FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
Provisional Specification
(See section 10 and rule 13)
A novel gel and the process for making the same.
Apex Laboratories Private Limited
SIDCO Garment Complex, III Floor, Guindy, Chennai-600 032, Tamil Nadu
State, India
An Indian company registered under the Companies Act, 1956

The following specification describes the invention:
356 MUM 2009
1 8 FEB 2009

A NOVEL GEL AND THE PROCESS FOR MAKING THE SAME
BACKGROUND OF THE INVENTION:
The skin is the body's first barrier against bacteria that cause infections. Bacterial skin infections can affect a small spot or may spread, affecting a large area. They can range from a treatable infection to a life threatening skin condition. Common skin infections include cellulitis, erysipelas, impetigo, folliculitis and furuncles & carbuncles. Cellulitis is an infection of the dermis and subcutaneous tissue that has poorly demarcated borders and is usually caused by Streptococcus or Staphylococcus species. Erysipelas is a superficial form of cellulitis with sharply demarcated borders and is caused almost exclusively by Streptococcus. Impetigo is also caused by Streptococcus or Staphylococcus and can lead to lifting of the stratum corneum resulting in the commonly seen bullous effect. Folliculitis is an inflammation of the hair follicles. When the infection is bacterial rather than mechanical in nature, it is most commonly caused by Staphylococcus. If infection of the follicle is deeper and involves more follicles, it moves into the fliruncle & carbuncle stages and usually requires incision and drainage. All of these infections are typically diagnosed by clinical presentation and treated empirically.
Numerous treatments both topical and systemic are currently employed for the
treatment of primary and secondary skin infection caused by sensitive Gram +ve
organisms such as Staphylococcus aureus. Streptococcus spp etc. Topical and
systemic bacterial infection treatment compositions typically employ an active
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ingredient in combination with a base component. The active ingredients typically comprise an antibiotic/antibacterial such as Sodium Fusidate, and the like.
Primary Infections:
Three forms of impetigo are recognized on the basis of clinical, bacteriologic, and histologic findings. The lesions of common or superficial impetigo may contain group A -hemolytic Streptococci, S aureus or both, and controversy exists about which of these organisms is the primary pathogen. The lesions have a thick, adherent, recurrent, dirty yellow crust with an erythematous margin. This form of impetigo is the most common skin infection in children. Impetigo in infants is highly contagious and requires prompt treatment.
The lesions in bullous (staphylococcal) impetigo, which are always caused by S.aureus are superficial, thin-walled, and bullous. When a lesion ruptures, a thin, transparent, varnish like crust appears which can be distinguished from the stuck on crust of common impetigo. This distinctive appearance of bullous impetigo results from the local action of the epidermolytic toxin.
Ecthyma is a deeper form of impetigo. Lesions usually occur on the legs and other
areas of the body that are generally covered, and they often occur as a
complication of debility and infestation. The ulcers have a punched out
appearance when the crust or purulent materials are removed. The lesions heal
slowly and leave scars.
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Streptococcus pyogenes is the most common agent of cellulitis, a diffuse inflammation of loose connective tissue, particularly subcutaneous tissue. No absolute distinction can be made between streptococcal cellulitis and erysipelas. Clinically, erysipelas is more superficial, with a sharp margin as opposed to undefined border of cellulitis.
Folliculitis can be divided into two major categories on the basis of histologic location: Superficial and deep. The most superficial form of skin infection is Staphylococcal folliculitis manifested by minute erythematous follicular pustules without involvement of the surrounding skin. In deep folliculitis, infection extends deeply into the follicle and the resulting perifolliculitis causes a more marked inflammatory response than that seen in superficial folliculitis. In sycosis barbae (barber's itch), the primary lesion is a follicular pustule pierced by a hair. Bearded man may be more prone to this infection than shaven men.
A furuncle (boil) is a staphylococcal infection of a follicle with involvement of subcutaneous tissue. The preferred site of furuncles are the hairy parts or areas that are exposed to friction and macerations. A carbuncle is a confluence of boils, a large indurated painful lesion with multiple draining sites.
Erysipeloid, a benign infection that occurs most often in fishermen and meat
handlers is characterized by redness of the skin (usually on finger or the back of
