WO2016199002A1

WO2016199002A1 - A medicinal cream made using mometasone furoate and incorporating a biopolymer and a process to make it

Info

Publication number: WO2016199002A1
Application number: PCT/IB2016/053261
Authority: WO
Inventors: Subramaniam Vanangamudi Sulur; Murali MR. S; Madhavan MR. SRINIVASAN
Original assignee: Individual
Current assignee: Individual
Priority date: 2015-06-10
Filing date: 2016-06-03
Publication date: 2016-12-15
Anticipated expiration: 2017-12-10

Abstract

The present invention is directed to a composition for treating skin inflammation (Dermatitis), skin regeneration & rejuvenation and wound healing containing a Chitosan component used for the treatment of skin regeneration & rejuvenation and wound healing, Mometasone Furoate used in treating skin inflammations, a cream base containing any of the ingredients selected from a group comprising primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, buffering agents, anti-oxidants, chelating agents and humectants, and purified water. The invention has the advantage that it reduces blood clotting time, increases epithelial effect, and provides faster relief from infection and inflammation. The invention also provides an integrated unit-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations. Furthermore, the invention is adequately stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage.

Description

A Medicinal Cream Made Using Mometasone Furoate And Incorporating A Biopolymer And A Process To Make It

Background of Invention

Dermatitis is an inflammation of the skin. Dermatitis actually refers to a number of skin conditions that inflame the skin. Dermatitis is characterized by skin that may be red, swollen, blistered, scabbed, scaly, oozing, or itchy. Some types of dermatitis are caused by allergies, while the majority does not have any known causes.

There are many types of dermatitis that require clinical care by a physician or other healthcare professional. The following are some of the examples of Dermatitis: Atopic Dermatitis (Eczema), Contact Dermatitis, Dermatitis Herpetiformis, Generalized Exfoliative Dermatitis, Seborrheic Dermatitis.

Wounds are heterogeneous and the wound healing process is of a multifactorial nature, influenced by many factors and compounds, introduced externally.

Throughout history, humans have searched for materials to promote wound healing. A great variety of preparations and products have been used, ranging from hot oils, papyri and waxes of the Egyptians to the cotton and gauze tissues, which are still used. Until the 1960s, there had been a minimum of research and development into wound management products, and very few of the products have been shown to be of great benefit. Since the understanding of wound-healing biology has advanced, it may now be the time when the rational design of effective drug formulations to promote healing is a real possibility.

In order to understand the field of wound healing relative to the use of compounds or agents, a few statements have to be made. The definition of wound pharmacology is the study of agents and their actions in wound environment. Three classes of agents can be discussed; drugs, biologies and special biologies such as those produced by biotechnology. Conventional drugs can be categorized by route of administration (Topical, Systemic or Both). The kinetics are relatively easy to study and can serve as a guide for development of more complex agents. In contrast, biologies are naturally occurring synthetic or modified proteins and carbohydrates. There are generally large molecules that possess an increased complexity and a pleiotropic effect. In current dermatological therapy there are some unmet medical needs, which have to be addressed. For example, Dermatological conditions are often caused by allergy accompanied by inflammation, tissue damage, irritation and itching.

Numerous treatments both topical and systemic are currently employed for the treatment of above skin inflammations. Topical and systemic inflammatory treatment compositions typically employ corticosteroids in a base component. The active ingredients typically comprise Corticosteroids such as Betamethasone dipropionate, Beclomethasone dipropionate, Hydrocortisone, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Mometasone furoate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate, Diflorasone diacetate, Prednicarbate and like.

Chitosan is a biopolymer with skin regeneration and rejuvenation properties due to its unique physical nature. Chitosan acts as a biocatalyst in accelerating the wound healing. Due to its positive charge it couples with negatively charged blood cells and aids in clotting of blood. It also helps in controlling the microbial mobility because of its charge and prevents spread of infections. As a micro-film forming bio material, Chitosan helps in reducing the width of the wound, controls the oxygen permeability at the site, and absorbs wound discharge, which is very much essential for faster wound healing. It also reduces the itching by providing a soothing effect.

Therefore the combination of Chitosan with steroids is a unique and novel since these combinations are not available globally and presented in patient friendly cream formulations.

Wound Healing:

Wound healing, or wound repair, is the body's natural process of regenerating dermal and epidermal tissue. When an individual is wounded, a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damage.

There are two types of cutaneous wounds. They are

a) Full-Thickness Wounds

b) Partial-Thickness Wounds

Physiology of Wound Healing

Wound healing is a complicated process that recruits at least 4 distinct cell types. Though the process is continuous, it is commonly referred to as occurring in "phases." The main phases of wound healing include coagulation, which begins immediately after injury; inflammation, which initiates shortly thereafter; a migratory and proliferate process, which begins within days and includes the major processes of healing; and a remodeling process, which may last for up to a year and is responsible for scar tissue formation and development of new skin.

