Technical field:

A new topical formulation with high stability is provided, the composition comprising clobetasol or pharmaceutically acceptable salts thereof. It is associated with disorders including psoriasis, eczema, and other forms of dermatitis with exhibiting physical and chemical stability at long term shelf life stability condition.

Prior Art:

Clobetasol propionate is a synthetic, fluorinated corticosteroid with chemical name 21- chloro-9-fluoro-1 ip-hydroxy-16p-methyl-3,20- dioxopregna-1 ,4-dien- 17-yl propanoate, and it has the following structural formula (Formula I) with having only one polymorphic form and chiral with 8 stereogenic centers:

Formula I

Clobetasol propionate has an empirical formula of C25H32CIFO5 and a molecular weight of 467 g/mol. It is a white to cream-colored crystalline powder practically insoluble in water. It has been shown to be physically and chemically stable at room temperature (25°C/60% RH). Clobetasol is a very potent topical corticosteroid indicated for adults, elderly and children over 1 year for the short term treatment only of more resistant inflammatory and pruritic manifestations of steroid responsive dermatoses unresponsive to less potent corticosteroids. These include the following psoriasis (excluding widespread plaque psoriasis), recalcitrant dermatoses, lichen planus, discoid lupus erythematosus and other skin conditions which do not respond satisfactorily to less potent steroids.

Topical clobetasol propionate is a corticosteroid that is currently one of the most used treatments for psoriasis and its safety and efficacy is well defined in the medical literature. The cream dosage form of clobetasol propionate is commercially marketed under the trade name of Dermovate® (GlaxoSmithKline, UK) comprising clobetasol propionate 0.05% (w/w).

Dermatitis is a superficial inflammation of the skin, characterized by vesicle formation, erythema, edema, oozing, scaling or crusting lesions, and intense itching. Different types of dermatitis can be distinguished: contact dermatitis, caused by irritants in contact with the skin or by non-irritating substances, to which the subject is allergic; atopic dermatitis, characterized by strong itching and a chronic course; and seborrheic dermatitis, a scaling disease mainly affecting the face and scalp.

One particular form of dermatitis is psoriasis, a chronic, inflammatory, hyper proliferative recurring disease, which affects the skin and joints. In its most typical form, it causes thick, red, scaly patches, called psoriatic plaques, to appear on the skin. Skin rapidly accumulates at these sites and takes on a silvery-white appearance. Plaques most often occur on the skin of the elbows, knees, scalp, lower back, face, palms, and soles of the feet but can affect any skin site.

Another form of dermatitis or inflammation of the epidermis is eczema, persistent skin conditions including dryness and recurring skin rashes. Other skin and mucous membrane conditions include disorders in the mouth, in the vagina, anus, ear and the eyes. Lichen planus is a chronic mucocutaneous disease that affects the skin and the oral mucosa, and presents itself in the form of papules, lesions or rashes.

Psoriasis is a lifelong disorder with onset at any time throughout life, affecting men and women equally and afflicts almost all races in varying frequency rates. Psoriasis usually appears first between the ages of 15 and 30 years and may occur anywhere on the body. Psoriasis causes significant psychological and social distress, and significantly impacts quality of life. Unsatisfactory treatment of the disorder has a considerable adverse impact on patient’s quality of life with patients complaining about the messiness of the topical agents used.

Clobetasol propionate is commercially available in compositions for topical application in form of lotion, spray, cream or shampoo. Moreover, various topical pharmaceutical compositions comprising clobetasol propionate has been proposed in the prior art, claiming the use of particular carriers or excipients.

WO 2006115987 in the name of Dow Pharmaceutical Sciences provides a method for treating psoriasis by spraying a pharmaceutical composition containing an effective amount of clobetasol propionate onto the skin with psoriasis, using a daily treatment for at least 4 weeks. The preferred composition is a spray formulation of clobetasol propionate 0.05%, containing alcohol, isopropyl myristate, an anionic surfactant such as sodium lauryl sulfate, and optionally an antimicrobial compound such as an antifungal compound like undecylenic acid.