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hand), which persists for several days. The infection is caused by Erysipelothrix rhusiopathiae.
Pitted keratolysis is a superficial infection of the plantar surface, producing a punched out appearance. The areas most often infected are the heels, the ball of the foot, the volarpads and the toes. Humidity and high temperature are frequent aggravating factors. Gram + ve Coryneform bacteria have been isolated from the lesions.
Erythrasma is a chronic, superficial infection of the pubis, toe web, groin axilla and inflammatory folds. Corynebacterium minutissimum is responsible for this.
Trichomycosis involves the hair in the axillary and pubic regions and is characterized by development of nodules of varying consistency and colour. Coryne forms bacteria are associated with trichomycosis.
Secondary Infections:
Intertrigo is most commonly seen in chubby infants or obese adults. In the skin fold, heat, moisture and rubbing produce erythema, maceration or even erosions.
Acute infections eczematoid dermatitis arises from a primary lesion such as boil or a draining ear or nose, which are sources of infectious exudates.
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Pseudofolliculitis of the beard, a common disorder, occurs most often in the beard area of people who shave.
Ulcers are deep skin infections due to injury or disease that invade the subcutaneous tissue and on healing leave scars. Ulcers can be divided into primary and secondary ulcers, but all become secondarily infected with bacteria.
Some of the more commonly used active compounds found in topical primary and secondary bacterial skin infections treatment formulations include topical Sodium Fusidate, and the like.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to a composition for treating primary and secondary bacterial skin infections containing
(a) An active ingredient used in treating primary and secondary bacterial skin infections.
(b) A gel base containing Natural or Semisynthetic or Synthetic Polymers, co-solvents, acids, and preservatives, buffering agents, anti oxidants, chelating agents, humectants.
(c) Water
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The present invention is also directed to an innovative process of in-situ conversion of a salt into an acid. The process uses Sodium Fusidate as starting material which is dissolved in a co-solvent system. By addition of an acid, while stirring at controlled speed and using nitrogen-purging tehniques and under vacuum, Fusidic acid is regenerated. The regeneration process carried out in an entirely oxygen-free environment. The regenerated active ingredients are incorporated in gel base for use in treating primary and secondary skin infections caused by sensitive strains of Staphylococcus aureus, Streptococcus spp and Corynebacterium minutissimum on human skin involving contacting human skin with the above identified composition.
DETAILED DESCRIPTION OF THE INVENTION
Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients are understood as being modified in all instances by the term "about".
The active compounds which may be employed in the present invention are either acid based actives or their salts well known in the art of bacterial primary and secondary treatment. Examples of suitable acid-based actives or their salts which may be used include, but are not limited to Sodium Fusidate.
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These acid based active compounds or their salts require a base component to be used in the pharmaceutical composition that uses the compounds, since the compounds cannot, by themselves, be deposited directly on to human skin due to their harshness.
The base component usually contains Natural or Semisynthetic or Synthetic Polymers, co-solvents, acids, and preservatives, buffering agents, anti oxidants, chelating agents, humectants and the like.
Most of the topical products are formulated as creams, ointments, or gels. A cream is a topical preparation used for application on the skin. Creams are semi¬solid emulsions which are mixtures of oil and water in which APIs (Active Pharmaceutical Ingredients) are incorporated. They are divided into two types: oil-in-water (OAV) creams which compose of small droplets of oil dispersed in a continuous water phase, and water-in-oil (W/O) creams which compose of small droplets of water dispersed in a continuous oily phase. Oil-in-water creams are user-friendly and hence cosmetically acceptable as they are less greasy and more easily washed with water. An ointment is a viscous semisolid preparation containing APIs which are used topically on a variety of body surfaces. The vehicle of an ointment is known as ointment base. The choice of a base depends upon the clinical indication of the ointment, and the different types of ointment bases normally used are:
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• Hydrocarbon bases, e.g. hard paraffin, soft paraffin
• Absorption bases, e.g. wool fat, bees wax
