WO2010122477A1

WO2010122477A1 - A medicinal antifungal, antibacterial and steroid cream incorporating a biopolymer and a process to make it

Info

Publication number: WO2010122477A1
Application number: PCT/IB2010/051693
Authority: WO
Inventors: Sulur Subramaniam Vanangamudi; Madhavan Srinivasan; Neelakandan Narayanan Chulliel; Balkrishnana Selvaraj
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-04-20
Filing date: 2010-04-19
Publication date: 2010-10-28
Anticipated expiration: 2011-10-20

Abstract

The present invention is directed to a composition for treating fungal/bacterial skin infections & skin inflammation, along with skin rejuvenation containing a) a biopolymer in the form of Chitosan, b) a combination of active pharmaceutical ingredients (APIs), namely Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate, used in treating fungal & bacterial skin infections and skin inflammations, c) a cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants, and d) water. The active ingredients, namely chitosan, a corticosteroid Dexamethasone Acetate, an antibacterial in the form of Framycetin Sulphate and an antifungal agent in the form of Clotrimazole, are incorporated in cream base for use in treating fungal & bacterial skin infections and skin inflammation due to allergy & itching, & wounds on human skin involving contacting human skin with the above identified composition.

Description

A Medicinal Antifungal, Antibacterial And Steroid Cream Incorporating A Biopolymer And A Process To Make It

Field Of Invention

The present invention relates to a composition for treating fungal/bacterial skin infections & skin inflammation, along with skin rejuvenation. More particularly, the present invention relates to a pharmaceutical cream comprising a biopolymer in the form of chitosan, a corticosteroid in the form of Dexamethasone Acetate, an antibacterial active ingredient in the form of Framycetin Sulphate and an antifungal active ingredient in the form of Clotrimazole.

Background Of The Invention:

Skin disorders can be broadly categorized as those arising from bacterial forms or fungi. Antifungal or antibacterial compositions are traditionally applied as lotions, creams or ointments. Furthermore in many instances, it is difficult to ascertain whether the skin condition is due to a bacterial agent or a fungus.

One approach to treating skin disorders is through elimination by trial and error. Antibacterial or antifungal compositions are applied in turn and response monitored and treatment modified. A major disadvantage of this approach is that treatment needs to be applied many times a day during the treatment period. This is greatly inconvenient and also not cost effective for a majority of human population, particularly in the under-developed nations.

There are several treatments available to treat skin disorders caused by bacteria or fungi. Typically, such compositions use steroids, antibacterial agents or antifungal agents, (or a fixed dose combination of these) and focus on these pharmaceutically active ingredients. The composition of such formulations is such as to enhance their physical/chemical/bio-release profile.

Many skin disorders caused by inflammation and bacterial attacks lead to itching and subsequent scratching, which, among other causes, can in turn lead to serious and complicated secondary infections. The conventionally available treatments do not focus on skin healing or rejuvenation; normally these two aspects are left to heal naturally.

The word healing as related to compromised skin conditions (cuts, wounds, infections, inflammations, abrasions, etc.) are not only about prevention, control, elimination of the source cause such as bacteria or fungi but also to restore the skin to its pre-infection state.

The current approaches of skin treatment can be broadly categorized into two stages, a. healing b. restoration of skin to pre-ailment state. The healing part comprises elimination, to the best possible extent, of the root cause of the disorder. This may be elimination of bacteria or fungi causing the infection through a suitable treatment of antibacterial or antifungal agents or reducing the inflammation through steroid treatment. While this treatment is under way, the ongoing compromised condition of the skin continues to be susceptible to secondary infections which can be of quite serious nature. In the case of scratched or wounded skin, it is important for blood clotting to occur quickly as it reduces chances of secondary infections. The focus of such treatments, which are administered through creams, lotions, ointments is on the action of active pharmaceutical ingredients. Cream bases or ointment bases are merely viewed as carriers to take APIs to the sites of disorder.

However, the aspect of restoring the skin back to its pre-disorder state is almost completely left to nature. Therefore one key drawback of the existing skin treatment approaches is that they run the risk of secondary infections due to slow blood clotting and wound healing process.

Furthermore, from the study of the prior art several lacking aspects of the existing prescription derma products used for topical treatment of skin disorders. This is manifested by the fact that the cream base matrix or the ointment base has been overlooked for any potential therapeutic benefits. In particular none of the available prior art suggests that: Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main APIs such that the therapeutic outcome of the main APIs is enhanced.

The addition of biologically active polymers (the so-called biopolymers) is a complex process in which the stability of the formulations could be compromised if the right biopolymer or naturally interacting formulation excipients or process parameters are not well thought through and optimized to enhance and complement therapy outcomes at the drug design stage itself. - Incorporation of a functionally bio-active excipient polymer in cream matrix while retaining the functional stability of the API in a single dose format of dermaceutical cream involves resolution of problems specific to the physical stability of cream matrix.

A look at some of the existing patents illustrates the above points.

US patent 7601707 discloses a method for treating an inflamed tissue includes locally applying a solution comprising a corticosteroid and an anesthetic agent to the inflamed tissue so that the solution directly contacts the inflamed tissue. The corticosteroid maybe a 4 mg/ml dexamethasone solution and the anesthetic agent may be a 1% lidocaine solution. The dexamethasone solution and the lidocaine solution may be mixed in a 1 to 3 ratio. Locally applying the solution may include penetrating the skin with a hypodermic needle, directing the hypodermic needle parallel to and past the inflamed tissue, and while withdrawing the hypodermic needle, spraying the solution directly onto the surface of the inflamed tissue. The inventiveness is claimed on the basis that

The method described therein is apparently curative, palliative, or beneficial for any biologic, medical, or veterinary condition, affliction, illness, or disease that is acute, sub-acute, or chronic and involves inflammation or pathologic muscle contraction, either external or internal. The method can apparently be applied to any condition, affliction, illness, or disease that ends with the suffix "itis" or has the clinical signs and symptoms of inflammation. The combination of medicines apparently also has previously undiscovered muscle relaxant properties.