Wound healing is affected by several factors. These include local factors (growth factors, edema and ischemia, low oxygen tension, and infection), regional factors (arterial insufficiency, venous insufficiency and neuropathy), systemic factors (inadequate perfusion and metabolic disease) and other miscellaneous factors, such as nutritional state, preexisting illnesses, exposure to radiation therapy and smoking. In general, chronic wounds may be managed by preventing or medically treating infections through debridement and occlusive dressings. For wounds that are unresponsive to such interventions, the use of skin replacements is becoming a viable option. Wound healing is essential to continued life. Its components overlap and are commonly seen as "phases". Coagulation performs its function of hemostasis, initiating healing and leaving behind messengers that bring on an inflammatory process. Inflammation protects the wound from infection and leaves behind its own set of messengers, important signals that bring on the migration and proliferation of macrophages, lymphocytes, fibroblasts, keratinocytes and endothelial cells. A phase follows in which fibroblasts become dominant and a collagenous matrix is deposited. Finally, there is a remodeling process that rarely restores full, normal structure. Each of these components plays a specific and irreplaceable role in the continuum of healing. A delay in, or absence of any one can result in a prolongation or even a prohibition of healing.

Factors Affecting Wound Healing

Given the complex interplay of multiple phases and components in wound healing, it is not surprising that many factors affecting the healing process have been identified. Recognizing and understanding such factors may lead to improved clinical management of recalcitrant or chronic wounds. Patients with risk factors for wound healing may be identified and treated more aggressively or may be better managed for prevention of infection and/or nonhealing wounds. Factors affecting wound healing fall into several categories, based on their source; local, regional or systemic. Some of the more commonly used active compounds found in topical skin inflammations, skin regeneration & rejuvenation treatment formulations include Topical skin regeneration & rejuvenation agent such as Chitosan and the like and topical Corticosteroids such as Mometasone Furoate, and like. Brief Description Of Figures

Figure 1 shows the film formed when using the formulation of the present invention.

Brief Summary of the Invention

The present invention is directed to a composition for treating skin inflammation (Dermatitis), skin regeneration & rejuvenation and wound healing containing a) A Chitosan component which is an unbranched binary polysaccharides consisting of the two units N-acetyl-D-glucosamine and D-glucosamine used for the treatment of skin regeneration & rejuvenation and wound healing. b) Corticosteroids like Mometasone Furoate used in treating skin inflammations. c) A cream base containing any of the ingredients selected from a group comprising primary and secondary emulsifiers, waxy materials, co- solvents, acids, preservatives, buffering agents, anti-oxidants, chelating agents and humectants. d) Water

The active ingredients a Chitosan component, a corticosteroid are incorporated in cream base for use in treating 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 active compounds which may be employed in the present invention are topical corticosteroids like Mometasone Furoate and a bio polymer for treating skin inflammation and wounds. 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, Mometasone Furoate, and like.

These actives require a base component to be used in the pharmaceutical composition that uses the actives, since the actives 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, chelating agents, humectants and the like. Chitosan

Chitosan is an un-branched binary polysaccharide consisting of the two units N-

Acetyl-D-glucosamine and D-glucosamine linked in β (1, 4) manner.

The chemical name of Chitosan is Poly-β- (1, 4)-2-Amino-2-deoxy-D-glucose. Chitosan is produced by partial deacetylation (Not less than 70 %) of Chitin, which is extracted from the shells of shrimp and crab. Chitosan finds its application in various areas including Pharmaceutical, Cosmetics and Food industry. It is official in Ph. Eur. and proposed to be official in USP as an excipient. It is used as a film forming, mucoadhesive and viscosity-increasing agent. It is also 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 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. The properties of Chitosan allow it to rapidly clot blood, and have recently gained approval in the USA for its use in bandages and other hemostatic agents. Chitosan is hypoallergenic, and has natural anti-bacterial properties, further supporting its use. A therapeutic application for chitin was first recognized by fishermen in ancient China who revered it for its natural wound healing properties. More recently a number of scientific studies have been conducted to investigate how chitin and its derivative chitosan may modulate wound healing.

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.

Wound repair is a complex process involving an integrated response by many different cell types controlled by a variety of growth factors. During the initial inflammatory phase fibroblasts start to enter the wound where they synthesize and later remodel new extracellular matrix material of which collagen is the main component. The dermal response is only one aspect of cutaneous wound repair however, the outermost and vital barrier layer, the epidermis which is composed of several layers of keratinocytes must also be restored. In injured skin, basal layer keratinocytes migrate from the wound edge and from injured epidermal appendages (hair follicles and sweat glands) into the defect, moving over the newly formed dermal scaffolding. They proliferate, stratify and differentiate to produce a neo-epidermis to cover the wound and restore the skin's barrier function.

