HK1182321B - A pharmaceutical spray composition comprising a vitamin d analogue and a corticosteroid - Google Patents

Description

Pharmaceutical spray composition containing vitamin D analogue and corticosteroid

Technical Field

The present invention relates to topical spray compositions comprising a biologically active vitamin D derivative or analogue and a corticosteroid and their use in the treatment of skin diseases and conditions.

Background

Psoriasis is a chronic inflammatory skin disease that manifests as erythema, dryness, desquamation plaques due to hyperkeratosis of the skin. Plaques are most commonly found at the elbows, knees and scalp, but more extensive damage may occur in other parts of the body, most notably the lumbosacral area. The most common treatment of mild to moderate psoriasis involves topical application of compositions containing corticosteroids as the active ingredient. Although effective, the use of corticosteroids has the disadvantage of more side effects such as skin atrophy, skin streaks, acne-like eruptions, perioral dermatitis, overgrowth of skin fungi and bacteria, hypopigmentation of darker skin and rosacea.

However, for many years, the beneficial non-steroidal treatment of psoriasis has been topical treatment using formulations prepared as follows: ointment composition containing calcipotriol, a vitamin D analogue compound (from LEO Pharma)OrCommercially available as ointment), a solution or cream composition containing calcipotriol (available from LEO Pharma)OrCream is marketed under the trade name). The solvent in the ointment composition is propylene glycol, which has the advantage of increasing the penetration of the active ingredient into the skin, thereby improving the therapeutic effect, but it is also known to be irritating to the skin. Thus, it has been reported that topical compositions containing propylene glycol often lead to the development of Contact Dermatitis in patients (one study reported multiple irritant responses to 12.5% propylene glycol, see M.Hannuksela et al, Contact Dermatitis 1,1975, p.112-116), and that when propylene glycol is used at high concentrations, the magnitude of the irritant response increases (for review: J.Catanzaro and J.Graham Smith, J.Am.Acad.Dermatol. 24,1991, p.90-95). Since the improved penetration of calcipotriol into the skin is due in particular to the presence of propylene glycol, it was found thatThe ointment is used for treating psoriasis lesionsCreams are more effective but also cause skin irritation in a significant proportion of patients with psoriasis.

Recently, by LEO PharmaOintments are commercially available combinations for treating psoriasis. The product comprises calcipotriol and betamethasone dipropionate which are prepared in an ointment composition as active ingredients, wherein the calcipotriol is dissolved in polyoxypropylene-15-stearyl ether, and the betamethasone dipropionate exists in a suspension. Although the efficacy of the composition is significantly better than the efficacy of the respective active ingredient itself, it can be seen that the ointment is cumbersome to use because it requires prolonged rubbing into the skin of the affected area and that many patients, particularly those with extensive psoriatic lesions, desire more convenient application, such as that provided by spray compositions.The ointment does not contain any penetration enhancers, such as propylene glycol, which has been found to be detrimental to the chemical stability of calcipotriol (see example 2 of WO 00/64450). It is believed that there is a need to further improve the biological efficacy of the combination of two active ingredients by providing a formulation vehicle through which the penetration of the active ingredients into the skin is improved compared to commercial products.

WO 00/64450 discloses a pharmaceutical composition comprising a vitamin D analogue and a corticosteroid formulated in a solvent with a carrier in which the two active ingredients are chemically stable. A preferred embodiment of the composition is an ointment and there is no mention of providing a spray composition having improved properties compared to ointments.

US 2005/0281749 discloses a spray composition comprising a corticosteroid and a vitamin D derivative dissolved in an oily phase consisting of one or more oils. The oil may be selected from vegetable oil, mineral oil, animal oil, synthetic oil or silicone oil. There is no suggestion that occlusion may need to be provided, and therefore there is no suggestion that semi-solid and occlusion excipients be added to the composition. There is no indication whether the composition exhibits improved penetration properties.

US 2005/0281754 discloses a spray composition comprising a corticosteroid and a vitamin D derivative formulated in a carrier comprising an alcohol phase and an oil phase. The alcohol phase is composed, for example, of ethanol, isopropanol or butanol. The oily phase may consist of mineral, vegetable or synthetic oils. There is no suggestion of including a semi-solid and a blocking excipient into the composition and no indication of whether the composition exhibits improved osmotic properties.

Summary of The Invention

It is an object of the present invention to provide a topical spray composition comprising a vitamin D derivative or analogue and a corticosteroid as active ingredients, which composition has advantages over the prior artThe skin penetration and biological activity of the ointment, but it contains solvents for the active ingredient which, unlike propylene glycol, are not detrimental to the chemical stability of the vitamin D derivative or analogue or the corticosteroid.

Human skin, particularly the outer stratum corneum, provides an effective barrier against the penetration of microbial pathogens and toxic chemicals. This characteristic of the skin is often beneficial, but the situation becomes complicated for dermal application of drugs, since a large, if not large, proportion of the active ingredient applied to the skin of a dermatologic patient may not penetrate the active layer of the skin where it is intended to exert its active effect. To ensure adequate penetration of the active ingredient into the dermis and epidermis, a solvent is usually present in the form of an alcohol (e.g., ethanol or a glycol, such as propylene glycol), and the active ingredient is usually preferably in a dissolved state. Propylene glycol is a well-known penetration enhancer, i.e., capable of penetrating into the stratum corneum and "drawing" the low molecular weight components (e.g., therapeutically active ingredients) in the vehicle into the epidermis. Propylene glycol itself can cause significant skin irritation, and it can also "drag" low molecular and potentially irritating carrier components into the epidermis, resulting in the overall irritating effect of conventional carriers, including propylene glycol. For this reason, the presence of propylene glycol as a solvent in compositions for the treatment of inflammatory skin diseases may exacerbate the inflammatory response of the skin.

It is another object of the present invention to provide compositions containing active ingredients with improved penetration and biological activity, andin contrast to ointments, there are no conventional penetration enhancers, such as propylene glycol, which are detrimental to the stability of vitamin D compounds (e.g., calcipotriol).

It is another object of the present invention to provide compositions wherein the vitamin D derivative or analogue and the corticosteroid are not significantly degraded. It is known, for example from WO 00/64450, that vitamin D compounds are chemically unstable in an acidic environment or in the presence of acid-reactive components or impurities in the formulation vehicle. Likewise, corticosteroids are known to be chemically unstable in alkaline environments or in the presence of alkaline reacting components or impurities in the formulation vehicle. In compositions containing both components, it is difficult to solve the problem of chemical instability by adding an acidic or basic neutralizing agent separately. Conversely, the excipients included in the composition must be selected so as not to contain components that are detrimental to the chemical stability of either active ingredient.

Unlike the spray compositions disclosed in the references cited above, the object of the present invention is to provide a spray composition containing a significant amount of a occlusive and semi-solid carrier vehicle, since the known oily spray formulations are more likely to spread to uninfected areas upon application, whereas the semi-solid component makes the composition of the present invention less "run off", so that the active ingredient is preferentially applied to the infected skin areas.

Thus, in one aspect, the present invention relates to a sprayable, storage-stable, substantially anhydrous topical composition comprising a therapeutically effective amount of a vitamin D derivative or analog and a therapeutically effective amount of a corticosteroid, the vitamin D derivative or analog and corticosteroid being dissolved in a pharmaceutically acceptable propellant or propellant mixture comprising a first propellant selected from the group consisting of dimethyl ether, diethyl ether and methyl ethyl ether and a propellant selected from the group consisting of C_3-5A second propellant which is an alkane, a hydrofluoroalkane, a hydrochloroalkane, a fluoroalkane and a chlorofluoroalkane, the composition further comprising a pharmaceutically acceptable lipid carrier dissolved or suspended in said propellant or mixture of propellants, said lipid carrier comprising one or more lipids, said lipids forming a semi-solid and a closed layer at the site of application after application to the skin and evaporation of the propellant.