The method described therein is apparently more effective than the then current treatments. The method described therein apparently restores normal function instantly with complete resolution of signs and symptoms in the locations treated. The resolution is permanent, unless significant re-injury occurs. Thus, the cost of treatment is apparently less. The use of the medications locally apparently enables the use relatively low dosage by avoid reliance on the circulatory system for delivery. Non-targeted areas receive minimal exposure to the medications. There are several other benefits claimed.

With regards the use of framycetin in the pharmaceutical industry, the following documents are considered. GB987010 discloses an aqueous, water-permeable, colloid compositions substantially free from bacterial action comprise one or more antibiotics active against gram-negative bacteria and methyl or ethyl alcohol. The invention uses a mixture of antibiotics, e.g. a sulphate of neomycin, kanamycin, polymyxin B, streptomycin, colistin or framycetin. It claims inventiveness on the basis of their finding that when an antibiotic which is active against gram-negative bacteria is added, together with a small amount of methyl or ethyl alcohol, to an aqueous protein colloid, especially a gelatin composition, gram-negative bacteria are destroyed and the presence of the antibiotic in dry layers made therefrom inhibits bacteria growth therein even under humid conditions. The resulting aqueous water-permeable colloid compositions are essentially free from bacterial action.

GB 1090421 discloses a surgical dressing comprises, among other things, a textile material treated with a basic antibiotic and/or basic antibacterial substance. The compounds which may be present in the emulsions which are used in the product include neomycin, neomycin sulphate, or framycetin, and the like. GB 1090421 claims advantages over the related prior art due to their apparent applicability on burns and wounds which are non-adherent to raw wound surfaces and the resultant ease involved in their removal without causing damage to the delicate healing tissues. They further suggest that the antibiotic or antibacterial action provided by these wound dressings is advantageous. GB 1218978 discloses a polyvinyl pyrrolidone based which may also contain antibiotics such as the sulphates of framycetin, paromomycin, kanamycin, gentamycin and neomycin. It clearly states that the compositions maybe formulated for internal use, e.g. for anti- diarrhoea activity or for external use e.g. for anti-ulcer activity. GB 1218978. claims inventiveness on the assertion that the pharmaceutical compositions according to the invention possess valuable pharmacological properties, in particular an anti-diarrhoea activity when administered internally, and an anti-ulcer activity, when administered externally.

With regards the use of clotrimazole in the pharmaceutical industry, the following documents are considered.

PCT/GB2007/004373 provides medicaments and methods for the treatment of infections caused or contributed to by multi-drug resistant Staphylococcus species using effective amount of Clotrimazole, and its derivatives. PCT/GB2007/004373 claims novelty on the assertion that the pharmaceutical composition according to the invention possesses ability of inhibit methicillin resistant Staphylococcus species. The composition described in the invention by the applicant is use for orally administration, it can be used topically at the site of an infection, or intravenously. The said composition can also be used for sterilizing or cleaning solutions to decontaminate furniture, floors, equipment including for example specialized hospital equipment and/or surgical equipment

US 6,899,897 discloses a biological dressing comprising a sticky film of gum resin - benzoin, a pharmacologically active agent - clotrimazole is left on the skin or mucous membrane after the volatile solvent - ethanol has evaporated. The composition further may include penetration enhancer. US 6,899,897 claims novelty over the assertion that the dressing disclosed herewith is a clean and inexpensive vehicle/carrier of topically applied medications increasing the convenience and effectiveness of the treatment and decreasing the necessary time for the treatment. This is apparently associated with less waste and lower cost and improved treatment. The film formed is apparently extends retention on the skin since it is resistant to water and abrasion by clothing.

US 6,537,970 deals with a composition comprising clindamycin and clotrimazole use for the treatment of vaginal infection. US 6,537,970 claims novelty over the conventional therapy because of the unique combination of various mycotoxins present in the composition and synergitic effect of the same. It is also claimed that the said composition can be used for the treatment of bacterial infection, fungal infection and mixed infection. The treatment can also be carried out either orally or topically. US 6,080,744 deals with describes a topical composition for medical, veterinarian or dental use containing active antimycotic ingredient like, clotrimazole, ketoconazole, micanazole, nystatin, tolnaftate, propionic acid, sodium propionate, undecelynic acid and zinc undecelynate in a natural base such that the composition is capable of defeating a wide range of fungi and can clear topical fungal infection. US 6,080,744 claims advantage over the existing prior art on the bases that the ingredients used in the composition is blended in natural - cream base, also it is effective over a wide range of mycological illnesses and helps in speedy recovery.

It is evident from the forgoing discussion that none of the above mentioned patent applications teach or suggest:

Use of the cream base matrix as a functional element of the cream rather than a mere carrier for the main APIs - Use a known bio-polymer as a functional ex cipient along with anti fungal agent Clotrimazole, antibacterial agent Framycetin Sulphate and a steroid, Dexamethasone Acetate

Providing far superior healing effects as micro-film forming, blood clotting, supporting epidermal growth, microbial electrostatic immobilization take effect simultaneously rather than one after the other as would be the case in conventional single-drug therapy

Improve overall medicinal properties of the cream, complimenting the

API used in the cream matrix There is therefore a need for a single-dose multiple API topical treatment that will be provided in a cream base, which cream base provides therapeutical value complementary to that provided by the main APIs and serves the purpose over and above that of being a mere carrier or delivery mechanism.