WO 2007104895 and WO 2007104897 in the name of Galderma disclosed oil-in-water (o/w) anti-inflammatory emulsions, containing: a) a therapeutically effective amount of at least one steroidal anti-inflammatory agent, notably clobetasol propionate; b) a propenetrating system which includes at least one pro-penetrating glycol and at least one other pro-penetrating agent; a polymeric or non-polymeric emulsifier or one gelling agent. In both cases preferred pro-penetration system are: propylene glycol and isosorbide dimethyl, propylene glycol and ethanol; propylene glycol, monoethylether of diethylene glycol and propylene glycol laurate; propylene glycol and methyl pyrrolidone; propylene glycol, isosorbide dimethyl and ethanol; propylene glycol, methyl pyrrolidone and oleic alcohol.

Other documents of the prior art propose the use of clobetasol in combination with at least a further active ingredient, such as calcitriol (Vitamin D) (see for example W02008110815, EP 1854.466, EP 1875916, US Patent No.2005281850, US Patent No. 2006009426 and FR 2848454): a progesterone derivative (EP 1473300); a prostaglandin (W003092617); or tazarotene (CA2282682).

Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation. Topical corticosteroids can be absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the product formulation and the integrity of the epidermal barrier. Occlusion, inflammation, and/or other disease processes in the skin may also increase percutaneous absorption. Once absorbed through the skin, topical corticosteroids are metabolized, primarily in the liver, and are then excreted by the kidneys. Some corticosteroids and their metabolites are also excreted in the bile.

Dermatological corticosteroids and in particular clobetasol propionate have been provided in a variety of topical formulations such as creams, lotions, gels and the like in attempts to increase the delivery efficiency. However, while enabling direct, localized application of the active agent to the skin surface, these formulations have not provided a complete solution to the problems connected with the stability problems due to degradation of topical compositions. In previous literature studies, clobetasol propionate was found to be incompatible with alkaline substances. It is also known that since it is reactive with oxidizing agents, acidic and alkaline substances and sensitive to light, it should be stored in tightly closed containers that are resistant to light.

It has been recognized that topical dosage forms such as creams comprising clobetasol and other ingredients tend to exhibit stability problems, including phase separation and formation of degradation products in shelf-life stability conditions especially at high temperature and moisture. In addition, commercially available reference product of clobetasol propionate 0.05% Cream, Dermovate®, has the propension of undergoing formation of degradation products during the storage in the presence of heat and moisture. Consequently, there is a need to develop formulation and manufacturing process methods for the production of robust and stable product of clobetasol propionate containing topical formulations.

The problem which the present invention sets out to solve here is therefore to devise a physically and chemically stable composition that allows clobetasol propionate to be combined in a composition, the composition according to the invention also being easy to use and having an acceptable cosmetic character for application to all areas of the body.

The superiority of the present invention with the formulations described in the prior art and reference product is the enhanced stability of the topical formulation with optimizing the amount of used excipients while having same in vitro release which is shown by in vitro release testing for topical cream formulations.

The present invention showed to our surprise that the finished product, being formulated with certain proportions of cetocearyl alcohol and glyceryl stearate, and especially the formula containing citric acid, surprisingly prevents degradation of the product, and as a result the finished product has superior chemical stability, consequently providing the product a surprisingly long durability.

Description of the Invention:

An object of the present invention is to provide stabilized pharmaceutical topical formulation of clobetasol or pharmaceutically acceptable salts thereof as active ingredient. An object of the present invention is to formulate a storage stable pharmaceutical topical composition of clobetasol or pharmaceutically acceptable salts thereof, said formulation comprises 5.0% to 12.0% (w/w) of cetostearyl alcohol based on the total composition and 5.0% to 14.0% (w/w) of glyceryl stearate based on the total composition, wherein the composition with comprising comprises citric acid as pH modifier.