It has surprisingly been found that this is in contrast to commercially available penetration enhancers even in the absence of conventional penetration enhancersOintments, compositions of the present invention promote improved penetration of the active ingredient. It is presently believed that improved penetration may be the result of the formation of a supersaturated solution of the active ingredient on the skin after application and after evaporation of the propellant or propellant mixture (see Reid et al, pharm. res.25(11),2008, p.2573-2580). It is further believed that the propellant itself may act as a penetration enhancer, pushing the active ingredient into the skin. Finally, the semi-solid and occlusive layer formed at the application site may facilitate penetration of the active ingredient.

In another aspect, the invention relates to the use of a composition disclosed herein for treating a skin disease or disorder.

The compositions of the present invention may be administered from an aerosol container, which generally includes the type comprising a container body and a valve assembly. The container body may, for example, comprise a metal body, preferably sandwiching a chemically inert coating material, to avoid degradation of the composition due to interaction of the body and the composition.

The valve assembly may include a valve seat (sometimes referred to as a seat), a valve body or housing that houses a valve stem, a spring, a dip tube, and an actuator. The internal gasket typically seals the aperture in the valve stem, but when the actuator is operated, the valve stem moves so that the aperture is opened. Once exposed, the pressure generated by the propellant in the container body forces the composition through the orifice into the dip tube and valve stem and out through the actuator. It will be appreciated that when the actuator is released, the valve spring causes the valve stem to return to a position in which the aperture is again sealed.

The valve stem and actuator each contain one or more orifices (nozzles) and channels, the number, size and shape of which are determined by the physical properties of the particular composition formulation, so as to control the flow rate through the valve and the characteristics of the spray emitted by the actuator.

The spray pattern and flow rate can be controlled by a separate insert mounted to the outlet nozzle of the actuator, the insert providing the end nozzle for the actuator assembly. The passageway leading to the outlet via the insert typically includes a portion of narrower diameter than the actuator body passageway so that fluid emitted into the insert passageway by the actuator passageway swirls and breaks up into droplets. The insert may have a profile, for example it may be stepped, so as to urge the composition forward and out of the end nozzle in a forward motion, rather than the more common rotational motion. This results in a uniform or solid spray pattern, thereby allowing the user to better focus the composition on the area of skin being treated.

Since inhalation of the compositions of the present invention is not desired, the dimensions of the fluid passages, nozzles, inserts, etc. are preferably selected to avoid the generation of fine mist upon ejection.

The valve assembly may include a metering valve such that only a metered amount of the composition is administered per actuation of the actuator.

For storage, the actuator may be fitted with a protective cover or overcap, either alone or in combination, for safety and/or hygiene reasons. The cap is movable from a first position in which the distal nozzle is closed to a second position in which the nozzle is exposed, and in which the cap also acts as a direct nozzle, limiting the spray area. The actuator itself may comprise a simple push button actuator or may for example comprise a flip top or twist lock. In another arrangement, an overcap having an integral finger actuator may be secured to the container and include an underlying actuator button. The underside of the cap may include, for example, a number of projections for allowing the actuator button to be moved and trigger the valve to open by finger pressure from the operator.

Alternatively, or in addition, the actuator may be movable between a first position in which intentional or unintentional operation of the valve is prevented, and a second operating position. For example, part of the valve assembly may be rotatable at the valve stem so that in one rotational position the actuator is operated to spray product and in another rotational position the actuator is aligned with a projection or abutment on the container to prevent actuation. Such "twist and spray" mechanisms may include tactile or audible indications of the open and closed positions.

It is desirable to include a cork-evidence tab which must be broken before the aerosol container can be used for the first time.

Brief Description of Drawings

Fig. 1a and 1b are graphs showing the solubility of calcipotriol in 100% dimethyl ether (DME) and in varying proportions of DME and butane in the continuous phase (fig. 1a) and in mixtures of the continuous and dispersed phases (fig. 1 b).

Fig. 2a and 2b are graphs showing the solubility of Betamethasone Dipropionate (BDP) in 100% DME and different proportions of DME and butane in the continuous phase (fig. 2a) and in mixtures of the continuous and dispersed phases (fig. 2 b).

FIG. 3 is a graph showing similar applications compared to calcipotriolPenetration in ointment, figure of penetration of calcipotriol (MC 903) into active skin at 2, 6 and 21 hours after application of composition E of the invention.

FIG. 4 is a diagram showing similar applications compared to BDPPenetration in ointment, pattern of penetration of BDP into active skin at 2, 6 and 21 hours after application of composition E of the invention.

FIG. 5 is the passage of vitamin D in human keratinocytes₃Schematic representation of the gene encoding the antimicrobial peptide. The calcipotriol-containing composition of the present invention was applied to human epidermis using the antimicrobial peptide gene activation mechanism in bioassays using reconstituted human epidermis (human keratinocytes cultured to form epidermal layer characteristics of human skin) to activate the antimicrobial peptides detailed in example 5 below.

Fig. 6a shows a cross-sectional view of a container for pressurized spraying of a composition according to the invention, comprising a container body (1) to which is mounted a valve assembly comprising a valve seat (3), a valve body (5), an actuator (4) and a dip tube (2). As shown in this embodiment, the composition of the present invention may be a two-phase system comprising a composition phase (6) and a vapor phase (8).

Fig. 6b shows a cross-sectional view of a container for pressurized spraying of a composition according to the invention, comprising a container body (1) fitted with a valve assembly comprising a valve seat (3), a valve body (5), an actuator (4) and a dip tube (2). As shown in this embodiment, the composition of the invention may be a three-phase system comprising a carrier phase (6), a propellant phase (7) and a vapour phase (8).

Fig. 7 shows a cross-sectional view of a valve assembly mounted on the body of a container body (1) comprising a valve cup (3) containing a seal (31) and gasket (32) between the container body (1) and valve cup (3), a valve body (5) having a valve stem (51), and a spring (53) connected to an actuator (4), said actuator (4) having an insert (44) with a distal nozzle (41) through which the composition present in the container body (1) is ejected when the actuator (4) is depressurized. The valve stem (51) includes an aperture (52) through which the composition of the invention present in the container body (1) flows when the actuator (4) is depressurized. The valve body further comprises a tail pipe (55) to which the dip tube (2) is connected. The tail pipe (55) includes an aperture (54) to allow the composition to flow out of the dip tube (2).

Detailed Description

Definition of

The term "vitamin D derivative" is intended to mean a biologically active metabolite of vitamin D3, such as calcitriol, or a precursor of such a metabolite, such as alfacalcidol.

The term "vitamin D analogue" is intended to mean a synthetic compound comprising a vitamin D scaffold modified with side chain modifications and/or the scaffold itself. The analogs have biological activity at vitamin D receptors comparable to naturally occurring vitamin D compounds.

"calcipotriol" is a vitamin D analog having the following structure:

calcipotriol has been found to exist in two crystalline forms, anhydrate and monohydrate. Calcipotriol monohydrate and its preparation are disclosed in WO 94/15912.