Objects And Advantages Of The Inventions

There is therefore a need to provide a single dose multiple API Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate topical treatment formulation that will provide an effective treatment against fungal & bacterial skin infections, skin inflammations and also help actively heal the skin rejuvenate. Further objects of the present invention are to provide topical skin treatment formulations that:

Can deliver skin healing or regeneration beyond the activity of the main APIs - Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate such that the therapeutic outcome of the main APIs are enhanced. Contain biologically active polymers (the so-called biopolymers) without compromising the stability of the formulations could be compromised if the right biopolymer is not selected. - Incorporate a functionally bio-active excipient polymer in cream matrix while retaining the functional stability of the APIs in a single dose format Brief Description Of Figures:

Figure 1 - Non-homogeneous nature of creams containing chitosan with non- compatible excipient such as carbomer

Figure 2 - Film formation using chitosan

Summary Of The Invention:

The present invention is directed to a composition for treating fungal/bacterial skin infections & skin inflammation, along with skin rejuvenation containing

a) a biopolymer in the form of Chitosan

b) A combination of active pharmaceutical ingredients (APIs), Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate used in treating fungal & bacterial skin infections and skin inflammations,

c) A cream base containing primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti oxidants, chelating agents, and humectants.

d) Water

The active ingredients, namely chitosan, a corticosteroid Dexamethasone Acetate, an antibacterial in the form of Framycetin Sulphate and an antifungal agent in the form of Clotrimazole, are incorporated in cream base for use in treating fungal & bacterial skin infections and skin inflammation due to allergy & itching, & wounds 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 present invention provides a uni-dose multi-API Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate formulation for topical skin treatment in the field of prescription medicaments. The prescription medication is distinct in its use as compared with the so-called cosmeceuticals. The cosmeceuticals are aimed towards beautification or betterment of a more-or-less intact skin or of a skin not suffering from a serious disorder. On the other hand, prescription skin formulations are aimed to provide treatment for serious skin disorders resulting from infections and wounds.

From the study of the prior art several lacking aspects of the existing topical treatment formulations in the field of prescription medications are evident. The prior art does not teach or suggest that: Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main APIs such that the therapeutic outcomes of the main APIs are enhanced.

The addition of biologically active polymers (the so-called biopolymers) is a complex process in which the stability of the formulations could be compromised if the right biopolymer is not selected. Incorporation of a functionally bio-active excipient polymer in cream matrix while retaining the functional stability of the API in a single dose format of dermaceutical cream involves resolution of problems specific to the physical stability o f cream matrix.

The active compounds Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate which may be employed in the present invention are well known in the art of treatment of fungal & bacterial skin infections, skin inflammations respectively and a bio polymer for treating wounds and rejuvenating human skin involving contacting human skin with the above identified composition.

Examples of suitable biopolymer, which may be used, include, but are not limited to chitosan and the like.

Examples of suitable topical Corticosteroids, which may be used, include, but are not limited to, Betamethasone Valerate, Betamethasone dipropionate,

Beclomethasone dipropionate, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Diflorasone diacetate, Prednicarbate, Hydrocortisone acetate, Dexamethasone Acetate and the like.

Examples of suitable topical antibacterial agents, which may be used, include, but are not limited to, Sodium Fusidate, Calcium Mupirocin, Gentamycin, Neomycin, Silver Sulphadiazine, Ciprofloxacin, Framycetin Sulphate, Quinidochlor, Povidone-Iodine, Sisomicin, Nitrofural and the like.

Examples of suitable topical antifungal agents, which may be used, include, but are not limited to, Miconazole Nitrate, Oxiconazole, Clotrimazole, Ketoconazole, Terbinafine HCl, Ciclopirax, Tolnaftate, Nystatin and the like.

These active compounds, namely Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate, 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, preservatives, buffering agents, anti oxidants, chelating agents, humectants and the like. Chitosan

Chitosan is a linear polysaccharide composed of randomly distributed β-(l-4)- linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is known to have a number of commercial uses in agriculture and horticulture, water treatment, chemical industry, pharmaceuticals and biomedics.

It's known properties include accelerated blood clotting. However, it is not known to a person skilled in the art that chitosan's behaviour with a pharmaceutical active ingredient such as an antibacterial or antifungal agent needs to be treated with caution.

It is known to have film forming, mucoadhesive and viscosity-increasing properties and it has been used as a binder and disintegrating agent in tablet formulations.

Chitosan generally absorbs moisture from the atmosphere / environment and the amount absorbed depends upon the initial moisture content, temperature and relative humidity of the environment.

It is regarded as a non-toxic and non-irritant material. It is biocompatible with both healthy and infected skin and has been shown to be biodegradable as it is derived from shrimps, squids and crabs. Chitosan due to its unique physical property accelerates wound healing and wound repair. It is positively charged and soluble in acidic to neutral solution. Chitosan is bioadhesive and readily binds to negatively charged surfaces such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial surfaces. Chitosan's properties allow it to rapidly clot blood, and it has recently gained approval in the USA for use in bandages and other hemostatic agents.

Chitosan is nonallergenic, and has natural anti-bacterial properties, further supporting its use. As a micro-film forming biomaterial, chitosan helps in reducing the width of the wound, controls the oxygen permeability at the site, absorbs wound discharge and gets degraded by tissue enzymes which are very much required for healing at a faster rate. It also reduces the itching by providing a soothing effect. It also acts like a moisturizer. It is also useful in treatment of routine minor cuts and wounds, burns, keloids, diabetic ulcers and venous ulcers.

Chitosan used in the present invention comes in various molecular weights ranging from 1 kdal to 5000kdal.

Chitosan is discussed in the US Pharmacopoeia forum with regard to its functional excipient category. Since chitosan is basically a polymer, it is available in various grades depending upon the molecular weight. The various grades of chitosan include chitosan long chain, chitosan medium chain & chitosan short chain. The grades long, medium & short chain directly correspond to the molecular weight of the chitosan.

Generally the long chain grade has a molecular weight in the range of 500,000- 5,000,000 Da, the medium chain grade has a molecular weight in the range of 1,00,000-2,000,000 Da and the short chain grade has a molecular weight in the range of 50,000-1,000,000 Da.

The molecular weight of the chitosan plays an important role in the formulation, higher molecular weight chitosan imparts a higher viscosity to the system and lower molecular weight chitosan imparts a lower viscosity to the system.

However the medium chain grade chitosan delivered an optimum level of viscosity to the formulation. Since the dosage form is a cream, appropriate levels of viscosity is required to achieve a good spreadability over the skin.

