FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
Provisional Specification
(See section 10 and rule13)
A Novel Cream And A Process To Manufacture 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:.


A Novel Cream And A Process To Manufacture 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 furuncle & carbuncle stages and usually requires incision and drainage. All of these infections are typically diagnosed by clinical presentation and treated empirically.
Dermatological conditions are often caused by allergy accompanied by inflammation, irritation and itching. They are further complicated by bacterial infections.
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 and skin inflammations. Topical and systemic bacterial infection inflammatory treatment compositions typically employ an active ingredient in combination with a base component. The active ingredients typically comprise an antibiotic/antibacterial

such as Sodium Fusidate, and the like and Corticosteroids such as Fluticasone propionate, and 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 (b-hemoltic 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.
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 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.
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.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to a composition for treating primary and secondary bacterial skin infections & skin inflammations containing
(a) Active ingredients used in treating primary and secondary bacterial skin infections & skin inflammations
(b) A cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, and preservatives, buffering agents, anti oxidants, chelating agents, humectants.
(c) Water
5

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 techniques and under vacuum, no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary.
Fusidic acid is regenerated. The regeneration process carried out in an entirely oxygen-free environment. The regenerated active ingredients are incorporated in cream base containing corticosteroids for use in treating primary and secondary skin infections caused by sensitive strains of Staphylococcus aureus, Streptococcus spp and Corynebacterium minutissimum and skin inflammations 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.
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 primary and secondary emulsifiers, waxy materials, co-solvents, acids, and preservatives, buffering agents, anti oxidants, chelating agents, humectants and the like.
Most of the topical products are formulated as either creams or ointments. 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 (O/W) 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:
• 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. Most of the topical products are available as cream formulation because of its cosmetic appeal.
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 provide 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.
Stability of Actives: Though both the actives Sodium Fusidate & Fusidic Acid are to be stored at 2-8°C throughout their bulk storage, transport, handling during use. It is a known fact in reality that there could be major excursions from these very stringent 2-8°C storage stipulations. In vast majority of zones temperature can vary from 15°C - 45° C during different periods/ time/location and power breakdown which are indeed a reality in common all over the world. With such a possibility the innovator studied the excursion of such temperature variation on the stability of the actives.
In a 3 months study with periodic testing by stability indicating analytical HPLC method the innovator found Fusidic Acid to be more unstable as compared to Sodium Fusidate (Refer: Table 1 & 2). In fact Sodium Fusidate at ambient excursions (30°C) during these periods complied with all the monograph specifications where Fusidic Acid was found to be Non compliant with regard to assay of actives. This raises serious concerns with regard to bulk stability of Fusidic Acid prior to its use in creams and use of Sodium Fusidate provides a significantly high level of confidence from the stability angle. This is another noteworthy feature on which the foundation of innovation rests.
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,

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 cream 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 cream base containing primary and secondary emulsifiers, waxy materials, 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 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 topicals that have a pH value close to that of skin of an 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 creams. Active compounds in cream formulations are available in ionized state, whereas in case of ointments these are present in non -ionized state. Generally, the cream formulations are the first choice of the formulators in design and development of topical dosage forms, as the cream 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.
The pH of the Sodium Fusidate cream with Fluticasone propionate 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.

It is essential that the active drug penetrates the skin for the optimum bio-dermal efficacy. The particle size of the active drug plays an important role here. It is necessary that the active drug is available in colloidal or molecular dispersed state for the product being highly efficacious form. Also this is to be achieved in the safe pH compatible environment of skin (4.0 to 6.0). To achieve all these, it is essential to choose proper vehicles or co-solvents for the dissolution or dispersion of the drug. The product of the present invention is highly efficacious due to the pronounced antibacterial activity of the regenerated Fusidic Acid which is available in ultra micro-size, colloidal form, which enhances skin penetration.
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 20% (w/w) to 60% (w/w) under inert gas purging and under vacuum and converted to in-situ Fusidic Acid by adding an acid such as HC1, 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 cream base 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.
Topical corticosteroids are a powerful tool for treating skin diseases. Understanding the correct use of these agents will result in the successful management of a varity of skin problems. Topical corticosteroids have anti inflammatory, antipuritic and vasoconstrictive properties.
The precise mechanism of the anti inflammatory activity of topical corticosteroids in the treatment of steroid-responsive dermatoses, in general, is uncertain. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of

their common precursor Arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Topical corticosteroid is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. Treatment beyond 4 consecutive weeks is not recommended. As with other highly active corticosteroids, therapy should be discontinued when control has been achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary.
Topical corticosteroids can be absorbed from intact health skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier: Occlusion, inflammation and/or other disease process in the skin may also increase percutaneous absorption. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Due to the fact that circulating levels are well below the level of detection, the use of Pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids is necessary. They are metabolized, primarily in the liver, and are then excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.
The following additional local adverse reactions have been reported with topical corticosteroids, but they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atropy, striae, and miliaria.
Systemic absorption of topical corticosteroids has produced reversible adrenal suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients.