The term "storage stability" or "storage stable" is intended to mean that the composition exhibits chemical and physical stability, characterized in that it is capable of being stored under freezing conditions or preferably at room temperature for a sufficient period of time to enable commercial distribution of the composition, for example for at least 12 months, in particular for at least 18 months, preferably for at least 2 years.

The term "chemical stability" or "chemically stable" is intended to mean that no more than 10%, preferably no more than 6%, of the active ingredient degrades at room temperature over the shelf life of the product (typically 2 years). An approximation of the chemical stability at room temperature was obtained by subjecting the composition to an accelerated stability test at 40 ℃, where the composition was placed in a heated drug cabinet at 40 ℃, and samples were taken at 1, 2 and 3 months and tested for the presence of degradation products by HPLC. If less than about 10% of the material degrades after 3 months at 40 ℃, this generally corresponds to a storage period of 2 years at room temperature. When the active ingredient contained in the composition is calcipotriol, "chemical stability" generally means that the calcipotriol in the finished drug does not significantly degrade over time to 24-epi-calcipotriol or other degradation products of calcipotriol.

The term "physical stability" or "physically stable" is intended to mean that the active ingredient does not precipitate out of the propellant or carrier phase over the shelf life of the composition.

The term "substantially anhydrous" is intended to mean that the free water content of the ointment composition does not exceed about 2% by weight of the composition, preferably not more than about 1% by weight.

The term "medium chain triglycerides" is used to denote chainsTriglycerides of fatty acids of 6-12 carbon atoms in length. A common example of such medium chain triglycerides is caprylic acid (C)₈) And capric acid (C)₁₀) A mixture of triglycerides, for example available under the trade name Miglyol 812.

The term "solvency" is intended to mean the ability of a solvent or solvent mixture to dissolve a given substance, expressed as the amount required to allow complete dissolution of the substance.

The term "semi-solid" is used to indicate a composition or vehicle having viscoelastic properties and is of non-newtonian character, i.e. does not flow under low shear stress, but has plastic, pseudoplastic or thixotropic flow properties at high shear rates at room temperature. Typical examples of semisolid compositions are ointments and creams.

The term "occlusive" is intended to mean providing a lipid layer on the skin surface that forms a hydration barrier sufficient to cause a reduction in transdermal water loss, resulting in hydration of the skin.

The term "skin permeability" is intended to mean the diffusion of the active ingredient to the different layers of the skin, namely the stratum corneum, epidermis and dermis.

The term "skin penetration" is intended to mean the flow of the active ingredient through the skin into the systemic circulation or, in the case of in vitro studies such as those shown in example 4 below, the recipient fluid in the Franz cell device used in the test.

The term "biological activity" is intended to mean the activity of a vitamin D derivative or analogue when the composition of the invention is applied to the skin. The biological activity of the compositions can be determined by an in vitro assay measuring the activation of the target gene encoding the antimicrobial peptide in a reconstituted human epidermal model containing cultured human keratinocytes according to the method detailed in example 5 below.

Embodiments of the invention

The vitamin D derivative or analogue comprised in the composition of the invention may be selected from calcipotriol, calcitriol, tacalcitol, maxacalcitol, paricalcitol and alfacalcidol. A preferred vitamin D analogue which has been shown to be effective in the treatment of psoriasis is calcipotriol. Before dissolution in the solvent mixture, calcipotriol may be in the anhydrous or monohydrate form, preferably in the monohydrate form.

The corticosteroid contained in the composition of the present invention may be selected from amcinonide, betamethasone, budesonide, clobetasol, clobetasone, cortisone, desonide, desoxycortisone, desoximetasone, dexamethasone, diflucortolone, diflunisal, fludrosone (flucortisonone), flumethasone, flunisolide, fluocinonide, fluocinolone, fluoromethalone, flupredlone, flurandrenolone, fluticasone, clobetasol, hydrocortisone, methylprednisolone, mometasone, paramethasone, prednisolone and triamcinolone or pharmaceutically acceptable esters or acetonides thereof (acetonides). The corticosteroid may preferably be selected from betamethasone, budesonide, clobetasol, desoximetasone, diflucortolone, diflorasone, fluocinonide, fluocinolone, clobetasol, halobetasol, hydrocortisone, mometasone and triamcinolone or pharmaceutically acceptable esters thereof. The corticosteroid ester may be, for example, betamethasone acetate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, dexamethasone acetate, flumethasone pivalate, fluticasone propionate, hydrocortisone acetate, hydrocortisone butyrate or mometasone furoate. The acetonide may be selected from fluocinolone acetonide or triamcinolone acetonide.

The compositions of the present invention may further comprise a non-evaporating oil co-solvent selected from at least one of the following solvent types:

(a) a compound of the general formula I

H(OCH₂C(CH₃)H)_xOR¹

Wherein R is¹Is straightChain or branch C_1-20Alkyl, and x is an integer from 2 to 60;

(b) straight or branched C_10-18Isopropyl esters of alkanoic or alkenoic acids;

(c)C_8-14a propylene glycol diester of an alkanoic or alkenoic acid;

(d) straight or branched C_8-24An alkanol or alkenol;

(e) highly purified vegetable oils, such as medium or long chain triglycerides; and

(f) n-alkylpyrrolidone or N-alkylpiperidinone.

The oil co-solvent may be used to maintain the solvency of the composition after evaporation of the propellant or propellant mixture, so that the active ingredients do not rapidly crystallize on the skin after evaporation of the propellant, but are present on the skin as a saturated solution so that they can penetrate into the skin (see Reid et al, pharm. res.25(11),2008, p. 2573-2580).

In one embodiment, the oil co-solvent comprised by the composition of the present invention may be a compound of formula I, such as polyoxypropylene-15-stearyl ether, polyoxypropylene-11-stearyl ether, polyoxypropylene-14-butyl ether, polyoxypropylene-10-cetyl ether or polyoxypropylene-3-myristyl ether.

In another embodiment, the oil co-solvent may be a straight or branched chain C_10-18Isopropyl esters of alkanoic or alkenoic acids, for example isopropyl myristate, isopropyl palmitate, isopropyl isostearate, isopropyl linoleate or isopropyl monooleate.

In a further embodiment, the oil co-solvent may be C_8-14Propylene glycol diesters of alkanoic acids, such as propylene glycol dipelargonate.

In a further embodiment, the oil co-solvent may be linear C_8-24Alkanols, for example octanol, lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol or myristyl alcohol,or is a branched chain C_8-24Alkanols, preferably C_18-24Alkanols, for example 2-octyllauryl alcohol.

In a further embodiment, the oil co-solvent is an N-alkylpyrrolidone, such as N-methylpyrrolidone.

In conducting the present study, it was surprisingly found that pure C was used_3-5The alkane (e.g., butane) does not cause sufficient dissolution of the active ingredient as a propellant such that the vitamin D analog precipitates out of solution over time and crystal growth of the corticosteroid is observed, i.e., the composition is not physically stable over the shelf life of the composition. It has surprisingly been found that when dimethyl ether is used as a propellant by itself or even when fed to C_3-5This problem does not occur when a propellant mixture is formed by adding a proportion of dimethyl ether to the alkane. Thus, in a presently preferred embodiment, the composition of the invention comprises dimethyl ether as the sole propellant or as the first propellant of the propellant mixture.

In the compositions of the invention, the second propellant of the propellant mixture is preferably C_3-5The alkane is preferably selected from n-propane, isopropane, n-butane or isobutane. Particularly preferred is C_3-5The alkane is n-butane and/or isobutane.