Topical Corticosteroids

Topical corticosteroids are a powerful tool for treating skin diseases. Corticosteroids include drugs like Mometasone Furoate , Betamethasone dipropionate, Beclomethasone dipropionate, Hydrocortisone, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, Halcinonide, Fluocinonide, Triamcinolone acetonide, Fluticasone propionate, Amcinonide, Hydrocortisone acetate, Diflorasone diacetate, Prednicarbate, etc. Understanding the correct use of these agents will result in the successful management of a variety of skin problems. Topical corticosteroids have anti-inflammatory, antipruritic and vasoconstrictive properties.

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 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 Mometasone Furoate, Betamethasone Dipropionate, Betamethasone Valerate, Diflorasone Diacetate, Clobetasol Propionate, Halobetasol Propionate, Desoximetasone, Diflorasone Diacetate, Fluocinonide, Triamcinolone Acetonide, etc. Low potency topical steroids include Desonide, Fluocinolone acetate, and Hydrocortisone, etc. Topical corticosteroid is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses.

Mometasone Furoate

Mometasone Furoate is a synthetic corticosteroid with anti- inflammatory activity Chemically, Mometasone Furoate is 9a, 21-dichloro-l ip, 17-dihydroxy-16a- methylpregna-1, 4-diene-3, 20-dione 17-(2 -Furoate), with the empirical formula C27H30CI2O6, and a molecular weight of 521.4 g/mol.

Mometasone Furoate is a white to off-white powder practically insoluble in water, slightly soluble in octanol, and moderately soluble in ethyl alcohol. Mometasone Furoate is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses. Pharmacology

Mometasone Furoate is a medium-potency synthetic corticosteroid with antiinflammatory, antipruritic, and vasoconstrictive properties. Mometasone Furoate depresses formation, release, and activity of endogenous mediators of inflammation, including prostaglandins, kinins, histamine, liposomal enzymes, and complements system; modifies body's immune response.

Mometasone Furoate have been shown to have a wide range of inhibitory effects on multiple cell types (e.g. mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (e.g. histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These antiinflammatory actions of corticosteroids may contribute to their efficacy in asthma and in skin lesions.

Mechanism of Action

Unbound Mometasone Furoate cross cell membranes and bind with high affinity to specific cytoplasmic receptors. Inflammation is decreased by diminishing the release of leukocytic acid hydrolases, prevention of macrophage accumulation at inflamed sites, interference with leukocyte adhesion to the capillary wall, reduction of capillary membrane permeability, reduction of complement components, inhibition of histamine and kinin release, and interference with the formation of scar tissue. The antiinflammatory actions of Mometasone Furoate are thought to involve phospholipase A₂ inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Mometasone Furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. Pharmacokinetics

Absorption

Compared with IV administration, bioavailability of an inhaled dose of Mometasone Furoate is less than 1%. Mean C_maX ranged from 94 to 114 pcg/mL and the time to C_maX ranged from about 1 to 2.5 h.

Distribution

The in vitro protein binding of Mometasone Furoate was found to be from 98% to 99%. Metabolism

Mometasone Furoate is primarily and extensively metabolized in the liver by the CYP3 A4 isozyme to multiple metabolites. Elimination

Terminal t _½ of Mometasone Furoate is about 5 h. Excretion up to 7 days is primarily in the feces (74%) and, to a lesser amount, in the urine (8%).

Indications

Mometasone Furoate is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses.

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 somewhere 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 provides 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 Chitosan Cream with Mometasone Furoate, of the present invention 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. This is to be achieved in the safe pH compatible environment of skin (3.0 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 invention is highly efficacious due to the pronounced anti-inflammatory and wound healing activity of the active ingredients, which are available in ultramicro-size/colloidal form, which enhances skin penetration.

Rationale for the Use of Mometasone Furoate and Chitosan Combination: In current dermatological therapy there are some unmet medical needs, which have to be addressed. For example, Dermatological conditions are often caused by allergy accompanied by inflammation, irritation and itching. Numerous topical treatments are currently employed for the treatment of skin inflammations. However there is no effective therapy for protecting the skin, skin regeneration & rejuvenation, controlling superficial wounds .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 regeneration & rejuvenation, wound healing properties with Mometasone Furoate is proposed as a novel cream.

Mometasone Furoate provides much wanted rapid relief of the pruritus. Therapy with only Mometasone Furoate is recommended for severe eczematic eruptions to provide instant relief to patients from itching and burning. Also the monotherapy with Mometasone Furoate will help in avoiding the allergenic response to antifungals and antibacterials. The inclusion of Chitosan in the formulation takes care of many attributes, which are considered to be very much essential in preventing the degradation of Mometasone Furoate.

The degradation of Mometasone Furoate depends on two factors:

1. pH

2. Presence of aqueous phase (Reference: X.W.Teng et a/. /International Journal of Pharmaceuticals 259 (2003) 129-141)

From the degradation pathway we can see that two groups involve in degradation

1. The C=0 group in Chloroacetyl group at Cn position.

2. The OH group at Cn position. Hence by forming Hydrogen Bond with these two groups the degradation of Mometasone Furoate can be prevented.

As we find from literatures,

1. Chen.C, et al. preparation and characterization of biodegradable Poly (L- lactide)/Chitosan blend. European polymer journal, 41(5), 2005, 958-66 - describes that Chitosan backbone contains many active amino and hydroxyl groups that provide hydrogen bonding. Hence by forming Hydrogen Bond with these two groups the degradation of Mometasone Furoate can be prevented.

2. Yusheng. Q., et al. Enhanced mechanical performance of Poly(propylene carbonate) via hydrogen bonding interaction with o-lauryl Chitosan. Carbonate polymer, 84, 2011, 329-34 - describes that the active amino and hydroxyl groups are participated in intermolecular interaction with the functional groups through hydrogen bonding.

3. Dunia.M., et al. physical interactions in macro porous scaffolds based on poly (Caprolactone)/ Chitosan semi-interpenetrating polymer network. Polymer 50,2009,2058-64- describes the preparation of polymer network with PCL and Chitosan. Here the picture shows the possible interaction between functional group of PCL and Chitosan.

From the above cited literatures, we can propose the possible interaction of Mometasone Furoate and Chitosan. The C=0 group at Cn may interact with NH₂ group and OH group of Chitosan by hydrogen bonding.

Hydrogen bonding interaction is derived from the electron transfer between proton acceptors and proton donars; for NH and C=0 groups, the electron density in N-H bonds may decrease, whereas that in the electron withdrawing C=0 group may increase. (C=0- -— +H-N).

The OH group at Cn position may interact with NH₂ group of Chitosan by hydrogen bonding. (N-H+ O-H) thus stabilizing the Mometasone Furoate.

The combination of Chitosan with Mometasone Furoate 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 with

Mometasone Furoate. As Chitosan is a film forming, biocompatible, non-allergenic biopolymer, it protects the skin by acting as a barrier. In a therapy, Mometasone Furoate takes care of the inflammation. But the issues like skin protection, mobility of pathogens from one site to another, etc are not addressed so far. This present invention will fill this gap by an innovative technology of incorporating Chitosan and tapping the required benefits of skin protection (by way of film forming property), immobilization of pathogenic microbes (due to its cationic electrostatic property) and wound healing.

Chitosan 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 and crabs.

Another reason of great biomedical interest is chemical similarity of Chitosan to GlycosAminoGlycans (GAGs). GAGs like Heparin, Heparin sulfate, Hyaluronic acid and Keratin sulfate are all derivatives of 2-amino-2-deoxy-D-glucose) and present in all parts of human body. GAGs are essential building blocks of macromolecular frame work of connective and other tissues. Fetal wounds are known to heal without scars and this has been attributed to fetal skins being rich in hyaluronic acid (Hyaluronan).

Chitosan/Polyglucosamine is structurally similar to hyaluronan and is expected to assist scarless wound healing. Heparin enhances mitogen by induction and stabilization of fibroblast growth stimulating factor (FGF). Polyglucosamine may promote tissue growth and wound healing by forming complexes with heparin and acting to prolong the half-life of the growth factors. Chitosan is hypoallergenic, and has natural anti-bacterial properties, further supporting its use.

As a 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.

The novel cream of the present invention, are most stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage - hence will go a long way in achieving the objectives.

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. The stability of the product is confirmed by the stability studies performed for 36 months as per ICH guidelines and a comparison of stress studies done for the present invention and samples of commercially available comparable products.

The present invention has a number of embodiments. Embodiment 1: A medicinal cream for topical treatment of skin inflammations, and for related wound healing, wherein said cream comprises Mometasone Furoate, and a biopolymer provided in a cream base, said cream base comprising at least one of each of a primary and a secondary emulsifier, a waxy material, a co-solvent, a preservative, an acid, penetration enhancer, a chelating agent, a buffering agent and water, preferably purified water.

Embodiment no. 2: A medicinal cream as disclosed in the embodiment no. 1, wherein said cream further comprising any of a group comprising an antioxidant, a humectant, or any combination thereof.