Rationale for the Use of Corticosteroid and antibiotic or antibacterial Combinations:
Use of Corticosteroid with antibiotic/antibacterials:
Topical antibiotic/antibacterial agents have profound efficacy in treatment of various bacterial primary and secondary infections due to its antibiotic/bactericidal properties. A drawback of the monotherapy with any topical antibiotic/antibacterials has been the relatively slow onset of the anti¬inflammatory effect compared to steroids. The advantage, however, was the longer remission or reduced need for intermittent application of the drug to maintain the remission.
On the worldwide basis, topical formulations combining steroids and antibiotic/antibacterials are commonly available. These combinations contain potent steroids such as Betamethasone valerate, Betamethasone dipropionate, Hydrocortisone, Clobetasol propionate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, and the like. But also other steroids from less potent classes, such as Triamcinolone and Hydrocortisone and the like. In addition, the steroid provides much wanted rapid relief of the pruritus. Some of these combination products have become so popular, and are considered so safe, that they have entered the field of the over-the-counter medicines in some countries.
Combining antibiotic/antibacterial agents with topical corticosteroids is expected to provide fast relief because of the steroid effect and a lingering post treatment antibacterial effect allowing for an overall reduction in intermittent use of the product. The topical antibacterial effect of antibiotic/antibacterial agents known to be sufficiently powerful in a daily application, and consequently the combination was likely to be active with the same dose regimen. In addition, daily applications of the moderately potent steroid were appealing for use over the skin without

running the risk of skin atrophy. The improvement induced by the combination therapy was fast and profound after 2 weeks of daily applications.
Fixed Dose Rationale:
Our innovative Fixed Dose Combinations provide a safe, timely and affordable alternative vis-a-vis the need for accurate diagnosis (identifying the causative agents through testing in a pathological laboratory) of the skin problem.
In fact such a holistic approach could be self-defeating in the sense that a vast majority of population all over the world cannot have Time, Reach, Access and Affordability for such an exhaustive diagnostic approach (in vast majority of cases).
Our invention addresses these socio-economic concerns in a
medically/therapeutically safe and affordable way. This aspect in itself is a critical
noteworthy feature of our innovation.
According to the preferred embodiment of the present invention, there is provided
a composition for the topical treatment of bacterial skin infections and skin
inflammations 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, from about 0.005% to about 2.5% by weight, preferably from
about 0.005% to about 1.00% by weight, and most preferably from about
0.005% to 0.05% by weight, of Fluticasone propionate

- a cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, and buffering agents preservatives, anti oxidants, chelating agents, humectants, water, all weights based on the weight of the composition, wherein
- primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like from about 1% (w/w) to 15% (w/w),
- waxy materials are selected from a group comprising White Soft Paraffin, Liquid Paraffin, Hard Paraffin and the like from about 5% (w/w) to 20% (w/w),
- co-solvents are selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400 and the like from about 20% (w/w) to 60% (w/w), acids such as HC1, H2So4, HN03, 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, Chlrocresol, Potassium sorbate 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) 15 to 40 percent Purified Water;
b) 1 to 2.5 percent Sodium Fusidate;
c) 0.005 to 0.1 percent Fluticasone Propionate;
d) 1 to 15 percent Emulsifying wax, preferably 12.5 percent Cetostearyl Alcohol;
e) 5 to 20 percent White soft paraffin; preferably 12.5 percent White Soft Paraffin
f) 1 to 5 percent Non ionic Surfactant/emulsifier; preferably 2 percent Polysorbate 80
g) 20 to 60 percent Propylene Glycol; preferably 35 percent Propylene Glycol
h) 0.05 to 0.5 percent Preservative; preferably 0.2 percent Benzoic Acid
i) 0.01 to 0.1 percent Antioxidant; preferably 0.01 Butylated Hydroxy Toluene j) 0.01 to 1 percent Chelating Agent; preferably 0,01 percent Disodium Edetate k) 0.005 to 0.5 percent Acid; preferably 4 percent 1 Molar HNo3 Solution 1) 0.01 to 0.1 percent Alkali; preferably 0.5 percent Disodium hydrogen ortho phosphate anhydrous solution (10 percent solution )
The therapeutic efficacy of topically applied innovative Sodium Fusidate cream with Fluticasone propionate 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 and skin inflammations 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 with Fluticasone propionate cream of the present invention is provided.
Details of the process of manufacturing the sodium fusidate with fluticasone propionate cream:
The novel Sodium Fusidate with Fluticasone Propionate cream formulation of the present invention is made by inventively modifying the standard procedure of manufacturing pharmaceutical creams. All ingredients are mixed thoroughly at ambient or elevated temperature. Sodium Fusidate is dissolved in propylene glycol under oxygen free 100% pure nitrogen flushing and added to the bulk emulsion formed. Fluticasone Propionate is dispersed in propylene glycol, passed through colloid mill and added to the bulk emulsion. The ingredients are thoroughly mixed so that the product is homogeneous.
Processing equipments suitable for preparing the cream are known in the art and include mixers, homogenizers, stirrers, colloid mill and the like.