The ratio of n-butane and/or isobutane to dimethyl ether in the propellant mixture may preferably be in the range 6:1 to 0:1v/v, for example 5:1 to 1:2, 4:1 to 1:1, 4:2 to 4:3 or 4:3 to 1: 1.

In a particular embodiment, the composition comprises

(a) About 0.00001-0.05% w/w vitamin D derivative or analog,

(b) from about 0.0005% to about 1% w/w corticosteroid,

(c) about 5-55% w/w lipid carrier, and

(d) about 45-95% w/w propellant or mixture of propellants.

More particularly, the present composition may comprise about 10-50% w/w, about 15-45% w/w or about 20-40% w/w lipid carrier.

More particularly, the composition of the invention may comprise about 50-90% w/w or about 55-70% w/w of the propellant or mixture of propellants.

In particular embodiments, the compositions of the present invention may further comprise about 0.1-10% w/w of an oil solvent as defined above, for example about 0.5-3% w/w, about 1-2.5% w/w or about 1.5-2% w/w of an oil solvent.

The lipid carrier may be of a chain length in the range C₅To C₆₀A hydrocarbon or a mixture of hydrocarbons. Frequently used ointment carriers are petrolatum or white soft paraffin, which peaks at about C_40-44Or petrolatum and liquid paraffin (consisting of a peak at about C)_28-40Of different chain length hydrocarbons). Although white soft paraffin provides occlusion of the treated skin surface, reduces the transdermal loss of water and enhances the therapeutic effect of the active ingredients in the composition, it tends to produce a greasy or sticky sensation that persists for some time after application. Thus, it may be preferred to use paraffins which consist of certain low chain length hydrocarbons, for example with a peak at C_14-16、C_18-22、C_20-22、C_20-26Paraffins consisting of hydrocarbons of chain length or mixtures thereof. These paraffins have been found to be more suitable for cosmetics because they are less greasy or sticky in use. Thus, it is desirable to include these paraffins in the present compositions to result in improved patient compliance. Suitable paraffins of this type, known as petrolatum (petroleum jelly), are produced by Sonneborn and are commercially available under the trade name sonecone, such as soneconem, sonecone DM1, sonecone DM2 and sonecone HV. These paraffins are further disclosed and characterized in WO 2008/141078, which is incorporated herein by reference. In addition to their good cosmetic properties, it has surprisingly been found that compositions containing these paraffins as carrier are more tolerable than compositions containing conventional paraffins. (the hydrocarbon composition of the paraffin wax is determined by gas chromatography). LipidThe carrier may also be an isoparaffin, such as isohexadecane.

The compositions of the invention may suitably comprise a lipophilic viscosity enhancing ingredient which is capable of imparting to the lipid carrier the property of forming a semi-solid and occlusive layer on the skin following application and evaporation of the propellant. The lipophilic viscosity increasing component may suitably be a wax, for example made from a high molecular weight hydrocarbon (e.g. saturated C)_35-70Alkanes) mixtures of mineral waxes, for example microcrystalline waxes. Alternatively, the wax may be a vegetable or animal wax, e.g. C_14-32Fatty acids and C_14-32Esters of fatty alcohols, for example beeswax, silicone wax or hydrogenated castor oil or mixtures thereof. The amount of viscosity enhancing ingredient may generally range from about 0.01 to 5% by weight of the composition. When the viscosity-increasing ingredient is hydrogenated castor oil, it is typically present in an amount ranging from about 0.05 to 1%, for example from about 0.1 to 0.5% by weight of the composition.

The composition may also comprise an emollient, which may be used to soften the thickened epidermis of the psoriatic plaque. Suitable emollients for inclusion in the compositions of the present invention may be volatile silicone oils, as the presence of silicone has also been found to aid penetration of calcipotriol into the skin. It was also found that compositions containing silicone oils produced less skin irritation. Suitable silicone oils for inclusion in the compositions of the present invention may be selected from cyclomethicone or dimethicone. The amount of silicone oil included in the composition of the invention is typically in the range of 0.3-3% w/w, for example about 0.5-1.5% w/w.

The compositions of the present invention may also comprise other components commonly used in skin formulations, such as antioxidants (e.g. alpha-tocopherol), preservatives, pigments, skin soothing agents, skin healing agents and skin conditioning agents such as urea, glycerol, allantoin or bisabolol, see CTFA Cosmetic ingredients handbook, 2 nd edition, 1992. In a preferred embodiment, the composition may comprise an anti-irritant, such as menthol, eucalyptol or niacinamide. The presently preferred anti-irritant is menthol, as it has also been found to enhance penetration of calcipotriol into the skin, see figure 1. Menthol may be included in the composition in an amount of about 0.001-1% w/w, particularly about 0.002-0.003% w/w of the composition.

The compositions of the present invention may be used to treat psoriasis, seborrheic psoriasis (sebopsoasis), palmoplantar pustulosis, dermatitis, ichthyosis, rosacea and acne and related skin disorders, typically by administering an effective amount of a composition of the present invention to a patient in need of such treatment. The method preferably comprises topically administering a therapeutically sufficient dose of the composition once or twice daily. For this purpose, the compositions of the invention preferably contain from about 0.001 to 0.5mg/g, preferably from about 0.002 to 0.25mg/g, in particular from 0.005 to 0.05mg/g of vitamin D derivative or analogue. It is believed that the compositions of the present invention may be advantageously used in the maintenance treatment of these skin diseases, i.e. the treatment is continued after the disappearance of the symptoms visible to the disease, in order to delay the recurrence of the symptoms.

In a further aspect, the present invention relates to a pressurised container suitable for applying a topical composition to an affected area of skin, the container comprising a composition of the invention and a valve assembly and actuator to release the composition in the form of a spray.

As shown in fig. 6a and 6b, an example of a container suitable for pressurized products may consist of a container body (1) storing the composition of the present invention, a dip tube (2), and a valve assembly comprising a valve seat (3), a valve body (5), and an actuator (4).

Generally, the container body (1) may be made of materials such as metal, glass, ceramic, polyester, polyethylene terephthalate (PET), or other polymers. The glass container may have a safety coating, such as polypropylene, to contain glass fragments that may form from impact with hard surfaces. Metallic container bodies are currently preferred because they are more resistant to impact and are easier to surface coat. Stainless steel, tinplate and aluminum (i.e., aluminum or aluminum alloys, including anodized aluminum) container bodies are particularly suitable materials for this purpose, with aluminum being presently preferred because it is light and not brittle.

The metal container is typically sandwiched or coated with an inert material to prevent the composition from reacting with the metal, thereby avoiding or substantially eliminating any degradation of the active ingredient or other components of the composition.

Inert materials include any suitable polymer, paint, resin, or other coating treatment that creates a barrier between the container and the composition to avoid any chemical interaction between the composition and the container. The inert material is preferably a non-metallic coating.

Known coatings for metal containers include acrylic, phenolic, polyester, epoxy, and vinyl resins. However, compositions containing vitamin D derivatives or analogues may be chemically degraded under acidic conditions or in the presence of acidic reactive compounds. Furthermore, corticosteroids are known to degrade chemically under alkaline conditions or in the presence of alkaline reacting compounds. Thus, the container coating used in the composition of the present invention should preferably be selected so that it does not itself exhibit acidic or basic reactivity and does not leach acidic or basic reactive impurities therefrom in the presence of the composition.

In the studies conducted in accordance with the present invention, it was found that, for example, a particular epoxy phenol resin lacquer was incompatible with one of the active ingredients, resulting in unacceptable chemical degradation of calcipotriol. This degradation may be due to the presence of rosin in the paint, which contains acidic groups. On the other hand, when a polyimide-polyamide resin is used as the undercoat layer, the chemical stability of calcipotriol is satisfactory.

