Title of Invention


Abstract The present invention relates to primary and secondary bacterial skin infections and in particular it relates to the treatment of these infections using a Fusidic acid cream that has been made using Sodium fusidate as the starting Active Pharmaceutical Ingredient (API). The invention discloses a dermaceutical cream containing Fusidic acid which is formed in situ from Sodium Fusidate as the starting raw material, wherein Sodium Fusidate is converted into Fusidic acid under oxygen-free environment. The cream of the present invention has greater shelf-life stability and the finer particle size of the API than the conventional creams containing Fusidic acid.
Full Text FORM 2
(39 of 1970)
The Patent Rules, 2003
Provisional Specification
(See section 10 and rule 13)
A novel cream
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:

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 follicle^ 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.
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 ingredient in combination with a base component. The active ingredients typically comprise an antibiotic/antibacterial such as Sodium Fusidate, Calcium Mupirocin, 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 p-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.
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.
Some of the more commonly used active compounds found in topical primary and secondary bacterial skin infections treatment formulations include topical Sodium Fusidate, Calcium Mupirocin, and the like.
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 cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, and preservatives, buffering agents, anti oxidants, chelating agents, humectants.
(c) Water

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 or Calcium Mupirocin as starting material which is dissolved in a co-solvent system. By addition of an acid, while stirring at controlled sp^ed and using nitrogen purging tehniques and under vacuum, fucidic acid or imxpirocin is regenerated. The regeneration process carried out in an entirely Oxygen-free environment. The regenerated active ingredients are incorporated in cream 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 skirj with the above identified composition.
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-ba^ed 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.
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. 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 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.
a) 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, PolyEthyleneGlycoI-400 and the like & dissolved the Sodium Fusidate in one of above co-solvents varying from about 5% (w/w) to 40% (w/w) under inert gas purging and under vacuum and converted to in-situ Fusidic Acid

by adding an acid such as HCl, H2S04, HN03, 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.
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 or calcium mupirocin, preferably sodium fusidate, and,
- a cream base containing primary and secondary emulsiflers. 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, PoIyEthylene GlycoI-400 and the like from about 5% (w/w) to 40% (w/w), acids such as HCl, 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).
The therapeutic efficacy of topically applied innovative Sodium Fusidate cream 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.

Dated this 19lh Day of December, 2008
The Controller of Patents
The Patent Office, Mumbai Branch



Patent Number 270291
Indian Patent Application Number 2645/MUM/2008
PG Journal Number 50/2015
Publication Date 11-Dec-2015
Grant Date 09-Dec-2015
Date of Filing 19-Dec-2008
# Inventor's Name Inventor's Address
PCT International Classification Number C12N 15/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA