion consisting of 1% Clotrimazole And 0.05% Betamethasone diproprionate was approved by FDA 20 years ago in topical cream or lotion formulation for treating superficial fungal infections.
Though there are prior arts having antifungal agent and corticosteroid in combination, none of them specifically evaluated the effect of using Sertaconazole nitrate along with Halobetasol propionate or Alclometasone dipropionate simultaneously. These drugs have entirely different modes of action and when combined in a single formulation, have synergistic effects which lead to more rapid clearing and are notably effective for controlling eczema and eradicating fungal infection which have not responded to the combination of Clotrimazole and Betamethasone diproprionate.
Therefore, present inventors have combined Sertaconazole broad spectrum antifungal drug with at least one synthetic corticosteroid selected from Halobetasol propionate or

Alclometasone dipropionate to avoid delay in therapeutic response of corticosteroid thereby preventing formation of secondary fungal infection.
SUMMARY OF THE INVENTION:
The present invention discloses a topical composition containing antifungal drug Sertaconazole nitrate along with at least one synthetic corticosteroid selected from Halobetasol propionate or Alclometasone dipropionate for the treatment of controlling eczema and eradicating fungal infection.
The present invention further discloses a process for preparation of said topical composition which is selected from cream, ointment, gel or lotion.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The term "topical" as employed herein relates to the use of the active ingredient incorporated in a suitable pharmaceutical carrier, and applied at the site of the disease for exertion of local action. The said also encompasses formulation such as cream, ointment, gel or lotion.
In accordance to the above objectives, the present invention provides the topical composition which comprises therapeutically effective amount of Sertaconazole nitrate with at least one synthetic corticosteroid along with pharmaceutically acceptable excipients.
The topical composition of the present invention is useful for effective treatment in controlling eczema and eradicating fungal infection such as superficial candidiasis, dermatophytosis, seborrhoeic dermatitis, pityriasis versicolor, swelling, inflammation,

and itching associated with skin conditions such as eczema, dermatitis, rashes, insect bites, poison ivy, and allergies.
In one of the preferred embodiment the topical pharmaceutical composition of the present invention comprises a combination of Sertaconazole nitrate and Halobetasol propionate, a synthetic corticosteroid, along with pharmaceutically acceptable exicipients.
in another preferred embodiment the topical pharmaceutical composition of the present invention comprises a combination of Sertaconazole nitrate and Alclometasone dipropionate, a synthetic corticosteroid, along with pharmaceutically acceptable exicipients.
In another embodiment, the topical formulation comprises Sertaconazole nitrate in an amount of 1-2.5 % w/w and Halobetasol propionate in an amount of 0.025-0.05 % vv/w along with the pharmaceutically acceptable exicipients.
In another embodiment the topical composition of present invention comprises Sertaconazole nitrate in an amount of 1-2.5 % w/w and Alclometasone dipropionate in an amount of 0.025-0.05 % w/w along with the pharmaceutical acceptable exicipients.
Accordingly, the topical cream/ointment formulation comprises Sertaconazole nitrate (1-2.5 % w/w) and Halobetasol propionate or Alclometasone dipropionate (0.025-0.05 % w/w) along with the pharmaceutically acceptable exicipients are selected from the group comprising of ointment/cream base like waxes, preservatives, antioxidants, buffering agent, chelating agent, penetration enhancer, surfactant, solubilizer, emulsifier and combinations thereof.
According to the embodiment, the topical cream of Sertaconazole nitrate (1-2.5 % w/w) and Halobetasol propionate or Alclometasone dipropionate (0.025-0.05 % w/w), comprises excipients selected from the group consisting of Cetostearyl alcohol, Cetomacrogol 1000, Light liquid paraffin White soft paraffin, Chlorocresol, Butylated Hydroxy Toluene, Propylene glycol, Disodium EDTA and Citric acid.