In addition to polyimide-polyamide resins, other materials suitable for sandwiching the interior of the metal container include polyamides, polyimides, polypropylenes, polyethylenes, fluoropolymers, including perfluoroethylene propylene copolymer (FEP), Fluororubber (FPM), Ethylene Propylene Diene Monomer (EPDM), Polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene copolymer (EFTE), perfluoroalkoxyalkyl, perfluoroalkoxy-olefins, or a blend of fluoropolymer and non-fluorocarbon polymer. The fluoropolymer may be used, for example, in combination with a polyimide-polyamide resin.

The container coating material may be applied as a single layer or as multiple layers, for example by curing (cure) each layer before applying the other. In addition to isolating the composition from the metal container, the application of more than one coating layer may also help to avoid adhesion of the active ingredient to the container walls.

For the same reason, the valve member of the container which is in contact with the composition is also preferably made of or coated with a material which does not cause degradation of the composition. For example, a metallic valve member (e.g., valve seat) may be coated with anodized silver, epoxy melamine, or polypropylene.

In addition to inhibiting leakage from the container, particularly from the propellant, the material used for the gasket or seal in the container should preferably also be chemically inert. For example, an intermediate gasket is used together to crimp (crimped) the container body and valve seat, said gasket being at least partially exposed to contact with the composition, so that over time it may cause degradation of the composition if the gasket is not made of an inert material.

Extensive testing of materials for gaskets in conventional aerosol container valves has shown that polymeric materials prepared by vulcanization using sulfur-containing accelerators (e.g., thiazoles) are not suitable as gasket materials for containers intended to contain the compositions of the present invention, possibly due to the reactivity of sulfur-containing residues or impurities with one or both active ingredients, resulting in chemical degradation.

Similarly, gasket materials that are permeable to the propellant contained in the compositions of the present invention are not suitable for use as gasket materials for the purposes of the present invention.

Suitable gasket or gasket materials for use with the compositions of the present invention include fluororubbers (e.g., Viton V600), fluorinated ethylene propylene copolymers (FEP), fluororubbers (FPM, e.g., VI500), or Ethylene Propylene Diene Monomer (EPDM).

Materials which have been found to be suitable for dip tubes are, for example, polyethylene and polypropylene. Materials which have been found to be suitable for the valve stem are, for example, polyamides and acetals (POM).

In the embodiment shown in fig. 6b, the composition comprises a carrier phase (6), a propellant phase (7) and a vapour phase (8). In this embodiment, the aerosol container should be shaken well before use so that the carrier phase (6) is uniformly suspended in the propellant phase (7).

As shown in fig. 7, the valve assembly may consist of a valve cup (3) attached to the container body (1) by crimping (crimping), the valve body (5) containing a valve stem (51) and a spring (53) connected to an actuator (4), the valve cup (3) typically being made of a metal such as aluminum, the actuator (4) being compressed for actuation to eject the composition from the container. The valve stem (51) contains at least one orifice (52) of diameter 0.05-1mm through which the composition present in the container can flow when the actuator (4) is compressed. The valve stem bore (52) may preferably contain a ball which allows the container to be used in different positions (e.g. inverted or tilted).

The actuator (4) comprises an insert (44), the insert (44) having a terminal nozzle (41) with a diameter of 0.3-1.5mm through which the composition is ejected. The actuator (4) should be designed for use in providing an aerosol spray from the nozzle (41), the size of the droplets being sufficiently small to ensure uniform spraying of the product, and sufficiently large to ensure that the composition droplets do not form a fine mist on ejection from the container such that droplets containing the biologically active substance may be accidentally inhaled.

The dimensions of the insert nozzle (41) and stem orifice (52) and the pressure within the container generally determine the width of the spray aperture formed when the composition is ejected from the aperture (4) and thus the size of the area covered by the sprayed composition.

In particular embodiments, the container may comprise means for metering a dose of the composition.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the claimed invention in any way.

Examples

Example 1

Testing of solubility of calcipotriol and BDP in different propellant mixtures

A2X 12100mL glass vial fitted with a valve and actuator was filled with a composition containing 67mg BDP, 13mg calcipotriol, 20g of carrier (including liquid paraffin, white soft paraffin and PPG-15-stearyl ether) and varying amounts of DME and butane as shown in Table 1. The composition forms a continuous phase and a dispersed phase which is believed to consist of long paraffins (chains. gtoreq.50 carbon atoms) present in the white soft paraffin wax. The dispersed phase was deposited on the bottom of the composition when left to stand. Thus, the upper part of the composition comprises only the continuous phase, while the bottom part of the composition consists of a mixture of continuous and dispersed phases.

TABLE 1

Sample (I)	DME(mL)	Butane (mL)
			C1	6.7	40.0
C2	13.3	33.3
			C3	20.0	26.7
C4	23.3	23.3
			C5	1.3	45.3
C6	4.0	42.7
			C7	30.0	16.7
C8	40.0	6.7
			C9	46.7	0.0
D1	6.7	40.0
			D2	13.3	33.3
D3	20.0	26.7

D4	23.3	23.3
			D5	1.3	45.3
D6	4.0	42.7
			D7	30.0	16.7
D8	40.0	6.7
			D9	46.7	0.0

C1-9 is a sample taken from the continuous phase in the bottle.

D1-9 is a sample taken from the mixture of the continuous and dispersed phases in the bottle.

The vial was shaken vigorously before sampling until the contents appeared homogeneous, after which the vial was left overnight in the dark, resulting in deposition of the dispersed phase mixed continuous phase at the bottom of the vial. Samples were taken from the top and bottom of the composition through dip tubes connected to the valve and extending to the continuous phase or mixed continuous-dispersed phase so that samples of any phase were sprayed into the brown bottle. During handling, samples were taken carefully without shaking the bottle so that the remaining dispersed phase was deposited on the bottom of the composition. The sprayed sample was placed in a water bath at 40 ℃ for 5 hours until the propellant evaporated. The sample was then cooled at room temperature for 1 hour.

The amounts of calcipotriol and BDP present in each sample were determined by HPLC under the following operating conditions:

column: agilent Zorbas Eclipse Plus C18, 150X 4.6mm, 3.5 μm

Mobile phase: acetonitrile/methanol/0.01M (NH)₄)₂HPO₄，pH 6.0，25:45:30(v/v/v)

Flow rate: 1.2 mL/min

And (3) detection: 225-320 nM. Calcipotriol is calculated at 264nm and BDP is calculated at 240 nm.

Column oven: 30 deg.C

Automatic sample injector: 20 deg.C

Operating time: 30 minutes

Sample introduction: 80 μ L

The results for calcipotriol are shown in fig. 1a and 1b, and the results for BDP are shown in fig. 2a and 2 b. The figure shows that both calcipotriol and BDP are completely dissolved in the propellant and carrier phases when the butane to DME ratio is 4: 3. Furthermore, calcipotriol and BDP were shown to be completely soluble in 100% DME as propellant.

The physical stability of the calcipotriol and BDP in the composition was determined by polarized light microscopy. The results show that neither calcipotriol nor BDP recrystallize when the composition was left for 4 months.