Embodiment no. 3: A medicinal cream as disclosed in the embodiment no. 1 wherein

- said Mometasone Furoate is added in an amount between about 0.001% (w/w) and about 5% (w/w), preferably between about 0.01 % (w/w) and about 1%

(w/w), and most preferably about 0.1 % (w/w) and,

- said biopolymer is in the form of chitosan, added in an amount between about 0.01% (w/w) and about 10% (w/w) by weight, and added in an amount preferably from about 0.01% (w/w) to about 1.5% (w/w) and most preferably about 0.5% (w/w) said chitosan being US pharmacopeia 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 50 kDa to 5000 kDa,

- said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Cetyl alcohol, Stearyl alcohol, Isopropyl Myristate, Polysorbate-80, Span-80 and the like from about 1% (w/w) to 25% (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 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 HC1, H₂SO₄, HNO₃, Lactic acid and the like, or any combination thereof, and added in an amount from about 0.005% (w/w) to 1% (w/w); said penetration enhancers are selected from a group comprising Iso Propyl Myristate, Dimethyl Sulphoxide, 2-Pyrrolidone and the like from about 1% (w/w) to 20% (w/w), said preservative is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid, Phenoxyethanol, Benzyl alcohol and the like, or any combination thereof, and added in an amount from about 0.02% (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 35% (w/w) to 60% (w/w), preferably purified water. Embodiment no. 4: A novel cream as disclosed in the embodiment no. 1 and the embodiment no. 2, further comprising a buffering agent which is selected from a group comprising Orthophosphoric acid, Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof, and added in an amount from about 0.01% (w/w) to 1.% (w/w).

Embodiment no. 5: A novel cream as disclosed in the embodiment no. 1, 2, or 3, further comprising an antioxidant which is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, either singly or any combination thereof, to form a proportion from about 0.001% (w/w) to 5% (w/w).

Embodiment no. 6: A novel cream as disclosed in the embodiments 1 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. 7: A novel cream as disclosed in the embodiments 1 to 6, further comprising a humectant which is selected from a group comprising Glycerin, Propylene Glycol, Sorbitol, and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 20% (w/w).

Embodiment no. 8: A process of making a cream is disclosed, said process comprising the steps of providing Mometasone Furoate, and chitosan as a biopolymer in a cream base comprising at least one of each of a primary and a secondary emulsifier, a waxy material, a co-solvent, a preservative, a chelating agent, a buffering agent, a penetration enhancer, an acid, and water, preferably purified water, and mixing all the ingredients together to form a homogeneous cream.

Embodiment no. 9: A process of making a cream as disclosed in the embodiment no. 8, wherein the ingredients further comprise any of a group comprising an antioxidant, a humectant, or any combination thereof.

Embodiment no. 10: A process of making a cream as disclosed in embodiments 7 or 8, wherein said Mometasone Furoate is provided in an amount between about 0.001% (w/w) to about 5% (w/w) by weight, preferably from about 0.01% (w/w) to about 1%) (w/w) by weight and most preferably about 0.1 % (w/w) by weight, and,

said chitosan is being provided in an amount between about 0.01% (w/w) to about 10%) (w/w) by weight, preferably from about 0.01%> (w/w) to about 1.5% (w/w) by weight and most preferably about 0.5% (w/w) by weight (Molecular Weight - 50 kDa to 5000 kDa).

said primary and secondary emulsifier is selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Cetyl alcohol, Stearyl alcohol, Isopropyl Myristate, Polysorbate-80, Span-80 and the like from about 1% (w/w) to 25% (w/w), said waxy material is selected from a group comprising White Soft Paraffin, Liquid Paraffin, Hard Paraffin and the like 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 and the like from about 5% (w/w) to 50% (w/w),

said acid is selected from a group comprising such as HC1, H₂SO₄, HNO₃, Lactic acid and the like from about 0.005% (w/w) to 1% (w/w), said penetration enhancers are selected from a group comprising Iso Propyl Myristate, Dimethyl Sulphoxide, 2-Pyrrolidone and the like from about 1% (w/w) to 20% (w/w),

said preservatives are selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid,

Phenoxyethanol, Benzyl alcohol and the like from about 0.02% (w/w) to 0.5% (w/w),

said chelating agents are selected from a group comprising Disodium

EDTA and the like from about 0.05% (w/w) to 1% (w/w),

said buffering agents are selected from a group comprising

Orthophosphoric acid, Di Sodium Hydrogen Ortho Phosphate, Sodium

Hydrogen Ortho Phosphate and the like from about 0.01% (w/w) to 1.%

(w/w), - said water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 35% (w/w) to 60% (w/w), preferably purified water,

said antioxidant is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, either singly or any combination thereof, to form a proportion from about 0.001% (w/w) to 5%

(w/w),

said humectants are selected from a group comprising Glycerin, Propylene Glycol, Sorbitol, and the like from about 5% (w/w) to 20% (w/w), and combining/mixing the above ingredients to make a pharmaceutically acceptable cream.