According to another embodiment, the ointment of Sertaconazole nitrate (1-2.5 % w/w) and Halobetasol propionate or Alclometasone dipropionate (0.025-0.05 % w/w) comprises excipients selected from the group consisting of Butylated hydroxy Toluene, Sorbitan Sesquioleate, Propylene glycol, Hexylene Glycol, White soft paraffin, White bees wax, Cetyl alcohol, Lanolin anhydrous and Liquid paraffin.
According to the invention, the topical composition of Sertaconazole nitrate with Halobetasol propionate or Alclometasone dipropionate is in the form of cream that can be prepared by mixing oil phase and water phase under stirring for the emulsion formation at 60-70°C, this is followed by adding preservatives, penetration enhancer, anti-oxidantant etc., followed by cooling till stable cream formation takes place. Active ingredient can be added before cream formation or while the cream formation is taking place.
According to the invention, the topical composition of Sertaconazole nitrate with Halobetasol propionate or Alclometasone dipropionate is in the form of ointment that can be prepared by melting ointment base excipients and mixing surfactant to ointment base, active ingredient is dissolved either in Propylene glycol or Hexylene Glycol and added under constant stirring, followed by adding solubilizer, surfactant etc.
In further embodiment, the topical gel/lotion formulation comprises Sertaconazole nitrate (1-2.5 % w/w) and Halobetasol propionate or Alclometasone dipropionate (0.025-0.05 % w/w) along with pharmaceutical excipients selected from the group comprising preservatives, antioxidants, buffering agent, chelating agent, penetration enhancer, co-solvent, Carbopol, pH adjuster along with vehicle, surfactant, solubilizer, and combinations thereof.
According to another preferred embodiment, the lotion of Sertaconazole nitrate (1-2.5 % w/w) and Halobetasol propionate or Alclometasone dipropionate (0.025-0.05 % w/w) comprises excipients selected from the group consisting of Cetyl alcohol, Sodium Lauryl Sulphate, Propylene glycol, White soft paraffin and Chlorocresol, Benzyl Alcohol, Polyethylene Glycol, Butylated Hydroxy Toluene.

According to another preferred embodiment, the gel of Sertaconazole nitrate and Halobetasol propionate or Alclometasone dipropionate comprises excipients selected from the group consisting of Carbopol 980, Carbopol 940; Hydroxy Propyl Cellulose, Disodium EDTA, Chlorocresol, Benzyl Alcohol, Ascorbic Acid, Propylene glycol, Citric acid, Sodium Citrate, Triethanolamine, Sodium Hydroxide, Diethanolamine, Purified Water and IPA
According to the invention, the topical composition of Sertaconazole nitrate with Halobetasol propionate or Alclometasone dipropionate is in the form of lotion that can be prepared by melting emulsifier, oil base and preservatives by heating at 70-80°C; mixing oil phase and water phase under stirring for the emulsion formation at 60-70°C, followed by adding preservatives, emulsifier, surfactants, solubilizer etc. for the stable lotion formation. Active ingredient can be added before emulsion formation or while the emulsion formation is taking place.
Alternately, lotion can be prepared by dissolving Halobetasol Propionate or Alclometasone Dipropionate in hot Propylene Glycol and dissolving Sertaconazole in Propylene glycol in separate beakers. Simultaneously, dissolving Butylated Hydroxy Toluene in PEG 400; and then adding all the solutions into one vessel followed by mixing, till clear solution is obtained.
According to the invention, the topical composition of Sertaconazole nitrate with Halobetasol propionate or Alclometasone dipropionate is in the form of gel that can be prepared by soaking carbopol 980 slurry in purified water overnight; dissolving chelating agent and buffering agent in sufficient quantity of purified water and adding to carbopol slurry. Active drugs can be dissolved in co-solvent such as Propylene Glycol and added to carbopol gel and mixed properly, followed by adding IPA, then adjusting pH with triethanolamine or Diethanolamine or sodium hydroxide solution. Other in actives can be added to product.
The invention is further illustrated by following non-limiting examples of this combination product:

EXAMPLES:
Example 1: Composition for the Preparation of Cream:
Table 1:

Ingredients Concentration wAv
Active Ingredients Sertaconazole nitrate 1-2.5%
Halobetasol propionate 0.025-0.05 %
Emulsifier Cetostearyl alcohol 2-10%
Cetomacrogol 1000 1 - 5%
Oil base Light liquid paraffin 2-8%
White soft paraffin 2-15%
Preservative Chlorocresol 0.05-0.15%
Antioxidant Butylated hydroxy toluene 0.01-0.025%
Penetration enhancer / Solubilizer Propylene glycol 5-25%
Chelating agent Disodium EDTA 0.005-0.2%
Buffering agent Citric acid 0.01-0.1%
Vehicle Purified water q.s.
Table 2:

Ingredients Concentration w/w
Active Ingredients Sertaconazole nitrate 1-2.5%
Alclometasone dipropionate 0.025-0.05 %
Emulsifier Cetostearyl alcohol 2-10%
Cetomacrogol 1000 1- 5%
Oil base Light liquid paraffin 2-8%
White soft paraffin 2-15%
Preservative Chlorocresol 0.05-0.15%
Antioxidant Butylated hydroxy toluene 0.01-0.025%
Penetration enhancer / Solubilizer Propylene glycol 5-25%

Chelating agent Disodium EDTA 0.005-0.2%
Buffering agent Citric acid 0.01-0.1%
Vehicle Purified water q.s.
Process for preparing Cream formulation is as follows:
1. Melting oil base excipients, emulsifier and antioxidant;
2. dissolving, chelating agent in sufficient quantity of purified water;
3. mixing oil phase and water phase under stirring for the emulsion formation at 60°-70°C;
4. dissolving active ingredients in Solubilizer and adding to bulk of step 3.
5. adding preservative to bulk of step 4 under stirring;
6. cooling and stirring of the bulk till cream formation takes place;
7. checking the pH and adjusting if required with buffering agent; and
8. adjusting the weight with purified water.
Example 2: Composition for the Preparation of Ointment:
Table 3:

Ingredients Concentration w/w
Active Ingredients Sertaconazole nitrate 1-2.5%
Halobetasol propionate 0.025-0.05 %
Surfactants Sorbitan sesquioleate 0.1-2.0%
Solubilizer Propylene glycol 5-15%
Ointment base White soft paraffin 80-95%
White bees wax 2-10%
Table 4:

Ingredients Concentration w/w
Active Ingredients Sertaconazole nitrate 1-2.5%
Alclometasone dipropionate 0.025-0.05 %
Surfactants Sorbitan sesquioleate 0.1-2.0%
Solubilizer Propylene glycol 5-15%
Hexylene glycol 5-15%

Ointment base White soft paraffin 80-95%
White bees wax 2-10%
Process for preparing Ointment formulation is as follows:
1. Melting ointment base excipients and mixing surfactant to ointment base;
2. adding active ingredients to bulk (melted ointment base) either by dissolving or dispersing in Solubilizer; and
3. cooling and stirring the bulk till ointment formation takes place.
Example 3: Composition for the Preparation of Lotion:
Table 5:

Ingredients Concentration w/v
Active Ingredients Sertaconazole nitrate 1-2.5%
Halobetasol propionate 0.025-0.05 %
Emulsifier Cetyl alcohol 1.5-2.5%
Surfactants Sodium lauryl sulphate 0.1-0.4%
Solubilizer Propylene glycol 5-15%
Oil base White soft paraffin 0.5-5%
Preservative Chlorocresol 0.05-0.15%
Methyl paraben 0.1-0.2%
Propyl paraben 0.01-0.05%
Vehicle Purified water q.s.
Table 6:

Ingredients Concentration w/v
Active Ingredients Sertaconazole nitrate 1-2.5%
Halobetasol propionate 0.025-0.05 %
Solubilizer PEG 400 40-75 %
Propylene glycol q.s
Antioxidant Butylated hydroxy toluene 0.01-0.025%

Table 7:

Ingredients Concentration w/v
Active Ingredients Sertaconazole nitrate 1-2.5%
Alclometasone dipropionate 0.025-0.05 %
Emulsifier Cetyl alcohol 1.5-2.5%
Surfactants Sodium lauryl sulphate 0.1-0.4%
Solubilizer Propylene glycol 5-15%
Oil base White soft paraffin 0.5 - 5%
Preservative Chlorocresol 0.05-0.15%
Methyl paraben 0.1-0.2%
Propyl paraben 0.01-0.05%
Vehicle Purified water q.s.
Table 8:

Ingredients Concentration w/v
Active Ingredients Sertaconazole nitrate 1-2.5%
Alclometasone dipropionate 0.025-0.05 %
Solubilizer PEG 400 40-75 %
Propylene glycol q.s
Antioxidant Butylated hydroxy toluene 0.01-0.025%
Process for preparing Lotion formulation is as follows:
1. Melting emulsifier, oil base and preservatives by heating at 70-80°C;
2. mixing oil phase and sufficient water phase under stirring for the emulsion formation at 60°-70°C;
3. dissolving or dispersing active ingredients in solubilizer;
4. adding active drug either before emulsion formation or during emulsion formation;
5. dissolving surfactant in sufficient purified water and then adding to bulk;
6. cooling and stirring the bulk till lotion formation takes place and then making up the volume.

