WO2016198997A1

WO2016198997A1 - A medicinal cream made using betamethasone valerate and incorporating bio-polymer and a process to make the same

Info

Publication number: WO2016198997A1
Application number: PCT/IB2016/053256
Authority: WO
Inventors: Subramaniam Vanangamudi Sulur; Murali S; Madhavan 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, Betamethasone Valerate 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 Betamethasone Valerate And Incorporating Bio-polymer And A Process To Make The Same

Background Of The 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. Fishermen in ancient China first recognized a therapeutic application for chitin for its natural wound healing properties. More recently a number of scientific studies have been conducted to investigate how chitin and its chitosan derivative may modulate wound healing. 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 Valerate, Betamethasone dipropionate, Beclometasone dipropionate Hydrocortisone, Clobetasol propionate, Clobetasone butyrate, Halobetasol propionate, 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 and rejuvenation treatment. Formulations include topical skin regeneration and rejuvenation agent such as Chitosan and the topical Corticosteroids such as Betamethasone Valerate, 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 Betamethasone Valerate 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 ingredient corticosteroid and chitosan component are incorporated in cream base for use in treating skin inflammation due to allergy, itching and wounds on human skin, above identified composition have good contact with the wounded human skin.

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 Betamethasone Valerate 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, Betamethasone Valerate, 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, 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 European Pharmacopeia and official in USP/NF 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 formulation.

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. Chitosan's properties allow it to rapidly clot blood, and has recently gained approval in the USA for 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 chitosan derivatives 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 extracelluar 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 Betamethasone Valerate, Betamethasone Dipropionate, Beclometasone 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 antiinflammatory, 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 Betamethasone Valerate, 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.

Betamethasone Valerate

Betamethasone is a moderately potent glucocorticoid steroid with antiinflammatory and immunosuppressive properties. Unlike other drugs with these effects, betamethasone does not cause water retention. It is applied as a topical cream, ointment, foam, lotion or gel to treat itching (e.g. from eczema). Betamethasone sodium phosphate is sometimes prescribed as an intramuscular injection (I.M) for itching from various ailments including allergic reactions to poison ivy and similar plants.

The compound is available as a number of ester derivatives: Dipropionate (branded as Diprosone, Diprolene and others), Sodium Phosphate and Valerate (branded as Betnovate, Celestone and others). Betamethasone Valerate is chemically designated as 9-Fluoro-l ip, 17, 21- trihydroxy- 16P-methylpregna- 1 ,4-diene-3 ,20-dione 17-valerate.

The molecular formula and weight of Betamethasone Valerate are C27H37FO6 and 476.58 g/mol respectively. 1.2 mg of Betamethasone Valerate is equivalent to 1.0 mg Betamethasone. The topical corticosteroids constitute a class of primarily synthetic steroids and are used as anti-inflammatory and antipruritic agents. Betamethasone Valerate is a white to practically white, odorless powder. It melts at 190° C with decomposition. It is practically insoluble in water, freely soluble in acetone and in chloroform, soluble in alcohol, and slightly soluble in benzene and in ether. Pharmacology & Mechanism of Action

Betamethasone Valerate as a topical corticosteroid, has anti-inflammatory, antipruritic and vasoconstrictive actions.

The mechanisms of anti-inflammatory activity of the topical corticosteroids are unclear. Various laboratory methods, including vasoconstrictor assay, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. The exact mechanism of anti-inflammatory action of Betamethasone Valerate is unknown, however it produces multiple glucocorticoid and mineralocorticoid effects. 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

Betamethasone Valerate is 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 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 Chitosan Cream with Betamethasone Valerate, 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. 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 anti-inflammatory & wound healing activity of the active ingredients, which are available in ultramicro-size, colloidal form, which enhances skin penetration.

Rationale for the Use of Betamethasone Valerate 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 and rejuvenation, controlling superficial wounds. To meet this need and to bring affordable, safe therapy to the dispersed segment of population across all countries/communities, a therapy with unique combination of Chitosan, a biopolymer with skin regeneration and rejuvenation, wound healing properties with Betamethasone Valerate is proposed as a novel cream.

Betamethasone Valerate provides much wanted rapid relief of the pruritus.

Therapy with only Betamethasone Valerate is recommended for severe eczematic eruptions to provide instant relief to patients from itching and burning. Also the monotherapy with Betamethasone Valerate 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 treating skin ailments.

The combination of Chitosan with Betamethasone Valerate 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 Betamethasone Valerate. As Chitosan is a film forming, biocompatible, non-allergenic biopolymer, it protects the skin by acting as a barrier.