Example 2

Carrier composition

Compositions A to E

To prepare compositions A-E, the white soft paraffin wax was melted at 80 ℃ and then cooled to 70 ℃ and maintained at that temperature. Calcipotriol monohydrate is dissolved in polyoxypropylene-15-stearyl ether to form a solution, which is added to molten paraffin and stirred. BDP was dispersed in liquid paraffin and the dispersion was added to the paraffin mixture containing calcipotriol with stirring. Thereafter, the mixture was cooled to below 30 ℃. A 30g portion of the mixture was transferred to an aluminum spray container containing a polyamide-polyimide lacquer (HOBA 8460), after which the valve cup was fixed to the container body by crimping. The required amount of propellant mixture was added through the tube, after which the container was shaken for 5 minutes to allow complete dissolution of calcipotriol and BDP.

Composition A

Composition B

Composition C

Composition D

Composition E

Composition F

To prepare composition F, hydrogenated castor oil is melted together with liquid paraffin at 85-90 ℃ and cooled to about 60 ℃ with homogenization. The mixture was then cooled to 25-30 ℃ with stirring. BDP was suspended in liquid paraffin and added to the homogenized mixture. Calcipotriol monohydrate is dissolved in polypropylene-15-stearyl ether and added to the mixture of the other ingredients, and the formulation is homogenized to ensure uniform distribution of the active ingredient. A 30g portion of the mixture was transferred to an aluminum spray container containing a polyamide-polyimide lacquer (HOBA 8460), after which the valve cup was fixed to the container body by crimping. The required amount of propellant mixture was added through the tube, after which the container was shaken for 5 minutes to allow complete dissolution of calcipotriol and BDP.

Composition F

Compositions G and H

To prepare composition G, a solution of calcipotriol monohydrate in N-methylpyrrolidone was mixed with medium chain triglycerides and polyoxypropylene-15-stearyl ether. Sonnecone DM1 and microcrystalline wax were melted at 80-85 ℃ and a solution of alpha-tocopherol in liquid paraffin was added with stirring at 80 ℃ until molten. After cooling to 70-75 ℃, the solvent mixture containing calcipotriol monohydrate is added with stirring. After cooling to about 40 ℃, menthol is added and the resulting mixture is stirred while cooling to below 30 ℃. A 30g portion of the mixture was transferred to an aluminum spray container containing a polyamide-polyimide lacquer (HOBA 8460), after which the valve cup was fixed to the container body by crimping. The required amount of propellant mixture was added through the tube, after which the container was shaken for 5 minutes to allow complete dissolution of calcipotriol and BDP.

Composition G

To prepare composition H, the white soft paraffin was melted at 80-85 ℃ and cooled to 70-75 ℃ and the solvent mixture was added with stirring. A 30g portion of the mixture was transferred to an aluminum spray container containing a polyamide-polyimide lacquer (HOBA 8460), after which the valve cup was fixed to the container body by crimping. The required amount of propellant mixture was added through the tube, after which the container was shaken for 5 minutes to allow complete dissolution of calcipotriol and BDP.

Composition H

Compositions I-P

Composition I was prepared by mixing medium chain triglycerides, caprylic/capric glycerides and polyethylene glycol 40 hydrogenated castor oil and stirring the mixture with a magnetic stirrer at 50 ℃ for 15 minutes. Calcipotriol monohydrate was dissolved in the mixture at 40 ℃ and a magnetic stirrer was applied for 15 minutes. The white soft paraffin was melted at 80 ℃. The three component surfactant-solvent mixture containing calcipotriol monohydrate was added to the melted paraffin and stirred until the ointment mixture was homogeneous. The homogenized mixture was cooled to 30 ℃ with stirring. Composition J was prepared in a similar manner except that glyceryl monooleate 40 was used as the co-surfactant instead of glyceryl caprylate/caprate. A 30g portion of the mixture was transferred to an aluminum spray container containing a polyamide-polyimide lacquer (HOBA 8460), after which the valve cup was fixed to the container body by crimping. The required amount of propellant mixture was added through the tube, after which the container was shaken for 5 minutes to allow complete dissolution of calcipotriol and BDP.

Composition (% w/w)	Composition I	Composition J
			Calcipotriol monohydrate	0.002	0.002
Betamethasone dipropionate	0.03	0.03
			Medium chain triglycerides (Miglyol 812)	1.1
Long chain triglyceride (sesame oil)		1.1
			Caprylic/capric acid glycerides (Akoline MCM)	1.3
Glyceryl monooleate 40(Peceol)		1.3
			Polyethylene glycol 40 hydrogenated Castor oil (Cremophor RH 40)	1.8	1.8

White soft paraffin	31.2	31.2
			Dimethyl ether	36.2	36.2
Butane	28.4	28.4

Compositions K-P were prepared in a similar manner to composition I, but with suitable alternatives of surfactants, co-surfactants and solvents as shown in the table below.

Example 3

Chemical stability of calcipotriol and BDP in different compositions

Composition E, prepared as described in example 2 above, was stored in a spray container at 40 ℃ for 3 months. Samples of the composition were taken at 1, 2 and 3 months of standing, respectively, and the content of calcipotriol and BDP and possible degradation products (related impurities) was determined by HPLC. The results are shown in the table below as a percentage of the theoretical initial values.

It can be seen from the results that there was a deviation between the loss of calcipotriol and the amount of impurities measured after 3 months at 40 ℃. This indicates that the apparent loss of calcipotriol is not a result of the degradation of calcipotriol during storage, but may be due to other causes, such as adsorption of calcipotriol onto one or more container members, possibly dip tubes or paint interiors. Thus, we believe that both active ingredients are chemically stable under the conditions described, which indicates that the shelf life of the composition at 25 ℃ may be about 2 years.

Example 4

Penetration study

To study the penetration (penetration) and penetration (permentation) of calcipotriol from the compositions of the present invention into the skin, skin diffusion tests were performed. Full thickness skin obtained from pig ears was used in the study. The ears were frozen at-18 ℃ before use. The day before the test, the ears were placed in a refrigerator (5. + -. 3 ℃) and thawed slowly. On the day of the test, the hair was removed using a veterinary hair trimmer. The skin was cleaned of subcutaneous fat using a scalpel, two pieces of skin were cut from each ear, and placed in Franz diffusion cells fixed in a balanced sequence.

Franz, "The fine field technical as a valid in vitro model for The study of human percutaneous absorption using a limited dose technique as an effective in vitro model", Current applications in Dermatology,1978, J.W.H.Mall (Ed.), Karger, Basel, pages 58-68, using a substantially similar method, with an effective diffusion area of 3.14cm²And receiving static Franz-type diffusion cells with chamber volumes ranging from 8.6 to 11.1 mL. The specific volume of each cell was determined and recorded. A magnetic bar was placed in the receiving chamber of each well. After the skin was fixed, saline (35 ℃) was injected into each receiving chamber for hydration of the skin. The cell was placed in a temperature controlled water bath which was placed on a magnetic stirrer set at 400 rpm. The circulating water in the water bath was maintained at 35 + -1 deg.C so that the temperature of the skin surface was at about 32 deg.C. After 1 hour, the saline was replaced by the receiving chamber medium, 0.04M isotonic phosphate buffer (35 ℃ C.) at pH 7.4, which contained 4% bovine serum albumin. The conditions of the cell were maintained throughout the study, i.e. the concentration of active compound in the receiving chamber medium was less than 10% of the solubility of the compound in the medium.

In vitro skin permeation assays for each test composition were performed in six replicates (i.e., n = 6). Each test composition was sprayed onto the skin membrane at 0 hour. The composition was applied uniformly to the skin surface using a glass spatula.