The inventors finalized the chitosan medium chain grade for the present invention since it imparted the required rheologic properties to the cream without compromising the therapeutic activity of the actives, namely Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate and chitosan. The concentration of chitosan medium chain grade was carefully arrived based on several in house trials and Preclinical animal studies for efficacy. Topical Corticosteroids

Topical corticosteroids are a powerful tool for treating skin diseases. Corticosteroids include drugs such as Betamethasone Valerate, Betamethasone dipropionate, Beclomethasone dipropionate, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide,

Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide,

Hydrocortisone acetate, Dexamethasone Acetate, Diflorasone diacetate, Prednicarbate, etc.

Topical corticosteroids are classified by their potency, ranging from weak to extremely potent. They include weak potent steroids, moderate potent steroids, potent steroids, very potent steroids and extremely potent steroids. The high potency steroids include Betamethasone Dipropionate, Betamethasone Valerate, Diflorasone Diacetate, Clobetasol Propionate, Halobetasol Propionate, Desoximetasone, Diflorasone Diacetate, Fluocinonide, Mometasone Furoate, Triamcinolone Acetonide,Fluticasone Propionate, Dexamethasone Acetate etc. Low potency topical steroids include Desonide, Fluocinolone acetate, and Hydrocortisone acetate, etc.

Topical corticosteroid is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. Dexamethasone Acetate

Dexamethasone Acetate is a low to moderately potent synthetic adrenal corticosteroid with anti-inflammatory and immunosuppressive properties.

In addition to binding to specific nuclear steroid receptors, dexamethasone also interferes withNF-kB activation and apoptotic pathways. Dexamethasone acetate is chemically 9-fluoro-l 1 D,17-dihydroxy-16 D-methyl- 3,20-dioxopregna-l,4-dien-21-yl acetate. The molecular formula and weight of Dexamethasone acetate are C24H31 FO6 and 434.5 respectively.

Dexamethasone acetate is a white or almost white, crystalline powder, practically insoluble in water, freely soluble in acetone and in alcohol, slightly soluble in methylene chloride. Dexamethasone acetate shows polymorphism

Pharmacology & Mechanism of Action

Dexamethasone and its derivatives, dexamethasone sodium phosphate and dexamethasone acetate, are synthetic glucocorticoids are used for their antiinflammatory or immunosuppressive properties. Dexamethasone is used alone to manage cerebral edema and with tobramycin to treat corticosteroid-responsive inflammatory ocular conditions. Dexamethasone is a glucocorticoid agonist. Unbound dexamethasone crosses cell membranes and binds with high affinity to specific cytoplasmic receptors. This results in a modification of transcription and, hence, protein synthesis in order to achieve inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, suppression of humoral immune responses, and reduction in edema or scar tissue. The antiinflammatory actions of dexamethasone are thought to involve phosp ho lipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.

Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. Indications

Topical Dexamethasone Acetate is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. It is also used topically and systemically in the treatment of endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, gastrointestinal diseases, respiratory diseases, hematologic disorders, neoplastic diseases, edematous states and cerebral edema.

Topical Anti-bacterials Topical Anti-bacterials are intended to target skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Methicillin Resistance Staphylococcus Aureus (MRSA) etc.

Anti-bacterials act by inhibiting cell wall synthesis by combining with bacterial ribosomes and interfering with mRNA ribosome combination. In another hypothesis it is believed that anti-bacterials induce ribosomes to manufacture peptide chains with wrong amino acids, which ultimately destroy the bacterial cell.

Framycetin Sulphate Framycetin Sulphate belongs to the group of medicines known as antibiotics. Framycetin Sulphate is an antibiotic with bactericidal effect with a wide antibacterial spectrum, belonging to the aminoglycoside group and a sulp hated salt of Neomycin B. It is used to treat bacterial infections, by killing or stopping the growth of the bacteria responsible.

The molecular formula of Framycetin Sulphate is C23H46NeOi3,xH2SO4, and the molecular weight is 614.64374. The chemical name is (2R,3S,4R,5R,6R)-5-

Amino-2-(aminomethyl)-6-[(lR,2R,3S,4R,6S)-4,6-diamino-2-[(2R,3R,4S,5R)-4- [(2S,3S,4S,5R,6R)-3-amino-6-(aminomethyl)-4,5-dihydroxy-oxan-2-yi]oxy-3- hydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-3-hydroxy-cyclohexyl]oxy-oxane- 3,4-diol sulphate. It is a White or yellowish- white, hygroscopic powder soluble in water.

Pharmacology & Mechanism of Action

Framycetin is active against Staphylococcus spp., including coagulase-negative Staphylococci, Escherichia coli, Klebsiella spp., Salmonella, Shigella, Enterobacter spp., Proteus spp., Serratia marcescens, Pasteurella spp., Vibrio spp., Borellia and Leptospira spp.anά Mycobacterium tuberculosis including also Streptomycin-resistant strains. Framycetin shows comparatively high activity against some strains of Pseudomonαs aeruginosa, which is a main problematic pathogen. The resistance to framycetin is hardly achieved after often and very prolonged use. For avoidance the occurrence of resistance or with reference to the extension of the therapeutic spectrum, usually in drug forms with framycetin are included other antibacterial agents, as well as steroid antiphlogistics. In dermatological practice framycetin is administered for treatment of wounds, ulcers, burns and other skin defects, infected with susceptible microorganisms. The antibiotic is preferred agent for treatment of bacterial dermatoses and pyodermes as impetigo, furunculosis etc.

In ophthalmology the antibiotic is successfully applied for treatment of conjunctivas, blepharitis and infections of the front ocular segments. The topical forms with framycetin manifest high effect at the treatment of corneal ulcers.

In spite of the possible manifestation of ototoxicity Framycetin Sulphate alone or in combination with other antibacterial or anti-inflammatory agents is used also for preparation of ear drops. With reference to the wide usage of framycetin in otorhinolaryngology and the single incidents, it is accepted that the ototoxicity risks are insignificant after topical application. Topical forms containing framycetin are successfully used at the treatment of rhinitis caused by Staphylococci.

The mechanism of action of framycetin appears to be related to inhibition of bacterial protein synthesis via binding to ribosomal subunits.

Indications

Framycetin sulphate is active against a wide variety of both Gram-positive and

Gram-negative bacteria commonly found in superficial infections: staphylococci (including strains resistant to other antibiotics), Pseudomonas aeruginosa, coliform bacteria and pneumococci. It is exceptionally well tolerated by the tissues.