Both above bases are oily and greasy in nature and this leads to the undesired effects like difficulty in applying & removal from the skin. In addition this also leads to staining of the clothes-Gels are semisolid systems in which a liquid phase is constrained within a three dimensional polymeric matrix in which a high degree of physical cross-linking has been introduced. The polymers used to prepare pharmaceutical gels include the natural gums tragacanth, pectin, carrageen, agar, and alginic acid and such synthetic and semi-synthetic materials as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and the carbopols, which are synthetic vinyl polymers with ionisable carboxy groups. Gels are generally clear transparent to opaque in nature semisolids. Gels may be single phase or two phase system based on the particle size of the dispersed system. Gels may also be classified as hydrophobic or hydrophilic gels. In hydrophobic gels the bases usually consist of liquid paraffin with polyethylene or fatty oils gelled with colloidal silica or aluminium or zinc soaps. In hydrophilic gels the bases usually consist of water, glycerol, or propylene glycol gelled with suitable gelling agents such as tragacanth, starch, cellulose derivatives, carboxy vinyl polymers, and magnesium silicates. Single phase hydrophilic gels are being used more frequently in pharmacy and cosmetics because of several properties
which include semi-solid state, high degree of clarity, ease of application, ease of
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removal and use. The gels often provide a faster release of drug substance, independent of water solubility of the drug, as compared to creams and ointments.
Fusidic Acid is an antibiotic derived from fermentation of Fusidium coccineum. Fusidic Acid is available as Fusidic Acid cream or Sodium Fusidate Ointment worldwide. Fusidic Acid is highly unstable and prone for oxidation. In the currently available Fusidic Acid creams, Fusidic Acid in powder form is used as a microfine particle in the size range 5 to 20 microns. This enhances its dermal contact (large specific surface area) and penetration and provides a smooth feel on application to skin. However, a serious shortcoming/limitations of the micro size of Fusidic Acid particles is that it presents an enormous surface area for contact and reactions with molecular Oxygen during manufacture handling and processing of the cream, thereby leading to major concern on chemical instability and rapid fall in potency of the active compound in the cream formulation.
Oxidative degradation is a major cause of drug instability. The deterioration in the fusidic acid samples exposed to oxygen ranged between 2% to 8.5% for conditions ranging from room temperature to 45 °C. The deterioration values for Sodium Fusidate for similar conditions ranged between 0% to 2%.
Stabilization of drugs against oxidation involves observing a number of precautions during manufacture and storage. The Oxygen in pharmaceutical containers should be replaced with inert gases such as Nitrogen, Carbon dioxide,
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Helium and the like; contact of the drug with heavy metal ions which catalyze oxidation should be avoided and storage should be at reduced temperatures. Because of its inherent nature to be prone for oxidation, Fusidic Acid is to be stored at 2°C to 8°C in a tight container. This makes the material Fusidic Acid difficult to handle; as manufacturing involves dispensing, handling, processing & storage. As the exposure time of the material to Oxygen is more, it is difficult to stabilize Fusidic Acid as such in a formulation. The inventor has come out with an innovative and insightful process of making a gel with Sodium Fusidate as the active compound and by in-situ conversion the Sodium Fusidate is converted into Fusidic Acid in a totally oxygen free environment. The Fusidic Acid thus obtained is stabilized Fusidic Acid is used in the treatment of bacterial skin infections.
Fusidic Acid, as mentioned above is very unstable in powder form since it is prone for oxidation and therefore difficult to handle during manufacturing process. On the other hand Sodium Fusidate, with a pH of around 7.5 to 9, is very stable compared to Fusidic Acid as an Active Pharmaceutical Ingredient (API). Through an innovative approach, the inventor has worked out a process where in Sodium Fusidate equivalent to Fusidic Acid was used as the starting input material and converted to Fusidic Acid in-situ by adding an acid, the resultant regenerated active "Fusidic Acid" was incorporated into the gel base containing Natural or Semisynthetic or Synthetic Polymers co-solvents, preservatives and buffering agents, acids, anti oxidants, chelating agents, humectants. The process uses Sodium Fusidate as a starting material and converts it in situ into Fusidic acid
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under controlled oxygen-free environment using inert gases such as Nitrogen, Carbon dioxide, Helium and like & and under vacuum.