Skin penetrationThe permeation test was carried out for 21 hours. Samples were then collected at 2, 6 and 21 hours from the following chambers: applications ofThe cuticles were collected by tape stripping 10 times (diameter 22mm, CuDerm corp., Dallas, Texas, USA). Each strip was applied to the test area, standard pressure was applied for 5 seconds, and the strip was removed from the test area in a gentle, continuous motion. The tear direction of each repeating strip is different. Samples of viable epidermis and dermis were then taken from the skin in a similar manner.

A sample (1mL) of the receiving chamber liquid held in the diffusion cell was collected and analyzed.

The concentration of calcipotriol in the sample was determined by LC mass spectrometry.

The results are given in figures 3 and 4 below, which show the amounts of calcipotriol and BDP found in viable skin (dermis and epidermis) and in the receiving chamber fluid at 2, 6 and 21 hours after application, respectively, expressed as% applied dose. The results show thatApplication of composition E resulted in a significant increase in skin penetration of calcipotriol and BDP compared to the ointment.

Example 5

Biological activity of the composition

As shown in fig. 5 below, the antimicrobial peptide is an antimicrobial peptide expressed in human keratinocytes. Skin infections or disruption of the skin barrier greatly induce the expression of antimicrobial peptides. In psoriasis, the level of antimicrobial peptides is increased in the damaged skin of psoriasis patients. It has been found that expression of genes encoding antibacterial peptides can be induced by vitamin D3 or vitamin D analogues such as calcipotriol by binding to vitamin D receptors (see TT Wang et al, J.Immunol.173(5),2004, p. 2909-2912; J Schauber et al, Immunology 118(4),2006, p. 509-519; Schauber and Gallo, J.Allergy Clin Immunol 122,2008, p. 261-266; M.Peric et al, ploS One 4(7), p. 7, 22, 2009, e 6340). This finding has been exploited to develop an assay: by determining the level of induction of the gene encoding the antimicrobial peptide, the uptake and biological activity of calcipotriol in human keratinocytes in the test compositions can be determined.

In the assay method, composition E prepared according to the method described in example 2 above was topically sprayed in triplicate onto reconstituted human epidermis consisting of a mixture of E and E at 0.5cm²Polycarbonate filter (fromLaboratories, Nice, France) for 12 days. The tissue was treated for two days, then the skin was separated on a polycarbonate filter and snap frozen in liquid nitrogen. RNA was extracted from the cells, and cDNA was synthesized by a conventional method. By Applied Biosystems: CAMP Hs0018038_ m1 and GAPDH Hs 9999999905 _ m1, real-time quantitative pcr (qpcr) was performed using the following assay. Expression levels of antimicrobial peptides were normalized to GAPDH and were determined byOintment comparisons were performed for relative quantification.

In the biological activation of antimicrobial peptides, withThe results obtained for the ointment show a 2.3 fold increase compared to the results obtained for the ointment.

Example 6

Chemical stability of calcipotriol/BDP in the Presence of different Lacquers

Different batches of composition a prepared according to the method described in example 2 and placed in aluminium spray containers containing two different types of lacquer, respectively, an epoxy phenol based lacquer (HOBA 7940/7407) and a polyimide-polyamide based lacquer (HOBA 8460), were tested for chemical stability of the active ingredient by spraying each batch of samples into a glass and subjecting them to HPLC analysis after 1 month at 40 ℃ according to the method described in example 3.

The results are shown in the table below.

EP: epoxy phenol based paints

PI-PA: polyimide-polyamide based paints

The table shows that when using epoxy phenol based paints as spray container internal paints, unacceptable degradation of calcipotriol occurs, whereas chemical stability is acceptable in the presence of polyimide-polyamide based internal paints. The chemical stability of betamethasone dipropionate is little affected by the composition of these lacquers. The degradation of calcipotriol shown in the table is believed to be caused by one or more acid reactive components in the epoxy phenol based HOBA 7940/7407 paint which may leach out of the paint due to the solvent action of the propellant mixture. This component is currently believed to be rosin because it contains acid groups.

Example 7

Testing the solubility of vitamin D analogues and corticosteroids in different propellant compositions

A100 mL glass vial equipped with a valve and actuator was filled with a composition containing an API (10mg of calcitriol, tacalcitol, maxacalcitol, 30mg of clobetasol propionate, 60mg of betamethasone 17-valerate, hydrocortisone 17-butyrate, 120mg of hydrocortisone valerate or 800mg of hydrocortisone) and varying amounts of DME and butane (46.7mL of butane, 6.7mL of DME and 40.0mL of butane, or 23.3mL of DME and 23.3mL of butane).

Before sampling, the bottles were shaken vigorously until the contents were homogeneous, after which the bottles were left overnight in the dark, resulting in precipitation of the undissolved API. Samples were taken from above the composition through a dip tube connected to a valve and sprayed into a scintillation glass. Care was taken in handling without shaking the bottle so that residual undissolved API was deposited at the bottom of the composition. The API in the glass was dissolved in the extraction solvent and diluted if necessary before injection into the HPLC.

The amounts of calcitriol, tacalcitol, maxacalcitol, betamethasone 17-valerate and clobetasol propionate present in each sample were determined by HPLC under the following operating conditions:

column: 4.6X 150mm Waters Sunfire C18.3.5 μm column

Mobile phase: acetonitrile-methanol-water (20:50:30)

Flow rate: 1.2 mL/min

And (3) detection: PDA 210nm-350nm

The calculation of betamethasone 17-valerate and clobetasol propionate was carried out at 240nm

The calculation of the vitamin D analogue was performed at 260 nm.

Column oven: 35 deg.C

Automatic sample injector: 20 deg.C

Operating time: 40 minutes

Sample introduction: different according to the standard curve of each API

Retention time: 6.2 min (Clobetasol propionate)

6.7 min (betamethasone 17 valerate)

10.5 minutes (maxacalcitol)

28.6 minutes (calcitriol)

32.6 minutes (tacalcitol)

The amounts of hydrocortisone, hydrocortisone valerate and hydrocortisone 17-butyrate present in each sample were determined by HPLC under the following operating conditions:

column: phenomenex Precolumn C184.0mm.times.2.0 mm or equivalent column + Waters Sunfire C183.5 μm,100mm times.4.6 mm or equivalent column

Mobile phase: mobile phase A: tetrahydrofuran (THF)

Mobile phase B: water (W)

Gradient:

flow rate: 1.0 mL/min

Volume of column precursor: corresponding to the size of the ring

And (3) detection: UV-254nm

PDA-detector 220-320nm

Sample introduction: different according to the standard curve of each API

Column oven: 40 deg.C

Automatic sample injector: ambient temperature

Operating time: minimum 4 times retention time of hydrocortisone

Retention time: 6.0 min (hydrocortisone)

12.7 min (hydrocortisone 17-butyrate)

14.5 min (hydrocortisone valerate)

The results for vitamin D analogues and corticosteroids are shown in table a and table b, respectively. The results in this table show that the solubility of vitamin D analogues and corticosteroids increases with increasing amounts of DME.

Table a: solubility of vitamin D analogs at ambient temperature. The values are the average of 2 measurements in the same bottle.

Table b: solubility of corticosteroid at ambient temperature. The values are the average of 2 measurements in the same bottle.

Example 8

Chemical stability of calcipotriol/BDP in the Presence of different gasket materials

To test the compatibility of the compositions with various gasket materials, a sample was prepared with composition E, see example 2, charged into an aluminum spray container containing a polyamide-polyimide lacquer, and sealed with a valve cup crimped onto the container body. In each container, 10 pieces or a substantial amount of the gasket test material was added to the spray container and allowed to submerge in the composition. The containers were stored at 25 ℃ or 40 ℃ and tested after 1 and 3 months at 40 ℃ and after 3 months at 25 ℃.