Embodiment no. 11: A novel cream as disclosed in any of the foregoing embodiments, wherein chitosan has a molecular weight range of 50 kDa to 5000 kDa.

The present invention will be further elucidated with reference to the accompanying examples, which are however not intended to limit the invention in any way whatever.

Examples

Table 1: Mometasone Furoate (0.1%) + Chitosan Cream

Table 2: Mometasone Furoate (0.1%) + Chitosan Cream

Experimental Data

API-stability experiments were carried out using the product of the present invention and products currently commercially available. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the API over a period of time. Tests were also carried out to assess the stability by subjecting the product to stress studies such as autoclave test and oxidative degradation test. Further, in vitro antimicrobial zone of inhibition studies and preclinical studies such as blood clotting studies, in vitro diffusion study& skin blanching study were also carried out over a period of time. Each gram of product of the present invention used for the tests contained Mometasone Furoate (0.1% w/w) in the finished product. The product used for the Stability Studies tests contained approximately 5% extra API (overages). The product of the present invention used for studies contained Mometasone Furoate (0.1% w/w). It was packaged in an aluminum collapsible tube and each gram of the product contained 1 mg of Mometasone Furoate (in conformance with USP).

PRODUCT NAME: MOMETASONE FUROATE CREAM

PACK: Aluminum collapsible tube Composition: for each g: Mometasone Furoate 0.1% (w/w)

Table 3: Description Test, Batch No: MFC-25

Measured parameter: Physical appearance

0 Initial (best) value of measured parameter: Homogeneous white to off white viscous cream (HWOWVC) (C indicates compliance with acceptance limit value) Method of measurement: Observation by naked eye

5 Table 4: pH test Batch No: MFC-25

Measured parameter: pH Limit of measured parameter: 4.0 - 5.5

Method of measurement: Digital pH meter

Table 5: Assay (%) Test, Batch No: MFC-25

Measured parameter: Assay (%) Limit of measured parameter: 90

Method of measurement: HPLC method

Table 6: Description Test, Batch No: MFC-26

Measured parameter: Physical appearance

Initial (best) value of measured parameter: Homogeneous white to off white viscous cream (HWOWVC) (C indicates compliance with acceptance limit value) Method of measurement: Observation by naked eye

Table 7: pH Test, Batch No: MFC- 26

Measured parameter: pH Limit of measured parameter: 4.0 -

Method of measurement: Digital pH meter

Table 8: Assay (%) Test, Batch No. MFC-26

Measured parameter: Assay (%) Limit of measured parameter: 90

Method of measurement: HPLC method

Table No 9: Description Test, Batch No: MFC-27

Measured parameter: Physical appearance

Table 10: pH Test, Batch No. MFC- 27

Measured parameter: pH Limit of measured parameter: 4.0 - 5.5

Method of measurement: Digital pH meter

Table 11: Assay (%) Test, Batch No: MFC-27

Measured parameter: Assay (%) Limit of measured parameter: 90

Method of measurement: HPLC method

It is apparent from tables 3-11 that on all counts, the pH value, the physical appearance, and stability, the product of the present invention is quite good. The present invention will be further elucidated with reference to the accompanying example containing the composition and stability studies data, which are however not intended to limit the invention in any way whatever.

From the above data, it is evident that product of the present invention is quite stable at ambient conditions and also at elevated temperature & humid conditions of storage. This is a major advantage over the currently available Mometasone Furoate Cream. The stability of the product is further ascertained by the shelf-life prediction of the formulation using Arrhenius plot of degradation employing Nova-LIMS software. The enhanced stability of the present invention is achieved by the addition of biopolymer to the formulation.

Method of Application of 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. Three aspects were tested - Blood clotting time, In-vitro diffusion study, Film forming and Vasoconstrictor In-vivo Bioequivalence Study. A. Blood Clotting Time

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 19.35% was observed for the blood clotting time using the product of the present invention.

B. In-vitro Diffusion Study

The Formulations of test product and reference product were evaluated by performing the release studies by diffusion using keshary chein apparatus. Formulation of test and reference product was released about 38.6% and 28.5% of the label claim at the end of 9 hours respectively.