Alternate process for preparing Lotion formulation is as follows:
1) Dissolving active ingredients separately in hot Propylene glycol;
2) dissolving antioxidant in PEG 400;
3) adding all the solutions into one vessel and mixing well till clear solution is obtained and making up the volume of the solution with propylene glycol or PEG 400.
Example 4: Composition for the Preparation of Gel: Table 9:

Ingredients Concentration w/w
Active Ingredients Sertaconazole nitrate 1-2.5%
Halobetasol propionate 0.025-0.05 %
Gelling Agent Carbomer 980, Carbomer 940 0.5-5%
Chelating Agent Disodium EDTA 0.005-0.2%
Preservative Chlorocresol 0.05-0.15%
Methyl paraben 0.1 -0.2%
Propyl paraben 0.01 -0.05%
Penetration enhancer, Solubilizer Propylene glycol 5 - 40%
Buffering agent Citric acid 0.01-0.1%
pH Adjustment Triethanolamine q.s.
Vehicle Purified Water, IPA q.s.
q.s.
Table 10:

Ingredients Concentration w/v
Active Ingredients Sertaconazole nitrate 1-2.5%
Alclometasone dipropionate 0.025-0.05 %
Gelling Agent Carbomer 980, Carbomer 940 0.5-5%
Chelating Agent Disodium EDTA 0.005-0.2%
Preservative Chlorocresol 0.05-0.15%
Methyl paraben 0.1-0.2%
Propyl paraben 0.01-0.05%

Penetration enhancer, Solubilizer Propylene glycol 5 - 40%
Buffering agent Citric acid 0.01-0.1%
pH Adjustment Triethanolamine q.s.
Vehicle Purified Water, IPA q.s. q.s.
Process for preparing Gel formulation is as follows:
1. Preparing Carbopol 980 slurry in sufficient quantity of purified water;
2. dissolving chelating agent and buffering agent in sufficient quantity of purified water and adding to carbopol slurry of step 1;
3. dissolving or dispersing active ingredients and preservative in Solubilizer and adding to bulk of step 2;
4. adding IPA to the bulk of step 3 under stirring;
5. checking the pH and adjusting pH with 20% pH adjusting agent about 4.0 to 6.0 till gel formation takes place;
6. adjusting the final weight with purified water and mixing well.
Overages of Sertaconazole nitrate and Halobetasol propionate or Alclometasone dipropionate can be added for the long term stability purpose.
STABILITY DATA:
Stability study of the product is carried out as per ICH guideline for 6 months at accelerated condition of 40°C / 75% RH and real time condition of 30°C / 65% RH. Product is stable.

We Claim,
1. A topical pharmaceutical composition comprising therapeutically effective amount of Sertaconazole nitrate with at least one synthetic corticosteroid along with pharmaceutically acceptable exicipients, useful for the treatment of controlling eczema and eradicating fungal infection.
2. The topical pharmaceutical composition as claimed in claim 1, wherein the composition comprises a combination of Sertaconazole nitrate and Halobetasol propionate, a synthetic corticosteroid, along with pharmaceutically acceptable exicipients.
3. The topical pharmaceutical composition as claimed in claim 1, wherein the composition comprises a combination of Sertaconazole nitrate and Alclometasone dipropionate, a synthetic corticosteroid, along with pharmaceutically acceptable exicipients.
4. The topical pharmaceutical composition as claimed in claim 1, wherein the Sertaconazole nitrate is present in an amount of 1-2.5%.
5. The topical pharmaceutical composition as claimed in claim 2, wherein the Halobetasol propionate is present in an amount of 0.025-0.05 %.
6. The topical pharmaceutical composition as claimed in claim 3, wherein the Alclometasone dipropionate is present in an amount of 0.025-0.05 %.
7. The topical pharmaceutical composition as claimed in claim 1. wherein the composition is selected from cream, ointment, gel or lotion.
8. The topical pharmaceutical composition as claimed in claim 7, wherein the cream formulation contains pharmaceutically acceptable excipients selected from the group consisting of Cetostearyl alcohol, Cetomacrogol 1000, Light liquid paraffin,