Topical drug delivery systems can be described as self-contained, discrete pharmaceutical semi-solid dosage forms designed to deliver an Active Pharmaceutical Ingredient (API) via the intact skin or body surface, for the purpose of generating a local or regional effect. Topical preparations for cutaneous application are usually comprised of one or more API dissolved or dispersed in a suitable semi-solid base which may be hydrophobic or hydrophilic. Topical dosage forms and their physical properties are summarized below;

Creams and emulsions are the most diverse and widely used dosage forms for topical dermatological applications. Creams are “creamy white” viscous semisolid dosage forms that contain one or more drug substances dissolved or dispersed in a suitable base. They are two-phase systems typically containing hydrophilic ingredient in an aqueous phase and lipophilic ingredients in an oil phase. The two-phase system term traditionally has been applied to semisolids that possess a relatively soft, spreadable consistency formulated as either water-in-oil or oil-in-water emulsions. They are two- phase systems typically containing hydrophilic ingredient in an aqueous phase and lipophilic ingredients in an oil phase. In order for topical emulsions to function effectively they require certain functional excipients. Their consistency and rheological behaviour depend on the properties and the nature of the materials used to produce the internal or dispersed phase. Therefore, selection of excipients and determination of the amount to be used are critical especially in two phase topical formulation in order to prevent phase separation. Consequently, this composition has been developed in order to eliminate the stability problems, especially phase separation and degradation, with respect to commercially available products.

All formulations contain excipients that form the vehicle that is necessary for delivering an API into and/or through the skin. In general, the vehicle is comprised of ingredients used to adjust the pH of the formulation, promote the delivery and prolong the effect of an API on the skin surface or in the stratum corneum in addition to making the topical product cosmetically appealing. The selection of components of a topical formulation depends on a number of factors. The surface area to be treated, the nature of the lesion and the degradation profile of the active substance are critical. Often an API is available in a number of different formulations and/or delivery systems and maintains a basic activity, regardless of the type of system. However their ease of use, cost and efficacy for the desired purpose are affected by the formulation selected as ideal, in addition to the method of application.

When developing formulations for topical delivery, the choices of excipients for a specific API and production methods influence the stability of the product, magnitude of absorption and consequently the bioavailability and efficacy of the API. The excipients that comprise the vehicle modulate the effects of partitioning and diffusion of the API into and through the stratum corneum. Furthermore, excipients used in topical composition and production methods of the composition play a major role in the appearance, feel and successful application of an API. It is therefore critical to choose the most appropriate excipients with proper percentages and the most appropriate production method for a topical composition in order to achieve a desired therapeutic outcome.

The term “therapeutically effective amount” refers to an amount, which achieves a desired effect, when administered to a living subject. In the present invention, the relative amount of the clobetasol propionate is 0.05% (w/w) based on the total composition.

In this invention, weight percentages (w/w) refer to the weight of the component relative to weight of the composition. The term "topical composition" (synonymously, "topical formulation") is used herein to refer to a pharmaceutical preparation intended for topical or local application to an afflicted region of a subject in need thereof, and includes such dosage forms as gel, cream, ointment, emulsion, suspension, solution, drops, lotion, spray or foam. In the present invention, the topical formulation is in the form of a cream.

As used herein, “stable” refers to a composition that substantially maintains its physical and chemical properties when stored. Especially, appearance, identification, content uniformity, pH, viscosity, assay, related compounds, microbiological tests and in-vitro release testing results of the composition should not be extremely changed after production (To, initially) and during the storage conditons throughout the shelf life.

"Physical stability" is understood according to the invention as applying to a composition that does not undergo any modification of macroscopic appearance (phase separation, change of colour or appearance, etc.) or microscopic appearance (recrystallization of active ingredients) after shelf life storage. No phase separation should be observed in either aqueous and/or non-aqueous components. More preferably, no phase separation should be observed in either aqueous and/or nonaqueous components for about 6 months at 40°C±2°C, 75%RH ± 5% and about 12 months at 25°C±2°C/ 60%RH ± 5%.