In a therapy, Betamethasone Valerate 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 present invention has the following embodiments. Embodiment 1: A novel dermaceutical cream for topical treatment of skin inflammations, and for related wound healing, wherein said cream comprises Betamethasone Valerate, 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, and water, preferably purified water.

Embodiment no. 2: A novel dermaceutical cream as disclosed in the 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. 3: A novel dermaceutical cream as disclosed in the embodiment no. 1 wherein

- said Betamethasone Valerate 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 0.12% (w/w) and,

- said biopolymer is in the form of chitosan, added in an amount between about 0.01%) (w/w) and about 2% (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%o (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 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 50% (w/w), more preferably 40% (w/w) to 49% (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 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% (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 Betamethasone Valerate, 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, 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 a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.

Embodiment no. 10: A process of making a cream as disclosed in embodiments 7 or 8, wherein said Betamethasone Valerate 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 0.12 % (w/w) by weight, and,

said chitosan is being provided in an amount between about 0.01% (w/w) to about 2% (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, 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 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 water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 35% (w/w) to 50% (w/w), more preferably 40% (w/w) to 49% (w/w), preferably purified water.

buffering agents are selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.05% (w/w) to 1% (w/w),

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.

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 of the composition, which are however not intended to limit the invention in any way whatever. Examples

Table 1: Betamethasone Valerate (0.12%) + Chitosan (0.5%)Cream

Table 2: Betamethasone Valerate (0.12%) + Chitosan (0.5%) Cream

The therapeutic efficacy of topically applied innovative anti-inflammatory cream with chitosan is due to the pronounced activity of the active Betamethasone Valerate - 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 invention, there is provided a process for treating skin inflammations and for skin regeneration & rejuvenation with wound healing by contacting human skin with the above-disclosed composition. Experimental Data:

API-stability experiments were carried out (see tables 3 - 11) using the product of the present invention and available reference product. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the API in present invention over a period of time. Tests were also carried out to assess the stability by subjecting the product (present invention) to stress studies such as autoclave and oxidative degradation test contained approximately 5% extra API (overages). It was packaged in an aluminium collapsible tube and each gram of the product contained 1.2 mg of Betamethasone Valerate (in conformance with USP) which is equivalent to 1 mg of Betamethasone (in conformance with USP). Further, in-vitro, preclinical and clinical studies were carried out over a period of time.

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

Table 3: Description test, Batch No. BVC-27

Measured parameter: Physical appearance Method of measurement: Observation by naked eye Best value of measured parameter: Homogeneous white to off white viscous cream (C indicates that the results comply with the initial state)

Table 4: pH test, Batch No. BVC-27

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

Method of measurement: Digital pH meter

Table 5: Assay % test, Batch No. BVC-27

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

Method of measurement: HPLC method

Table 6: Description test, Batch No. BVC-28

Measured parameter: Physical appearance Best value of measured parameter:

Homogeneous white to off white viscous cream (C indicates compliance with the initial state) Method of measurement: Observation by naked eye

Table 7: pH test, Batch No. BVC-28

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

Method of measurement: Digital pH meter

Table 8: Assay % test, Batch No. BVC-28

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

Method of measurement: HPLC method

10 Table 9: Description test, Batch No. BVC-29

Measured parameter: Physical appearance Best value of measured parameter:

Homogeneous white to off white viscous cream (C indicated compliance with initial value) Method of measurement: Observation by naked eye

15 Table 10: pH test, Batch No. BVC-29

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

Method of measurement: Digital pH meter

Table 11: Assay % Test, Batch No. BVC-29 Measured parameter: Assay (%) Limit of measured parameter: 90

Method of measurement: HPLC method

Table 12:

Table 13: Autoclave analysis (%) test

Measured parameter: Assay (%) Method of measurement: HPLC method

0 Table 14: Oxidative degradation analysis (%) test

Measured parameter: Assay (%) Method of measurement: HPLC method

From the above data, it is evident that, the product of the present invention is quite stable at ambient conditions, elevated temperature and humid conditions of 5 storage. Also the autoclave studies and oxidative degradation studies further confirm the stability of the product. 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. Experiments

In-vitro, preclinical and clinical experiments were carried out with the cream in laboratory using suitable models. Four aspects were tested - Diffusion study, Film forming study, Skin Erythema study and Clinical trial.