In dermato logical practice framycetin is administered for treatment of wounds, scalds, boils, ulcers, burns, cuts, sycosis barbae, otitis externa, paronychia, secondary infections in scabies and lice and other skin defects, infected with susceptible microorganisms. The antibiotic is preferred agent for treatment of bacterial dermatoses and pyodermes as impetigo, furunculosis etc.

Topical Antifungals:

Topical anti-fungals are intended to target skin for fungal infections caused by Tinea pedis, Tinea cruris, Tinea corporis etc. These include drugs like Miconazole Nitrate, Oxiconazole, Clotrimazole, Ketoconazole, Terbinafme HCl, Ciclopirax, Tolnaftate, Nystatin and the like.

Fungal infections are generally manifested with itching at the site. Antifungals act by altering the permeability of the fungal membrane by inhibiting the synthesis of sterols.

Clotrimazole

Clotrimazole is a synthetic antifungal agent having the chemical name {l-(o-Chloro-α, α-diphenylbenzyl)imidazole}; the molecular formula C₂₂H_nClN₂; a molecular weight of 344.84. Clotrimazole is an odorless, white crystalline substance. It is practically insoluble in water, sparingly soluble in ether and very soluble in polyethylene glycol 400, ethanol and chloroform. It is commonly available as an over-the-counter substance in various dosage forms, such as a cream and powder. Clotrimazole is used locally for treating various fungal skin infections.

Pharmacology: Clotrimazole is a broad-spectrum antifungal agent that is used for the treatment of dermal infections caused by various species of pathogenic dermatophytes, yeasts, and Malassezia furfur. The primary action of clotrimazole is against dividing and growing organisms.

In vitro, clotrimazole exhibits fungistatic and fungicidal activity against isolates of Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum cards and Candida species including Candida albicans. In general, the in vitro activity of clotrimazole corresponds to that of tolnaftate and griseofulvin against the mycelia of dermatophytes (Trichophyton, Microsporum, and Epidermophyton), and to that of the polyenes (amphotericin B and nystatin) against budding fungi (Candida). Mechanism of Action: The fungicidal concentration of clotrimazole caused leakage of intracellular phosphorus compounds into the ambient medium with concomitant breakdown of cellular nucleic acids and accelerated potassium efflux. Pharmacokinetics: Clotrimazole appears to be well absorbed in humans following oral administration and is eliminated mainly as inactive metabolites. Following topical and vaginal administration, however, clotrimazole appears to be minimally absorbed. Protein binding of Clotrimazole is about 90%. Clotrimazole is metabolized in liver

Indications: Clotrimazole Cream is indicated for the topical treatment of candidiasis due to Candida albicans and tinea versicolor due to Malassezia furfur.

Clotrimazole is also available as a nonprescription item which is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis.

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 semisolid 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.

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 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 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 cream of the present invention with a functional biopolymer such as chitosan with Clotrimazole, Framycetin sulphate & Dexamethasone Acetate is from about 3 to 6. On the other hand, 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.

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 antifungal/antibacterial/antiinflammatory & wound healing activity of the active ingredients Clotrimazole, Framycetin sulphate & Dexamethasone Acetate, which are available in ultra micro-size, colloidal form, which enhances skin penetration.

Rationale For Clotrimazole, Framycetin sulphate, Dexamethasone Acetate And Chitosan Combination:

Numerous topical treatments are currently employed for the treatment of fungal, bacterial skin infections and skin inflammations. However there is no effective single-dose therapy for protecting the skin, controlling superficial bleeding, wounds and burns. To meet this need and to bring affordable and safe therapy to the dispersed segment of population across all countries/communities, a therapy with unique combination of chitosan, a biopolymer with skin rejuvenation properties with Clotrimazole, Framycetin sulphate & Dexamethasone Acetate is proposed as a novel cream.

Topical Clotrimazole and Framycetin sulphate have profound efficacy in skin infections of varied etiology due to its antifungal and antibacterial properties. A drawback of the monotherapy with topical antifungal like Clotrimazole and antibacterial like Framycetin sulphate has been the relatively slow onset of the effect.

Steroids like Dexamethasone Acetate provide much wanted rapid relief of the pruritus. Combining Clotrimazole, Framycetin sulphate with topical Dexamethasone Acetate is expected to provide fast relief because of the steroid effect and a lingering post treatment antifungal, antibacterial effect allowing for an overall reduction in intermittent use of the product. Generally topical steroids of high potency are used for duration of one to two weeks; for low potency steroids the period maybe three to four weeks.

By employing Dexamethasone Acetate, Framycetin sulphate, Clotrimazole & chitosan in a formulation, the properties of steroids, antibacterials, antifungals and chitosan are optimized. As chitosan is film forming, biocompatible, non-allergenic material it helps in protecting the skin by acting as a barrier. It further controls the superficial bleeding caused by scratching and also arrests the mobility of pathogens due to its cationic charge.

The properties of Dexamethasone Acetate , Framycetin sulphate, Clotrimazole and chitosan's skin regenerative aspects are well exploited in the present invention and the maximum therapeutic benefit is passed on to the patient thereby aiding in faster healing. This ensures that the patient would benefit for the treatment of skin dermatitis, eczema, wounds, and fungal/bacterial infections.

The inclusion of chitosan in the formulation takes care of many attributes, which are considered to be very much essential in treating skin ailments. The combination of chitosan with Dexamethasone Acetate, Framycetin sulphate and Clotrimazole is unique and novel since this is not available commercially across the globe. The concept of the combination is justified by considering the physical, chemical and therapeutic properties of chitosan used in combination with Dexamethasone Acetate, Framycetin sulphate & Clotrimazole.

Inventive Aspects Of The Present Invention:

Another inventive aspect of the present invention is that the addition of a functional excipient in the cream base is not a straight forward process of mere addition. The inventor has found that the compatibility of the functional excipient such as chitosan with other agents in the cream is of critical importance. This is because incompatibility would compromise the stability of the final product. As examples, the inventors have found that well known excipients such as Xanthan Gum and carbomer which have been variously used as stabilising agents, cannot be used in combination with functional biopolymers such as chitosan.