The acidic scale of pH is from 1 to 7, and the base scale of pH is from 7 to 14. Human skins pH value is some where between 4.5 and 6. Newborn baby's skin pH is closer to neutral (pH 7), but it quickly turns acidic. Nature has designed this probably to protect young children's skin, since acidity kills bacteria. As people become older, the skin becomes more and more neutral, and won't kill as many bacteria as before. This is why the skin gets weak and starts having problems. The pH value goes beyond 6 when a person actually has a skin problem or skin disease. This shows that it is necessary to choose topical that have a pH value close to that of skin of a young adult
A slight shift towards the alkaline pH would provide a better environment for microorganisms to thrive. Most of the topical products are available as gels. Active compounds in gel formulations are available in ionized state, whereas in case of ointments these are present in non -ionized state. Generally, the gel formulations are the first choice of the formulators in design and development of topical dosage forms, as the gel formulations are cosmetically elegant, and also as the active compound is available in ionized state, and the drug can penetrate the skin layer fast which makes the formulation totally patient friendly.
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The pH of the Sodium Fusidate gel of the present invention is from about 3 to 6. On the other hand, Sodium Fusidate ointments that are commercially available are greasy and cosmetically non elegant. Furthermore, as the active compound in an ointment is in non ionized form, the penetration of skin is slow.
Sodium Fusidate due to the inherent alkalinity of the API (pH 7.5 to 9.0) is always formulated in greasy base, there by suppressing its harmful alkaline reactions during dermal applications. In the case of conventional ointments containing Sodium Fusidate although the alkaline nature is camouflaged through suppression of ionisation in the non-polar base, they could nevertheless present a non-optimum pH profile in the skin microenvironment. This is due to the presence of skin moisture from different layers such as stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, stratum corneum which will manifest the unfavourable alkaline pH profile of the active.
The inventor has screened different co-solvents such as Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol-400 and the like & dissolved the Sodium Fusidate in one of above co-solvents varying from about 5% (w/w) to 50% (w/w) under inert gas purging and under vacuum and converted to in-situ Fusidic Acid by adding an acid such as HCl, H2SO4, HNO3, Lactic acid and the like from about 0.005% (w/w) to about 0.5% (w/w) under stirring and obtained Fusidic Acid in more stabilized and solution form, which makes our final product in a gel base
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which easily penetrates the skin and highly efficacious, and also highly derma compatible by having a pH of about 3.0 to about 6.0.
According to the preferred embodiment of the present invention, there is provided a composition for the topical treatment of bacterial skin infections on human skin, the composition comprising
- from about 0.1% (w/w) to about 25% (w/w) by weight, preferably from about
0.5% to about 5% by weight and most preferably from about 1% (w/w) to 2%
(w/w) by weight, of an acid form active compound, preferably sodium
fusidate and.
a gel base containing Natural or Semisynthetic or Synthetic Polymers, co-
solvents, acids, and buffering agents preservatives, anti oxidants, chelating
agents, humectants, water, all weights based on the weight of the composition,
wherein
- Natural polymers are selected from tragacanth, pectin, carrageen, agar, and alginic acid and Synthetic & semi-synthetic polymers are selected from methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethyIcellulose and carbopols and the like from about 0.5% (w/w) to 10% (w/w),
- co-solvents are selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 and the like from about 5%
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(w/w) to 50% (w/w), acids such as HC1, H2So4, HNO3, Lactic acid and the like from about 0.005% (w/w) to 0.5% (w/w),
- preservatives are selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like from about 0.05% (w/w) to 0.5% (w/w),
- buffering agents are selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.05% (w/w) to 1.00% (w/w),
- anti oxidants are selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like from about 0.05% (w/w) to 5% (w/w),
- chelating agents are selected from a group comprising Disodium EDTA and the like from about 0.05% (w/w) to 1% (w/w),
- humectants are selected from a group comprising Glycerin, Sorbitol, and the like from about 5% (w/w) to 20% (w/w).
According to another preferred embodiment of the present invention, the composition of the present invention comprises:
a) 40 to 60 percent Purified Water; preferably 56.7%
b) 1 to 2.5 percent Sodium Fusidate; preferably 2.18%
c) 1 to 5 percent Polymer; preferably 1.25 percent Carbomer 934P