The cream of the present invention has a pH range from 3.0 to 6 and viscosity from 20,000 to 100,000 CPS. The 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 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 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
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Date of Receipt : 07.08.2008 Expiry date : 06.01.2011
Pack : Open & Closed Petri dish

Table 1: Results of 3 Months Old Fusidic Acid (API) 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

Table 2: Results of 3 Months Old Sodium Fusidate (API) Analysis by Stability 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).
> 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 with fluticasone propionate cream
A process of making the composition of the present invention is now disclosed. The process comprises the steps of:
1. Heating purified water in a water-phase vessel to 75 ° C +/- 5 ° C.
2. Adding a preservative, preferably Benzoic acid, preferably 0,05 to 0.5
percent, more preferably 0.2%

3. Adding a chelating agent, preferably Disodium edetate, preferably 0.01 to 1 percent, more preferably 0.01%.
4. Mixing the mixture using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 75 ° C +/- 5 ° C.
5. Adding an emulsifying wax, preferably Cetostearyl alcohol, preferably 1 to 15 percent, more preferably 12.5 percent and White Soft Paraffin, preferably 5 to 20 percent, more preferably 12.5 percent to an oil-phase vessel and melting them by heating to 75 ° C +/- 5 ° C.
6. Adding a non ionic Surfactant/emulsifier, preferably 1 to 5 percent,more preferably 2 percent Polysorbate 80 to the oil phase vessel and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 75 ° C +/- 5 ° C.
7. Transferring the contents of the water-phase and oil-phase vessels to a mixing vessel under vacuum conditions in the range of -1000 to -300 mm of Hg and at 75 ° C +/- 5 ° C and mixing the mixture at 10 to 50 RPM to form an emulsion.
8. Cooling the emulsion to 45 ° C preferably by circulating cold water (8 to 15 °C) from cooling tower in the jacket of the mixing vessel.
9. In an API vessel adding propylene glycol and dissolving an antioxidant, preferably 0.01 to 0.1 percent,more preferably 0.01 percent Butylated Hydroxy Toluene in it by continuous mixing.
10. Subjecting the contents of the API vessel to nitrogen gas flushing and
adding Sodium Fusidate to the mixture and dissolving it in the mixture.

11. Adjusting the pH of the mixture in the API vessel to below 2 by using an
acid, preferably 0.0005 to 0.5 percent; more preferably 4 percent of 1M
Nitric acid solution.
12. In another API vessel adding propylene glycol and dispersing Fluticasone Propionate in it by continuous mixing. Then passing the dispersion through colloid mill.
13. Transferring the contents of the Sodium fusidate from API vessel to 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.
14. Transferring the contents of the colloid milled Fluticasone Propionate from API vessel to the mixing vessel of step 8 with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under vacuum of-1000 to -300 mm of Hg.
15. Cooling the contents of the Mixing vessel to 30 ° C to 37 ° C using circulation of cooled water from cooling tower at 8 deg C to 15 deg C into the jacket of mixing vessel.
16. Adjusting the pH of the above bulk cream by adding 0.01 to 0.1 percent Alkali; preferably 0.05 percent Disodium hydrogen orthophosphate anhydrous in solution form.
17. Turning off the agitator and the homogenizer and removing the mixture of the Mixing vessel to a storage container.

The composition of the final cream obtained from the above described process is given in the Table 3 below.