Excipients for topical dosage forms include Polymers, Surfactants, Waxy Materials, and Emulsifiers etc. Polymers are used as gelling agents, suspending agents, viscosity builders, release modifiers, diluents, etc. Surfactants are used as wetting agents, emulsifiers, solubilising agents release enhancers, etc.

Generally Polymers & Surfactants may or may not possess ionic charge. They may be anionic or cationic or non-ionic in nature. If anionic excipients are included in the formulation they interact with cationic formulation excipients and produce products which are not homogenous, aesthetically not appealing and give rise to unwanted by products, possible allergens, impurities, toxic substances etc due to incompatibility.

Since the dosage is for the treatment of ailing patients, these incompatibilities in the products cannot be accepted and these add more complication to the patients.

The inventors carefully screened the excipients which included the Polymers and Surfactants for developing a formulation. A thorough study was performed after screening the short listed excipients. The possible interactions between the excipients were given much focus and detailed experiments were done.

To quote some examples about the anionic - cationic interaction in the cream dosage form the inventors made some formulations of Dexamethasone Acetate, Framycetin sulphate and Clotrimazole (see tables 1 - 5) containing Xanthan Gum & Chitosan, Acrylic acid polymer & Chitosan, Sodium Lauryl Sulphate & Chitosan, Docusate Sodium & Chitosan and Gum Arabic & Chitosan. The results clearly indicated the occurrence of interactions which was very much visible and seen as lumps into the entire system. The final product was also not aesthetically appealing without homogeneity. The attached Figure 1 clearly explains the interaction between chitosan and unsuitable anionic excipients. Based on the observations and thorough knowledge about the excipients, the inventors arrived at a robust formula without any possible interactions. Table 1: Formulation of Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate Cream with Chitosan and Xanthan Gum

Table 2: Formulation of Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate Cream with Chitosan and Acrylic Acid Polymer

Table 3: Formulation of Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate Cream with Chitosan and Sodium Lauryl Sulphate

Table 4: Formulation of Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate Cream with Chitosan and Docusate Sodium

Table 5: Formulation of Clotrimazole, Framycetin Sulphate & Dexamethasone Acetate Cream with Chitosan and Gum Arabic

The above products (tables 1 to 5) are examples of products that do not form homogeneous creams, and produce non-homogeneous creams of the type illustrated in figure 1. Yet the proportions stated in these examples are some things that a person skilled in the art may use based on currently available knowledge. Only after a thorough and extensive trials and errors would it be possible to arrive at right types and proportions of excipients.

As we have discussed earlier, in a combination therapy, steroids like Dexamethasone Acetate provide relief against inflammation, antibacterials like Framycetin sulphate provide relief against bacterial infections and antifungals like Clotrimazole provide relief against fungal infections. However, the aspects such as like skin protection, bleeding at the site, mobility of pathogens from one site to another, etc are not addressed so far in a single dose therapy. This present invention with its single-dose application fills this gap by incorporating chitosan and tapping the required benefits of skin protection (by way of film forming property), stopping the bleeding (by way of blood clotting property) and immobilization of pathogenic microbes (due to its cationic electrostatic property).

Therapeutic value addition by incorporation of a functional excipient in the form of a chitosan which is a biopolymer in the cream matrix. The value addition is an integrated sub-set of the following functional attributes of the biopolymer: formulation of a micro-film on the skin surface - accelerated blood clotting as compared to creams that do not contain film- forming biopolymers electrostatic immobilisation of surface microbes due to cationic charge of the biopolymer significant enhancement of the skin epithelisation or regeneration

The inventive efforts involved in developing the platform technology covered by incorporation of a functional biopolymer in prescription dermaceutical products are: in identification of the complementary therapeutic value that such incorporation delivers - in identification of issues related to physio -chemical stability of the product resulting from the incorporation of the biopolymer in providing a single dose format where the fungal & bacterial skin infection and skin inflammation has been identified The importance of a single dose treatment, particularly in the underdeveloped countries cannot be overemphasized. In absence of access to a general physician in most parts of south Asia or Africa, let alone a skin specialist, a single dose formulation dramatically increases chances of eliminating root cause of the skin disorder while also allowing the skin to regenerate.

During dermatological conditions, currently available therapies do not address the issues like protecting the skin, arresting the bleeding etc. The unique innovative formulation of the present invention takes care of the skin conditions by treating them along with controlling the superficial bleeding at the site. It is well understood that if the superficial bleeding is left untreated, it will lead to secondary microbial infections. The present invention advantageously provides a solution to this unmet need.

Further, with ever increasing pressures on medical support systems and the attendant scarcity/high cost of the same, there is an emergent need all across the globe to address the following issues in such cases -

• Patients waiting too long for treatment

• Staying unnecessarily long when they get to hospital • Having to come back more often than they need to

Reducing the length of stay is a key underlying problem to be tackled in most cases. The present invention with its single-dose therapy reduces the overall treatment time of a serious skin disorder significantly. Preferred embodiment 1: A novel dermaceutical cream for topical treatment of fungal & bacterial skin infections, skin inflammations, and for related wound healing, wherein said cream comprises an antifungal agent in the form of Clotrimazole, an antibacterial agent in the form of Framycetin Sulphate, a corticosteroid in the form of Dexamethasone Acetate and a biopolymer provided in a cream base, said cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co-solvent, an acid, and water, preferably purified water.

Embodiment no. 1 : A novel dermaceutical cream as disclosed in the preferred embodiment no. 1, wherein said cream further comprising any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.