Phase separation is a problem that can be encountered over time in topical forms when there is a tendency for phase decomposition. Thus, whilst the manufacturing process results in a homogeneous emulsion, if the product is stored for any length of time before being used, it may start to separate into aqueous and non-aqueous phases and present a "curdled" (volume of clear serum topped by a distinct "creamy" phase) product to the consumer. In general, this phenomenon may create an adverse impression in the minds of some consumers regarding the product's quality and acceptability.

"Chemical stability" is understood according to the invention as applying to a composition in which the active principle content remains stable. A stable active principle content means according to the invention that the content varies very little relative to the initial content, i.e. that the variation in active principle content at time T must not be less than 90% of the initial content at TO and preferably not less than 95% of the initial content at TO. The pharmaceutical compositions described herein can, if desired, include one or more pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, which may be used as a carrier or vehicle for delivery of a therapeutic agent to a subject or combined with a therapeutic agent (e.g., to create a pharmaceutical composition) to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralizing agents, if necessary), penetration enhancers, solubilizing agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odor, fragrances or taste, and substances added to improve appearance or texture of the composition.

Enhancers may interact with intercellular lipids to increase the diffusibility of an API into the horny layer of the skin. Furthermore, enhancers may increase the solubility of an API in a formulation vehicle and/or improve its partition coefficient. Propylene glycol, ethanol, dimethyl sulfoxide (DMSO) are examples of penetration enhancers. Propylene glycol is also known as propane-1-2 diol and is a clear, viscous, hygroscopic liquid that is miscible with water and alcohol. It is widely used in pharmaceutical manufacturing as a solvent or vehicle in order to dissolve insoluble API or those that are unstable in water.

The main purpose of an emulsifying agent is to form a condensed film around each of the droplets of the dispersed phase. A low concentration of emulsifier will have little/no effect on the stability of a cream. However an increase in the concentration of the emulsifying agent will increase the stability of a topical formulation dramatically. The selection of a suitable emulsifier is usually the first step in the development of a cream. The emulsifier must be compatible with all other formulation excipients and the API to be included in the formulation. It should be non-toxic, stable and promote emulsification to maintain the stability of the topical formulation for the intended shelf-life of a product. The presence of an emulsifier may also increase the skin penetration of any API contained in that formulation. In the present invention, glyceryl stearate, Arlacel 165 and PEG 100 stearate were used as emulsifier. Glyceryl stearate, also referred to as glyceryl monostearate, is essential for this invention.

An ideal topical cream formulation can be produced using a simple, flexible process. However, the development of topical formulations is complex and therefore requires tightly controlled processing parameters. The top five critical process parameters and additional strategies for optimizing the manufacturing process for topical cream dosage forms are as follows; Temperature, heating and cooling rates, mixing methods and speeds, mixing times, flow rates.

Other than critical process parameters, adding ingredients in the optimal phase and order are also critical for the production of the topical composition. Creams, for example, primarily comprise an aqueous phase and an oily phase. Phases are also important for the viscosity of the finished product. Adding ingredients in the correct phase contributes to overall stability. Also, the manufacturing process must be designed to protect active ingredient from physical and chemical degradation.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1.

Topical formulations contain several excipients and preservatives in addition to low concentrations of the API of interest, making the development of a stable topical formulation rather challenging. The choice of the excipients to be used to ensure that the API is stable and is released to the biological system under the best conditions is one of the most important factors to be assessed during formulation studies.

The physicochemical properties of the API both in the solid state and in solution must be assessed at an early stage of formulation development. Other relevant physicochemical properties include information relating to pH-solubility and stability profiles, drug-excipient compatibility, melting point of excipients and degradation studies of the API.

Clobetasol propionate, the active ingredient of Clobetasol Propionate 0.05% Cream, is an effective corticosteroid and is indicated for the relief of inflammatory and pruritic symptoms of corticosteroid-sensitive dermatoses.