C. Film Forming Property

It is evident that Chitosan does not lose its film forming property in the presence of the excipients used for cream preparations in the present invention. D. Skin inflammatory study

The Skin inflammatory Study was concluded statistically that the Croton oil application in to ear of rats has produced 70% edema in control group. The present invention formulations of Mometasone Furoate Cream and market Cream have reduced the edema produced by croton oil. The highest reduction in edema is by Mometasone Furoate Cream (invention) was found when compared with marketed product.

E. Acute dermal irritation study

The primary skin irritation is the production of reversible damage in the skin. Topical exposure of chemicals, drugs etc., can lead to the adverse skin effects. According to the severity and reversibility of effects, the products can be distinguished into irritant or corrosive. So the experimental study was performed to assess the possible hazard likely to arise from exposure of topical formulation to the human skin. Thus, primary skin irritation study was carried out for the newly formulated dermal cream - Mometasone Furoate Cream (invention) to determine its irritant response to the skin after single exposure. From the experimental study it was concluded that the formulation of Mometasone Furoate Cream (invention) scored the primary skin irritation index of 0. Hence, the Mometasone Furoate Cream (invention) was non-irritant and dermal-friendly.

F. Vasoconstrictor In-vivo Bioequivalence Study

Skin Blanching study of the Mometasone Furoate cream of the present invention was determined through a randomized double blind Parallel group pharmacodynamic Skin Blanching Study with 23 healthy human voluntaries. The 90% CI value found to be a 88.5-112.6 it's within the limit range hence the invention cream formulation are bioequivalent with the conventional cream. An in-vivo bioequivalence study by comparison of vasoconstriction effect on present invention cream of Mometasone Furoate with the reference listed conventional cream carried out with 23 human healthy voluntaries an 8 patch of 4cm² area were marked on flexor surface of the subjects forearm concluded that as the number of evaluable subjects go up the 90% interval limits are also narrowed down suggesting the test product of Mometasone Furoate and the reference listed conventional cream tend towards bioequivalent.

G. Clinical study

A randomized parallel group, double blinded active controlled clinical trial have been done to comparing efficacy of Mometasone Furoate 0.1 % cream of invention with other commercially available cream.

The trial conducted unequivocally establishes the clinical therapeutic equivalence in both the test & reference products based on statistical analysis. VAS score data shows that mean visual analogue scale score for present invention of invention 2.4 whereas commercially available cream is 1.3 at visit 3, it clearly indicates that severity of wound is lesser in present invention. Global score index (GSI) data shows that mean Global Score Index for present invention is 0.2 whereas commercially available cream is 1 at visit 3, it clearly indicates that severity of wound is lesser in present invention. Physician global evaluation score (PGES) shows that 60% population from present invention achieved excellent results but only 20% achieved excellent results with commercially available cream at visit results with commercially available cream at visit 3.

Summary statistics of patient's compliance confirmed that 40 % of the study population has achieved score zero i.e. absence of signs of itching or indication of pain and 60 % of the study population has achieved score zero i.e. evidence of mild itching and irritation from the group that received present invention but only 40 % of the study population has achieved score zero i.e. absence of signs of itching or indication of pain and 30 % of the study population has achieved score zero i.e. evidence of mild itching and irritation, 30 % of the study population achieved score two i.e. evidence of moderate itching and irritation with the same with commercially available cream group at visit 3.

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 studies on animal and human subjects, with addition of Chitosan to Mometasone Furoate a corticosteroid shown in the following table (Table 12) by considering various aspects of therapeutic cure of a compromised skin condition:

Table 12

It is evident that the film forming ability of the Chitosan incorporated in the cream allows better access of the anti-inflammatory agent, Mometasone Furoate to the infected area and results in better functioning of this API.

The therapeutic efficacy of topically applied cream of the present invention is due to the pronounced anti-inflammatory activity of the Mometasone Furoate against the inflammation, 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 inflammations of the skin:

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 unit-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 with longer shelf-life.

The therapeutic efficacy of topically applied innovative anti-inflammatory cream with Chitosan is due to the pronounced activity of the active Mometasone Furoate - corticosteroid against skin inflammations - dermatitis & allergic conditions, the unique ability of actives to penetrate intact skin and skin regeneration & rejuvenation, wound healing and soothing properties of Chitosan.

According to another embodiment of the present invention, there is also provided a process for treating skin inflammations and for skin regeneration & rejuvenation with 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 skin inflammations, and for related wound healing, wherein said cream comprises Mometasone Furoate, and a biopolymer provided in a cream base, said cream base comprising at least one of each of a primary and a secondary emulsifier, a waxy material, a co-solvent, a penetration enhancer, a preservative, a chelating agent, a buffering agent, an acid, and water, preferably purified water.

A medicinal cream as claimed in claim 1, characterized in that said cream further comprising any of a group comprising an anti-oxidant, a humectant, or any combination thereof.