Embodiment no. 2 : A novel dermaceutical cream as disclosed in the preferred embodiment no. 1 wherein

- said Clotrimazole is added in an amount between about 0.05% w/w and about

5% w/w, preferably between 0.1 and 2.0% w/w, more preferably 1.0 w/w; and - said Framycetin Sulphate is added in an amount between about 0.05% w/w and about 5% w/w, preferably between 0.1 and 2.0% w/w, more preferably

1.0 w/w; and - said corticosteroid Dexamethasone Acetate is added in an amount between about 0.001% (w/w) and about 5% (w/w), preferably between about 0.01 % and about 2.5% w/w, more preferably 0.1 w/w and, said chitosan, added in an amount between about 0.01% and about 1% by weight, preferably added in an amount from about 0.01% w/w to about 0.5% w/w and most preferably about 0.25% w/w, said chitosan being US Pharmacopoeia conformant with regard to its functional excipient category and selected from any grades such as Long Chain, Medium Chain & Short Chain, and has a molecular weight in the range between 5OkDa to 5000 kDa, - said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80, and the like and added in an amount from about 1% (w/w) to 20% (w/w); said waxy materials is selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 30% (w/w); said co-solvent is selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400, Isopropyl Myristate and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w); said acid is selected from a group comprising HCl, H2SO4, HNO3, Lactic acid and the like, or any combination thereof, and added in an amount from about 0.005% (w/w) to

0.5% (w/w); said preservative is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, or any combination thereof, and added in an amount from about 0.05% (w/w) to 0.5% (w/w); said water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 45% (w/w) to 65% (w/w), more preferably 55% (w/w) to 62% (w/w), preferably purified water.

Embodiment no. 3: A novel cream as disclosed in the preferred embodiment no. 1 and the embodiment no. 2, further comprising a buffering agent which is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof, and added in an amount from about 0.05% (w/w) to 1.00% (w/w).

Embodiment no. 4: A novel cream as disclosed in the preferred embodiment no. 1 and the embodiments no. 2 and 3, further comprising an antioxidant which is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, and added in an amount from about 0.001% (w/w) to 1% (w/w).

Embodiment no. 5: A novel cream as disclosed in the preferred embodiment no. 1 and the embodiments no. 2 to 4, further comprising a chelating agent which is selected from a group comprising Disodium EDTA and the like, or any combination thereof, and added in an amount from about 0.05% (w/w) to 1% (w/w). Embodiment no. 6: A novel cream as disclosed in the preferred embodiment no. 1 and the embodiments no. 2 to 4, further comprising a humectant which is selected from a group comprising Glycerin, Sorbitol, Propylene Glycol and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w).

Embodiment no. 7: A process of making a cream is disclosed, said process comprising the steps of providing an antifungal agent, Clotrimazole, an antibacterial agent, Framycetin Sulphate, a corticosteroid, Dexamethasone Acetate, and a biopolymer in a cream base comprising at least one of each of a preservative, a primary and a secondary emulsifϊer, waxy material, a co-solvent, an acid, and water, preferably purified water, and mixing all the ingredients together to form a homogeneous cream.

Embodiment no. 8: A process of making a cream as disclosed in the embodiment no. 7, wherein the ingredients further comprise any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.

Embodiment no. 9: A novel cream as disclosed in any of the foregoing embodiments, wherein chitosan has a molecular weight range of lkdal to 5000kdal. The present invention will be further elucidated with reference to the accompanying examples containing the composition and stability studies data, which are however not intended to limit the invention in any way whatever.

Example: Table 6:_Clotrimazole (1%) + Framycetin Sulphate (1%) + Dexamethasone Acetate 0.1% + Chitosan Cream

A comparison of table 6, and tables 1 to 5 will illustrate the difference in the products that would be based on the conventional drug design and the innovative approach adopted in the present invention.

APIs- stability experiments were carried out (see tables 7- 9) using the product of the present invention. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the APIs over a period of time. The product used for the Stability Studies tests contained approximately 10% extra APIs (overages). It was packaged in an aluminium collapsible tube. Detailed test results for the product have been presented. The % of the corticosteroid, Dexamethasone Acetate, antibacterial, Framycetin Sulphate and the antifungal, Clotrimazole used in all examples are measured w/w with respect to the final product.

PRODUCT: FRAMYCETIN SULPHATE + DEXAMETHASONE ACETATE + CLOTRIMAZOLE + CHITOSAN CREAM PACK: Aluminum Collapsible tube

Composition: Each gm contains: Framycetin Sulphate IP 1.0 % w/w; Dexamethasone Acetate IP 0.1 % w/w; Clotrimazole IP 1.0 % w/w

Table 7: Description Test, Batch No. FDC-Ol Measured parameter: Physical appearance

Best value of measured parameter: Homogeneous White to off White Viscous cream; Method of measurement: Observation by naked eye

Table 8: pH Test, Batch No. FDC-Ol

Measured parameter: pH; Limits of measured parameter: 3-6 Method of measurement: Digital pH Meter

Table 9: Assay (%) Test, Batch No. FDC-Ol

Measured parameter: Assay (%); Method of measurement: HPLC Method Limits of measured arameter: 90-110

Method Of Application Of The Cream:

The cream is applied after thorough cleansing and drying the affected area. Sufficient cream should be applied to cover the affected skin and surrounding area. The cream should be applied two - four times a day depending upon the skin conditions for the full treatment period, even though symptoms may have improved.

Experiments:

Experiments were carried out with the cream in laboratory as well as using suitable animal models inflicted with excision wounds. Four aspects were tested - wound contraction, epithelisation, blood clotting time, and film forming. These aspects together would suggest that the microbes were immobilized thereby leading to effective wound healing.

A. Wound Contraction: Excision wound healing activity of the cream of the present invention was determined through animal testing. An excision wound 2.5 cm in diameter was inflicted by cutting away full thickness of the skin. The amount of contraction of the wound observed over a period indicated that the cream of present invention provides significantly improved wound contraction than a control (untreated wound).

B. Period Of Epithelisation:

Epithelisation of the wound occurred within shorter number of days using the cream of the present invention as compared to the days taken for epithelisation using the conventional cream Therefore one benefit of the cream of the present invention is that it facilitates significantly faster epithelisation of the skin than a control (untreated wound)..

C. Blood Clotting: Blood clotting time was observed in both groups of animals, untreated control group and the test group of animals treated with the product of the present invention. Statistically significant decrease in the blood clotting time in treated group animals was observed when compared with that of the control group animals. The mean percent reduction of 40 - 50 % was observed for the blood clotting time using the product of the present invention.