At the beginning of product development studies; PDR and literature, drug master file (DMF) of the active substance were used for the selection of excipients. In addition, the properties of the finished product were determined by taking into account the content, pH and viscosity of the formulation of the reference product. Clobetasol 0.05% Cream contains propylene glycol and water as a moisturizer, chlorocresol as an antimicrobial preservative, glyceryl monostearate and Arlacel 165 as an emulsifying agent, beeswax and cetostearyl alcohol as a thickener, and citric acid and sodium citrate dihydrate as pH regulator, apart from the active substance clobetasol propionate. All the excipients in the formula are excipients used in pharmaceutical technology and are included in the European Pharmacopoeia and USP monographs and comply with the relevant specifications.

The pharmaceutical composition according to the invention may also contain inert additives or combinations of these additives, such as wetting agents, flavour improvers, preservatives, stabilizers, humidity regulators, pH regulators, osmotic pressure modifiers, emulsifiers, penetrating agents, and synthetic polymers.

In a preferred embodiment of the invention, the pharmaceutical composition of the present invention has the following composition:

Table 1 : Composition of the product - Clobetasol Propionate %0,05 Cream

Raw Material Function

Clobetasol propionate Active substance

Propylene glycol Moisturizer

Sodium citrate dihydrate pH Adjuster

Citric acid monohydrate pH Adjuster

Cetostearyl alcohol Viscosity increasing agent

Arlacel 165 Emulsifier

PEG 100 Stearate Emulsifier

Chlorocresol Antimicrobial preservative

Glyceryl monostearate Emulsifier

Beeswax Viscosity increasing agent

Water Diluent

Based on the dissolution of clobetasol propionate active ingredient in propylene glycol, the active ingredient was dissolved in propylene glycol and mixed with sodium citrate dehydrate, citric acid and water; this mixture formed the aqueous phase. Cetostearyl alcohol, glyceryl monostearate, Arlacel 165 and beeswax were mixed to form oily phase. The antimicrobial preservative, chlorocresol, was mixed with oily phase. Aqueous phase and oily phase were mixed to form the cream composition. The final product has a pH between 5 to 7 initially. The final product is homogenized and packed. Example 2.

Amount % (w/w)

Test-1 Test-2 Test-3 Test-4 Test-5 Test-6

Clobetasol propionate 0.05 0.05 0.05 0.05 0.05 0.05

Propylene glycol 47.50 47.50 47.50 47.50 47.50 47.50

Sodium citrate dihydrate 0.05 0.05 0.05 0.05 0.05 0.05

Citric acid monohydrate . . . . o.O5 0.05

Cetostearyl alcohol 8.40 8.4 8.40 8.40 8.40 8.40

Arlacel 165 - - 11.00 8.75 6.00 2.50

PEG 100 Stearate 1.00 1.00

Glyseryl monostearate 5.00 12.50 - 11.00 5.80 10.00

Chlorocresol 0.10 0.10 0.10 0.10 0.10 0.10

Beeswax q.s. q.s. q.s. q.s. q.s. q.s.

Pure water q.s. q.s. q.s. q.s. q.s. q.s.

Test-1 was failed to form cream dosage form with having viscosity problems. Test-2 and Test-3 were failed with physical and chemical degradation (phase separation and yellowing problems in short term storage).

Test-4, Test-5 and Test-6 products were subjected to accelerated and long term storage stability tests. Example 3. In Vitro Release Testing

For a topical medicament to be effective, it must be readily released from the vehicle matrix and interact intimately with the skin to be treated. On this basis candidate compositions can be ranked based on in vitro release rates through artificial or post mortem skin membranes. This is routinely undertaken using the Franz Diffusion Cell methodology. The rate and extent to which the drug substance is released from the product matrix are particularly relevant to the prediction of relative efficacy of candidate formulations.