A medicinal cream as claimed in claims 1 or 2, characterized in that

said Mometaasone Furoate is added in an amount between about 0.001% (w/w) and about 5% (w/w), preferably between about 0.01 % (w/w) and about 1% (w/w), and most preferably about 0.1 % (w/w) and,

said biopolymer is in the form of chitosan, added in an amount between about 0.01% (w/w) and about 10% (w/w) by weight, and added in an amount preferably from about 0.01% (w/w) to about 1.5% (w/w) and most preferably about 0.5% (w/w), said chitosan being US pharmacopeia 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 50 kDa to 5000 kDa,

said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Cetyl alcohol, Stearyl alcohol, Isopropyl Myristate, Polysorbate-80, Span-80 and the like from about 1% (w/w) to 25% (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 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 HC1, H₂SO₄, HN03, Lactic acid and the like, or any combination thereof, and added in an amount from about 0.005% (w/w) to 1% (w/w); said penetration enhancers are selected from a group comprising Iso Propyl Myristate, Dimethyl Sulphoxide, 2-Pyrrolidone and the like from about 1 % (w/w) to 20% (w/w), said preservative is selected from a group comprising Methylparaben, Propylparaben, Chlorocresol, Potassium sorbate, Benzoic acid, Phenoxyethanol, Benzyl alcohol and the like, or any combination thereof, and added in an amount from about 0.02% (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 35% (w/w) to 60% (w/w), preferably purified water.

A medicinal cream as claimed in any of claims 1 to 3, characterized in that it further comprises a buffering agent which is selected from a group comprising Orthophosphoric acid, Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like, or any combination thereof, and added in an amount from about 0.01% (w/w) to 1% (w/w). A medicinal cream as claimed in any of claims 1 to 5, characterized in that it further comprises 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).

A medicinal cream as claimed in any of claims 1 to 4, characterized in that it further comprises an anti-oxidant, wherein said anti-oxidant is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, either singly or any combination thereof, to form a proportion from about 0.001% (w/w) to 5% (w/w).

A medicinal cream as claimed in any of claims 1 to 6, characterized in that it further comprises a humectant which is selected from a group comprising Glycerin, Propylene Glycol, Sorbitol, and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 20% (w/w).

A process of making a medicinal cream, characterized in that said process comprises the steps of providing Mometasone Furoate, and chitosan as a biopolymer in a cream base comprising at least one of the components selected from a group comprising a primary and a secondary emulsifier, a waxy material, a co-solvent, a penetration enhancer, a preservative, a chelating agent, a buffering agent, an acid, and water, preferably purified water, and mixing all the ingredients together to form a homogeneous cream.

A process as claimed in claim 8, characterized in that the list of components further comprises any of the components selected from a group comprising an antioxidant, a humectant, or any combination thereof. A process as claimed in any of claims 7 to 9, characterized in that said Mometasone Furoate is provided in an amount between about 0.001%) (w/w) to about 5% (w/w) by weight, preferably from about 0.01%> (w/w) to about 1%) (w/w) by weight and most preferably about 0.1 %> (w/w) by weight, and,

said chitosan is being provided in an amount between about 0.01%> (w/w) to about 10%) (w/w) by weight, preferably from about 0.01%> (w/w) to about 1.5% (w/w) by weight and most preferably about 0.5% (w/w) by weight ( Molecular Weight - 50 kDa to 5000 kDa ). said primary and secondary emulsifier is selected from a group comprising Cetostearyl alcohol, Cetomacrogol-1000, Cetyl alcohol, Stearyl alcohol, Isopropyl Myristate, Polysorbate-80, Span-80 and the like from about 1% (w/w) to 25% (w/w),

said waxy material is selected from a group comprising White Soft Paraffin, Liquid Paraffin, Hard Paraffin and the like from about 5% (w/w) to 30% (w/w),

said buffering agents are selected from a group comprising Orthophosphoric acid, Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.01% (w/w) to 1% (w/w), said water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 35% (w/w) to 60% (w/w), preferably purified water, said antioxidant is selected from a group comprising Butylated Hydroxy Anisole, Butylated Hydroxy Toluene and the like, either singly or any combination thereof, to form a proportion from about 0.001% (w/w) to 5% (w/w),

said chelating agents are selected from a group comprising Disodium

EDTA and the like from about 0.05% (w/w) to 1% (w/w), said humectants are selected from a group comprising Glycerin,

Propylene Glycol, Sorbitol, and the like from about 5% (w/w) to 20%

(w/w),

and combining/mixing the above ingredients to make a pharmaceutically acceptable cream. 11. A medicinal cream as claimed in any of claims 1 to 7, wherein said chitosan has a molecular weight range of 50 kDa to 5000 kDa.