White soft paraffin, Chlorocresol, Butylated hydroxy toluene, Propylene glycol, Disodium EDTA and Citric acid.
9. The topical pharmaceutical composition as claimed in claim 7, wherein the ointment contains pharmaceutically acceptable excipients selected from the group consisting of Butylated hydroxy toluene, Sorbitan sesquioleate, Propylene glycol, Hexylene glycol, White soft paraffin, White bees wax, Cetyl alcohol, Lanolin anhydrous and Liquid paraffin.
10. The topical pharmaceutical composition as claimed in claim 7, wherein the gel formulation contains pharmaceutically acceptable excipients selected from the group consisting of Carbopol 980, Carbopol 940, Hydroxy propyl cellulose, Disodium EDTA, Chlorocresol, Benzyl alcohol, Ascorbic acid, Propylene glycol, Citric acid, Sodium citrate, Triethanolamine, Sodium hydroxide. Diethanolamine, Purified water and IPA.
11. The topical pharmaceutical composition as claimed in claim 7, wherein the lotion contains pharmaceutically acceptable excipients selected from the group consisting of Cetyl alcohol, Sodium lauryl sulphate, Propylene glycol, White soft paraffin and Chlorocresol, Benzyl alcohol, Polyethylene glycol, Butylated hydroxy toluene.
12. The topical pharmaceutical composition as claimed in any one of the claims 1 to 7, wherein the cream formulation is prepared by,

a) Melting oil base excipients, emulsifier and antioxidant;
b) dissolving, chelating agent in sufficient quantity of purified water;
c) mixing oil phase and water phase under stirring for the emulsion formation at 60°-70°C;
d) dissolving active ingredients in Solubilizer and adding to bulk of step (c).
e) adding preservative to bulk of step (d) under stirring;
f) cooling and stirring of the bulk till cream formation takes place;
g) checking the pH and adjusting if required with buffering agent; and
h) adjusting the weight with purified water.

13. The topical pharmaceutical composition as claimed in any one of the claims 1 to
7, wherein the ointment is prepared by,
a) Melting ointment base excipients and mixing surfactant to ointment base;
b) adding active ingredients to bulk (melted ointment base) either by dissolving or dispersing in Solubilizer; and
c) cooling and stirring the bulk till ointment formation takes place.
14. The topical pharmaceutical composition as claimed in any one of the claims 1 to
7, wherein the gel formulation is prepared by,
a) Preparing Carbopol 980 slurry in sufficient quantity of purified water;
b) dissolving chelating agent and buffering agent in sufficient quantity of purified water and adding to carbopol slurry of step (a);
c) dissolving or dispersing active ingredients and preservative in Solubilizer and adding to bulk of step (b);
d) adding IPA to the bulk of step (c) under stirring;
e) checking the pH and adjusting pH with 20% pH adjusting agent about 4.0 to 6.0 till gel formation takes place;
f) adjusting the final weight with purified water and mixing well.
15. The topical pharmaceutical composition as claimed in any one of the claims 1 to
7, wherein the lotion is prepared by,
a) Melting emulsifier, oil base and preservatives by heating at 70-80°C;
b) mixing oil phase and sufficient water phase under stirring for the emulsion formation at 60°-70°C;
c) dissolving or dispersing active ingredients in solubilizer;
d) adding active drug either before emulsion formation or during emulsion formation;
e) dissolving surfactant in sufficient purified water and then adding to bulk;
f) cooling and stirring the bulk till lotion formation takes place and then making up the volume.

16. The topical pharmaceutical composition as claimed in any one of the claims I to 7, wherein the lotion is alternately prepared by,
a) Dissolving active ingredients separately in hot Propylene glycol;
b) dissolving antioxidant in PEG 400;
c) adding all the solutions into one vessel and mixing well till clear solution is obtained and making up the volume of the solution with propylene glycol or PEG 400.