d) 0.1 to 5 percent Alkalizing agent; preferably 0.4 percent Triethanolamine
e) 5 to 50 percent Propylene Glycol; preferably 35 percent Propylene Glycol
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f) 0.05 to 0.5 percent Preservative ; preferably 0.2 percent Benzoic Acid
g) 0.01 to 0.1 percent Antioxidant; preferably 0.01 Butylated Hydroxy Toluene h) 0.01 to 1 percent Chelating Agent; preferably 0.01 percent Disodium Edetate i) 0.005 to 0.5 percent Acid, preferably 4 percent 1 Molar HNO3 Solution
The therapeutic efficacy of topically applied innovative Sodium Fusidate gel is due to partly to the pronounced antibacterial activity of the regenerated Fusidic Acid against the organisms responsible for skin infections and partly to the unique ability of this regenerated antibiotic to penetrate intact skin because of the ultra micro-size and colloidal form of the active.
According to another embodiment of the present invention, there is also provided a process for treating primary and secondary bacterial skin infections involving contacting human skin with the above-disclosed composition.
According to yet another embodiment of the present invention, a process to manufacture the Sodium Fusidate gel of the present invention is provided.
Details of the process of manufacturing the sodium fusidate gel:
The novel Sodium, Fusidate gel formulation of the present invention is made by
modifying the standard procedure of manufacturing pharmaceutical gels. All
ingredients are mixed thoroughly at ambient or elevated temperature.
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Sodium Fusidate is dissolved in propylene glycol under oxygen free 100% pure nitrogen flushing and added to the bulk gel formed. The ingredients are thoroughly mixed so that the product is homogeneous.
Processing equipments suitable for preparing the gel are known in the art and include mixers, homogenizers, stirrers and the like.
The gel of the present invention has a pH range from 3.0 to 6 and viscosity from 10,000 to 100,000 CPS. pH was measured at 25 deg C using Cyber scan 510 pH meter. Viscosity was measured at 25 deg C using a Brookfield viscometer with Spindle 4 at 6 RPM.
One of the novel aspects of the process of the present invention is the selection of the API of required quality. It is a well known fact that the API in the form of fusidic acid currently available for use in preparation of fusidic acid cream is unstable when exposed to oxygen or atmosphere during the in general. Pharmaceutical products made from fusidic acid suffer from this drawback in that any exposure of fusidic acid to oxygen environment during the transport and manufacturing process will lead to degradation of the API. There is a need to minimize the degradation of the API used for manufacture of creams containing fusidic acid. The British Pharmacopia recommends that both fusidic acid and sodium fusidate are to be stored at a temperature between 2 to 8 °C. Although
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some degradation is expected of both substances when exposed to oxygen environment, it has been observed that sodium fusidate is much more stable than fusidic acid under the same conditions (see Tables 1 and 2).
The inventors have found that sodium fusidate, rather than fusidic acid, is used as the starting raw material the API in the finished product is of a superior quality than the API is the fusidic acid creams that are currently available.
The inventor has also found that the current methods of testing the quality of the starting raw ingredient of the API, namely the titration method, provide inaccurate or misleading results. For example the API degradation observed by the titration method suggests that the API is stable than it actually is (as indicated by the % degradation figure), in the case of both fusidic acid assays as well as the Sodium Fusidate assays.
The HPLC method designed by the inventors to test the stability of the API allows superior control over quality of API selected and in turn the quality of the end product.
In our present invention Sodium Fusidate API is analyzed by stability indicating, in-house developed HPLC method vis-a-vis titration method as per British Pharmacopoeia. The titration method is not stability indicating where as our in-house developed HPLC method is stability indicating .The Sodium Fusidate is
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used only if it complies with British Pharmacopoeia assay requirements of not less than 97.5% -101.0%.
Tables 1 and 2 show the comparison between the stability of the fusidic acid and sodium fusidate. A study was carried out to show the stability indicating nature of in-house developed HPLC method vis-a-vis the Titration method of British Pharmacopoeia for testing Fusidic Acid API / Sodium Fusidate API.
A. Fusidic Acid:
Name of the Sample: FUSIDIC ACID BP Manufactured by : Ercros, Spain
Lot Number : FS 228 Manufactured date : 08.07.2008
Date of Receipt : 07.08.2008 Expiry date : 06.01.2011
Pack : Open & Closed Petri dish