Film Forming Properties: It is evident from figure 1 that chitosan does not lose its film forming property in the presence of the excipients used for cream preparations in the present invention.

Results And Discussion:

It is evident that the properties of chitosan when used in formulations containing the excipients used in the current invention are not compromised in any way. This has been achieved through a careful selection of excipients. For example, our experiments show that widely used excipients such as xanthan gum or carbomer precipitate in combination with chitosan due to cationic, anionic interactions.

The therapeutic impact, as observed from the animal testing, of the addition of chitosan to corticosteroid, Dexamethasone Acetate, antibacterial Framycetin Sulphate & antifungal agent, Clotrimazole is shown in the following table by considering various aspects of therapeutic cure of a compromised skin condition: Table 10

It is evident that the film forming ability of the chitosan incorporated in the cream allows better access of the antifungal agent, Clotrimazole, antibacterial agent, Framycetin Sulphate and the corticosteroid, Dexamethasone Acetate to the infected / inflamed area and results in better functioning of these APIs.

The therapeutic efficacy of topically applied cream of the present invention is due to the pronounced antifungal & antibacterial activity of the Clotrimazole &

Framycetin Sulphate against the organisms responsible for skin infections, the antiallergic & anti-inflammatory property of corticosteroid, Dexamethasone Acetate, the unique ability of actives to penetrate intact skin and wound healing & soothing properties of chitosan.

It is evident from the foregoing discussion that the present invention offers the following advantages and unique aspects over the currently available dermaceutical compositions for fungal, bacterial skin infections & skin inflammations:

1. The cream of the present invention incorporates a skin- friendly biopolymer in the form of chitosan provides enhanced therapeutic outcomes. This is evident from the reduced blood clotting time, increased epithelial effect, and faster relief from infection and inflammation.

2. The cream of the present invention incorporates a biopolymer without compromising the stability of the cream matrix and without adversely affecting the functioning of known active pharmaceutical ingredients. This has been achieved through a careful selection of functional excipients to bypass undesirable aspects of physio- chemical compatibility/stability and bio-release. 3. The cream of the present invention provides an integrated uni-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations. 4. The novel cream of the present invention is adequately stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage - hence will go a long way in achieving these social objectives.

According to another embodiment of the present invention, there is also provided a process for treating fungal & bacterial skin infections, skin inflammations, and wound healing involving contacting human skin with the above-disclosed composition.

While the above description contains much specificity, these should not be construed as limitation in the scope of the invention, but rather as an exemplification of the preferred embodiments thereof. It must be realized that modifications and variations are possible based on the disclosure given above without departing from the spirit and scope of the invention. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents.

Claims

CLAIMS:

1. A medicinal cream for topical treatment of fungal & bacterial skin infections, skin inflammations, and for related wound healing, wherein said cream comprises an antifungal agent-Clotrimazole, an antibacterial agent in the form of Framycetin Sulphate, a corticosteroid in the form of and a biopolymer in the form of chitosan provided in a cream base, said cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co-solvent, an acid, and water, preferably purified water, said biopolymer being preferably chitosan.

2. A medicinal cream as claimed in claim 1, wherein said cream further comprising any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.

3. A medicinal cream as disclosed in claim 1 wherein:

- said Clotrimazole is added in an amount between about 0.05% w/w and about 5% w/w, preferably between 0.1 and 2.0% w/w; and more preferably about 1.0% w/w and

- said Framycetin Sulphate is added in an amount between about 0.05% w/w and about 5% w/w, preferably between 0.1 and 2.0% w/w; and more preferably about 1.0% w/w and

- said Dexamethasone Acetate is added in an amount between about 0.001% (w/w) and about 5% (w/w), preferably between about 0.01 % and about 2.5% w/w, and more preferably about 0.1% w/w, and - said chitosan is added in an amount between about 0.01% and about 1% by weight, preferably from about 0.01% w/w to about 0.5% w/w and most preferably about 0.25% w/w, said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Polysorbate-80, Span-80 and the like and added in an amount from about 1% (w/w) to 20% (w/w); said waxy materials is selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 30% (w/w); said co-solvent is selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene

Glycol-400, Isopropyl Myristate and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w); said acid is selected from a group comprising HCl, H₂SO₄, HNO3, Lactic acid and the like, or any combination thereof, and added in an amount from about 0.005% (w/w) to 0.5% (w/w); said preservative is selected from a group comprising

Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, or any combination thereof, and added in an amount from about 0.05% (w/w) to 0.5% (w/w); said water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 45% (w/w) to 65% (w/w), more preferably 55% (w/w) to 62% (w/w), preferably purified water.

4. A novel medicinal cream as claimed in claims 1 and 3 further comprising a buffering agent which is selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof and added in an amount from about 0.05% (w/w) to 1.00% (w/w).

5. A novel medicinal cream as claimed in claims 1 , 3, and 4 further comprising an antioxidant which is selected from a group comprising Butylated Hydroxy

Anisole, Butylated Hydroxy Toluene and the like, or any combination thereof, and added in an amount from about 0.001% (w/w) to 1% (w/w).

6. A novel medicinal cream as claimed in claims 1 and 3 to 5 further comprising a chelating agent which is selected from a group comprising Disodium EDTA and the like, or any combination thereof, and added in an amount from about

0.05% (w/w) to 1% (w/w).

7. A novel medicinal cream as claimed in claims 1 and 3 to 6 further comprising a humectant which is selected from a group comprising Glycerin, Sorbitol,

Propylene Glycol and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w).

8. A process of making a cream, said process comprising the steps of providing an antifungal agent in the form of Clotrimazole, an antibacterial agent in the form of Framycetin Sulphate, a corticosteroid in the form of Dexamethasone Acetate, and a biopolymer in the form of chitosan in a cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co-solvent, an acid, and water, preferably purified water, and mixing all the ingredients together to form a homogeneous cream.

9. A process of making a cream as claimed in claim 8, wherein the ingredients further comprise any of a group comprising a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.