A. Diffusion study

Diffusion study of the cream of the present invention was determined through pig ear skin. The results indicate the Betamethasone Valerate Cream of the invention and reference product was shown poor diffusion and hence negligible absorption when tested in In-vivo in human volunteers. Hence it can conclude that both the formulation can be applied for the treatment of local inflammation with an advantage that the drug will be localised at the site of inflammation there by providing better therapeutic effect. The release rate of Betamethasone Valerate Cream of the invention was found to be 9.21xl0^"5/hr when compared with reference product shown 6.91xl0^"5/hr at the end of 9 hrs.

B. Film forming property

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.

C. Skin erythema study

The skin inflammatory study was carried out in wistar rat divided in to three group i.e control group, group treated with product of the present invention and group treated with reference product. On application of croton oil in ear of rats has produced 70% edema in control group. The formulations of Betamethasone Valerate Cream of the invention and reference product were effective in reduction croton oil induced edema. Betamethasone Valerate Cream of the invention (67.15%) had shown the highest percentage of reduction in croton oil induced edema than reference product (66.79%).

Table 15: Effect of Betamethasone Valerate Cream of The invention and reference product on croton oil induced skin edema

D. Clinical trial

A randomized, parallel group, double blinded active controlled clinical trial comparing efficacy of Betamethasone Valerate 0.12% Cream of the invention with the reference product A. Visual Analogue Scale (VAS) score clearly indicates that severity of wound was lesser in Betamethasone Valerate Cream of the invention.

B. Global Score Index (GSI) indicates that severity of eczematous dermatitis was lesser in Betamethasone Valerate cream of the invention.

C. Summary statistics of Patient's Compliance confirmed that 70 % of study population has achieved score zero i.e. absence of signs of itching or indication of pain from the group that received Betamethasone Valerate Cream of the invention, but only 0% of study population achieved with reference product.

D. Physician Global Evaluation (PGE) score shows that 40 % population from group, that received Betamethasone Valerate Cream of the invention achieved good and excellent results but only 0 % achieved good and excellent results with reference product.

Based on the statistical results obtained from this study it is concluded that, Betamethasone Valerate 0.12% w/w Cream of the invention than the reference product, shown to be clinically equivalent in terms of anti-inflammatory activity.

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- Betamethasone Valerate Cream (the invention) to determine its irritant response to the skin after single exposure. From the experimental study it was concluded that the formulation of Betamethasone Valerate Cream (the invention) score for the primary skin irritation index was 0. Hence, the Betamethasone Valerate Cream (the invention) was non- irritant and dermal-friendly.

Results and Discussion

The therapeutic impact, as observed from the animal and human volunteers testing, and addition of chitosan to Betamethasone Valerate an anti-inflammatory agent, is shown in the following table (Table 16) by considering various aspects of therapeutic cure of a skin inflammatory condition.

Table 16

It is evident that the film forming ability of the chitosan incorporated in the cream allows better access of the anti-inflammatory agent to the inflamed area and results in better functioning of these API.

The therapeutic efficacy of topically applied cream of the present invention is due to the pronounced anti-inflammatory activity in pruritic manifestations of corticosteroid responsive dermatoses and 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 inflammatory and pruritic manifestations of corticosteroid responsive dermatoses 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 faster relief from inflammation and infection.

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 physicochemical 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.

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 dermaceutical cream for topical treatment of skin inflammations, and for related wound healing, wherein said cream comprises Betamethasone Valerate, 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, and water, preferably purified water.

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

A dermaceutical cream as claimed in claims 1 or 2, characterized in that said Betamethasone Valerate 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 0.12% (w/w) and,

said biopolymer is in the form of chitosan, added in an amount between about 0.01% (w/w) and about 2% (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 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 50% (w/w), more preferably 40%) (w/w) to 49%) (w/w), preferably purified water.

4. A dermaceutical 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 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% (w/w).

5. A dermaceutical 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),

6. A dermaceutical 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).

7. A dermaceutical 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).

8. A process of making a dermaceutical cream, characterized in said process comprises the steps of providing Betamethasone Valerate, 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 preservative, 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 a buffering agent, an antioxidant, a chelating agent, a humectant, or any combination thereof.

A process as claimed in any of claims 7 to 9, characterized in that said Betamethasone Valerate 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 0.12 % (w/w) by weight, and,

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),

Phenoxyethanol, Benzyl alcohol and the like 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 50% (w/w), more preferably 40% (w/w) to 49% (w/w), preferably purified water,

said buffering agents are selected from a group comprising Di Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen Ortho Phosphate and the like from about 0.05% (w/w) to 1% (w/w),

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 dermaceutical cream as claimed in any of claims 1 to 7, wherein said chitosan has a molecular weight range of 50 kDa to 5000 kDa.