S.No Conditions ♦Initial (%) Fusidic Acid Assay
(%) Percentage Drop (%) Remarks

Titration HPLC Titration HPLC API
analysed
After 3
Months
1 RT (Open) 100.6 . 99.21 92.93 1.39 7.67

2 RT (Closed)
99.02 94.37 1.58 6.23

3 45°C (Open)
98.52 89.52 2.08 11.08

4 45°C (Closed)
99.10 92.12 1.50 8.48

Table 1: Results of 3 Months Old Fusidic Acid (APD Analysis by Stability

Indicating HPLC Method and Titration Method


B. Sodium Fusidate:
Name of the Sample : Sodium Fusidate Bp Manufactured by : Ercros, Spain
Lot Number : FST 208 Manufactured date: 25.04.2008
Date of Receipt : 07.08.2008 Expiry date : 24.10.2010
Pack : Open & Closed Petri dish

S.No Conditions ♦Initial (%) Sodium Fusidate Assay(%) Percentage (%) Remarks

Titration HPLC Titration HPL C API
analysed
After 3
Months
I RT (Open) 98.7 97.71 96.25 0.99 2.45

2 RT (Closed)
98.85 97.67 -0.15 1.03

3 45°C (Open)
97.07 92.65 1.63 6.05

4 45°C (Closed)
97.16 92.96 1.54 5.74

Table 2: Results of 3 Months Old Sodium Fusidate (API) Analysis bv Stabilitv Indicating HPLC Method and Titration Method
In both studies the * Initial denotes the results of the samples tested at the time of receipt of the API from the supplier.
It can be seen from the above tables that:
In Fusidic Acid, there is about 7.67% loss in 3 Months at room
temperature condition (Open) and about 11.08% loss in 3 Months at 45°C condition (Open).
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> Meanwhile in Sodium Fusidate, there is about 2.45% loss in 3 Months at room temperature condition (Open) and about 6.05% loss in 3 Months at 45°C condition (Open).
> The above 3 Months data indicates how the in-house developed HPLC method is stability indicating vis-a-vis the non-stability indicating nature of Titration method (BP method) and better stability of Sodium Fusidate API over Fusidic acid API.
Details of the process of manufacturing the novel sodium fusidate gel:
A process of making the composition of the present invention is now disclosed. The process comprises the steps of:
1. Heating a part of Purified Water in a mixing vessel to 55 ° C +/- 5 ° C.
2. Adding a part of Propylene Glycol to the mixing vessel and thoroughly mixing using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 55 °C +/- 5 °C.
3. Adding a polymer, preferably 1 to 5 percent, more preferably 1.25 percent Carbomer 934 P to the mixing vessel and thoroughly mixing using an agitator at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM .and under vacuum of-1000 to -300 mm of Hg.
4. Cooling the mixture in the mixing vessel to 40 ° C preferably by circulating cold water (8 to 15 ° C) from cooling tower in the jacket of the
mixing vessel.
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5. In an API vessel adding a part of Propylene Glycol, preferably 5 to 50 percent, more preferably 25 percent Propylene Glycol and subjecting the contents to nitrogen gas flushing and adding Sodium Fusidate to the mixture and dissolving it.
6. Adjusting the pH of the mixture in the API vessel to below 2 by adding acid, preferably 0.005 to 0.5 percent, more preferably 4 percent 1 Molar Nitric acid solution.
7. Transferring the contents of the API vessel to the mixing vessel of step 4 with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under Nitrogen gas flushing and under vacuum of
-1000 to-300 mm of Hg.
8. Cooling the contents of the mixing vessel of step 7 to 30 ° C to 35 ° C using circulation of chilled water from cooling tower at 8 deg C to 15 deg C into the jacket of mixing vessel.
9. In a separate vessel adding another part of Propylene Glycol, preferably 5 to 50 percent, more preferably 5 percent Propylene Glycol and dissolving preferably 0.01 to 0.1 percent Antioxidant, more preferably 0.01 Butylated Hydroxy Toluene. Adding this mixture into the mixing vessel of step 8 with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under Nitrogen gas flushing and under vacuum of-1000 to-300 mm of Hg.
10. In a separate vessel adding part of purified water and dissolving 0.05 to
0.5 percent preservative, more preferably 0.2 percent Benzoic Acid, and
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Benzoic Acid and 0.01 to 1 percent Chelating Agent, more preferably 0.01 percent Disodium Edetate by mixing. Adding this mixture into the mixing vessel of step 9 with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under Nitrogen gas flushing and under vacuum of-1000 to -300 mm of Hg.
11. Adjusted the pH of the contents in mixing vessel of step 10 between 3.5
and 6.0 by. adding preferably 0.1 to 5 percent Alkalizing agent, more
preferably 0.4 percent Triethanolamine and mixing at 10 to 50 RPM under
Nitrogen gas flushing and under vacuum of—1000 to -300 mm of Hg.
12. Turning off the agitator and removing the contents of the Mixing vessel of
step 11 to a storage container.
The composition of the final gel obtained from the above described process is given in the Table 3 below.

S.No Ingredients Specification Quantity
For 350 Kg UOM Percentage
1 Sodium Fusidate BP 7.650 Kg 2.18%
2 Carbopol 934 P IP 5.250 Kg 1.25%
3 Triethanolamine IP 1.4 Kg 0.4%
4 Propylene Glycol IP 122.500 Kg 35%
5 Benzoic Acid IP 0.700 Kg 0.2%
6 Butylated Hydroxy Toluene IP 0.035 Kg 0.01%
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7 Disodium edetate IP 0.035 Kg 0.01%
8 1 M Nitric Acid Solution IP 14.000 Lit 4.0%
9 Purified Water IP 198.450 Kg 56.7%
Total 350.00 Kg
Table 3: Sodium Fusidate Gel composition
Dated this 18th February 2009

(Tase, Vijay Sharatchandra)
Patent Agent for the Applicant Registration Number IN/PA 987
To,
The Controller of Patents
The Patent Office, Mumbai Branch
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