In Vitro Release Testing (IVRT) is a useful test to assess product "sameness" under certain scale and post approval changes for semisolid products. The FDA Guidance on Scale up and Post Approval Changes for Semisolid (SUPAC-SS) describes suitable conditions for this testing. The apparatus used for IVRT is a Franz diffusion cell system. It consists of six individual cells. Each cell has a standard open cap ground glass surface with 15 mm diameter orifices, 35 mL volume capacity, and total diameter of 25 mm. About 300 mg of the semisolid preparation is placed uniformly on a synthetic membrane and kept occluded to prevent solvent evaporation and compositional changes. Multiple sampling times (at least 5 times) over an appropriate time period are suggested in order to generate an adequate release profile and to determine the drug release rate. Each aliquot removed is then typically analyzed, for example, by high performance liquid chromatography (i.e., HPLC). After each aliquot was removed, the cell was refilled with a volume of fresh medium equal to the volume of the aliquot that was removed.

The conditions used for IVRT for the example compositions of the invention are as follows:

Saline solution

Receptor medium (Potassium phosphate saline pH 7.4)

Speed 600 rpm

Membrane 0.45pm Nitrocellulose filter

Dosage 300 mg ± 30 mg

Temperature 32°C ± 0.5°C

Comparative in vitro release tests were conducted based on the above conditions. The test products (Test 4-6) comprising clobetasol propionate was tested in vitro and they were compared with a commercial reference product (Dermovate Cream 0.05% manufactured by GlaxoSmithKline).

As a result of in vitro release tests made, it was found that the reference product and Test products (Test 4-6) have similar release profiles according to the graphs obtained from the amounts of clobetasol propionate passing per unit cm ² .

Example 4. Stability Studies

Specification for the clobetasol propionate cream is adequate to ensure the identity, strength, purity, and quality of the drug product during its expiration dating period.

In order to examine the physical and chemical stability of the products, stability test was assessed under accelerated condition (40°C±2°C, 75% Relative humidity, RH±5%) and ambient temperature condition (25°C±2°C/ 60±5% Relative Humidity, RH±5%) for Test products (Test-4 to Test-6) and commercially available reference product (Dermovate 0.05% Cream - GlaxoSmithKline, 15C792).

Typical stability parameters are the homogeneity of the formulation, the absence of coalescence of the emulsion droplets (no “coagulation”), a practically constant viscosity, semisolid structures, and no subsequent crystallization of the active ingredient out of the emulsion. The pH of the product is monitored throughout the stability process and should have similar results to the pH value originally present.

Chlorocresol in the formulation of the present invention is an antimicrobial preservative and is important for topical products as they are used to prevent the growth of microorganisms and to protect pharmaceutical products from decomposition or fermentation, consequently it is monitored throughout the stability period.

The stability test results of assay and degradation are summarized in the Table 2 below.

Table 2. Stability results of Test Products (Test-4 & Test-5 & Test-6) and Reference Product (Dermovate 0.05% Cream)

* The pH of Test Products (Test-4 & Test-5 & Test-6) and Reference Product (Dermovate 0.05% Cream) were measured. Results were found between pH 5 - 7.

At room temperature, macroscopic observation makes it possible to guarantee the physical integrity of the products and microscopic observation makes it possible to verify that there is no recrystallization of the solubilized active ingredient. The microbiological examinations were within limits at all examinations. No Escherichia coli were found initially or after storage.

The inventive products of topical pharmaceutical composition comprising; a therapeutically effective amount of clobetasol or its pharmaceutically acceptable salt thereof, 5.0% to 12.0% (w/w) of cetostearyl alcohol based on the total composition, 5.0% to 14.0% (w/w) of glyceryl stearate based on the total composition, wherein the composition comprises citric acid as pH modifier, is chemically and physically stable. It also has a very good patient acceptability and tolerance, due to its cream formula, as described in the examples of the present invention. The composition according to the invention is therefore found to be particularly suitable for the treatment of dermatological complaints and more particularly for the treatment of psoriasis.