After storage, the composition was sprayed into glass bottles and the propellant was evaporated for 2 days. The non-volatile portion of the composition was analyzed for calcipotriol, betamethasone dipropionate and their associated organic impurities.

The amount of calcipotriol was determined by HPLC after liquid extraction and controlled isomerization at 50 ℃. Methyltestosterone was used as internal standard. HPLC analysis was performed using the following conditions:

column: LiChrospher RP-18,125X 4mm,5 μm

Mobile phase: acetonitrile/methanol/0.01M (NH4)2PO4(20:50:30)

Flow rate: 2.0 mL/min

And (3) detection: UV-264nm

Sample introduction: 50 μ L

Operating time: about 9 minutes

Following liquid extraction, organic impurities associated with calcipotriol were determined by HPLC using the following conditions:

column: YMC ODS-AM, 150X 4.6mm, 3 μm

Mobile phase: acetonitrile/methanol/0.01M (NH)₄)₂PO₄(20:50:30)

Flow rate: 1.0 mL/min

And (3) detection: UV-264nm

Sample introduction: 500 μ L of

Operating time: 2 times of the retention time of calcipotriol

After liquid extraction, beclometasone dipropionate is used as an internal standard and the amount of beclometasone dipropionate is determined by HPLC under the following HPLC conditions:

column: supersphere RP-18, 75X 4mm, 4 μm

Mobile phase: acetonitrile/water (50:55)

Flow rate: 1.5 mL/min

And (3) detection: UV-240nm

Sample introduction: 20 μ L

Operating time: about 9 minutes

Organic impurities associated with betamethasone dipropionate were extracted by liquid extraction and analyzed by HPLC using the following conditions:

column: LiChrospher RP-18, 125X 4mm,5 μm

Mobile phase: acetonitrile/0.05M (NH)₄)₂PO₄pH 7(50:55)

Flow rate: 2.0 mL/min

And (3) detection: UV-240nm

Sample introduction: 20 μ L

Operating time: about 20 minutes

The results are shown in the following table:

buna and NPR are nitrile rubbers, Viton is a fluoroelastomer, and EPDM is an ethylene-propylene-diene rubber.

The data show that both gasket types, Buna and NPR, resulted in decomposition of both calcipotriol and betamethasone dipropionate. Based on this compatibility test, it can be considered that both materials are not suitable for use in contact with the composition being tested. Viton and EPDM gaskets did not negatively affect the stability of calcipotriol and betamethasone dipropionate and therefore they are considered useful as gasket materials for the compositions tested.

Claims (38)

1. A sprayable, storage stable, topical composition having a moisture content of no more than 2% comprising a therapeutically effective amount of a vitamin D derivative or analog and a therapeutically effective amount of a corticosteroid, the vitamin D derivative or analog and the corticosteroid being dissolved in a pharmaceutically acceptable propellant selected from the group consisting of dimethyl ether, diethyl ether and methyl ethyl ether or in a composition comprising a first propellant selected from the group consisting of dimethyl ether, diethyl ether and methyl ethyl ether and a propellant selected from the group consisting of C_3-5A propellant mixture of a second propellant selected from the group consisting of alkanes, hydrofluoroalkanes, hydrochloroalkanes, fluoroalkanes and chlorofluoroalkanes, said composition further comprising a pharmaceutically acceptable propellantA paraffin carrier, dissolved or suspended in said propellant or propellant mixture, comprising one or more paraffins which form a semi-solid and occlusive layer at the site of application after application to the skin and evaporation of the propellant.

2. The composition of claim 1, wherein the vitamin D derivative or analog is selected from the group consisting of calcipotriol, calcitriol, tacalcitol, maxacalcitol, paricalcitol, and alfacalcidol.

3. The composition of claim 2, wherein the vitamin D analog is calcipotriol or calcipotriol monohydrate.

4. The composition of claim 1, wherein the corticosteroid is selected from betamethasone, budesonide, clobetasol, desoximetasone, diflucortolone, diflorasone, fluocinonide, fluocinolone, clobetasol, halobetasol, hydrocortisone, mometasone, and triamcinolone or a pharmaceutically acceptable ester thereof.

5. The composition of claim 4 wherein the corticosteroid ester is betamethasone dipropionate, betamethasone valerate, clobetasol propionate or hydrocortisone acetate or hydrocortisone butyrate.

6. The composition of claim 1, further comprising a non-evaporating oil co-solvent selected from at least one of the following solvent types:

(a) compounds of the general formula I

H(OCH₂C(CH₃)H)OR¹

Wherein R is¹Is straight or branched C_1-20Alkyl, and x is an integer from 2 to 60;

(b) straight or branched C_10-18Isopropyl esters of alkanoic or alkenoic acids;

(c)C_8-14a propylene glycol diester of an alkanoic or alkenoic acid;

(d) straight or branched C_8-24An alkanol or alkenol;

(e) highly purified vegetable oils; and

(f) n-alkylpyrrolidone or N-alkylpiperidinone.

7. The composition of claim 6, wherein the highly purified vegetable oil is a medium chain triglyceride or a long chain triglyceride.

8. The composition of claim 6, wherein the compound of formula I is polyoxypropylene-15-stearyl ether, polyoxypropylene-11-stearyl ether, polyoxypropylene-14-butyl ether, polyoxypropylene-10-cetyl ether, or polyoxypropylene-3-myristyl ether.

9. The composition of claim 6 wherein C is a straight or branched chain_10-18The isopropyl ester of an alkanoic or alkenoic acid is isopropyl myristate, isopropyl palmitate, isopropyl isostearate, isopropyl linoleate or isopropyl monooleate.

10. The composition of claim 6, wherein C_8-14The propylene glycol diester of an alkanoic acid is propylene glycol dipelargonate.

11. The composition of claim 6 wherein straight chain C_8-24The alkanol is octanol, lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol or myristyl alcohol, or a branched chain C thereof_8-24The alkanol being a branched chain C_18-24An alkanol.

12. The composition of claim 11 wherein the branch chain C_18-24The alkanol is 2-octyllauryl alcohol.

13. The composition of claim 6, wherein the N-alkylpyrrolidone is N-methylpyrrolidone.

14. The composition of claim 1 wherein the propellant is dimethyl ether.

15. A composition according to claim 1 wherein the first propellant of the propellant mixture is dimethyl ether.

16. A composition according to claim 1, wherein the second propellant of the propellant mixture is C_3-5An alkane.

17. The composition of claim 16, wherein C_3-5The alkane is selected from the group consisting of n-propane, iso-propane, n-butane and iso-butane.

18. The composition of claim 16, wherein C_3-5The alkane is n-butane and/or isobutane.

19. The composition of claim 18, wherein the ratio of n-butane and/or isobutane to dimethyl ether is in the range of 6:1 to 0:1 v/v.

20. The composition of claim 18, wherein the ratio of n-butane and/or isobutane to dimethyl ether is in the range of 5:1 to 1:2 v/v.

21. The composition of claim 18, wherein the ratio of n-butane and/or isobutane to dimethyl ether is in the range of 4:1 to 1:1 v/v.

22. The composition of claim 18, wherein the ratio of n-butane and/or isobutane to dimethyl ether is in the range of 4:2 to 1:1 v/v.

23. The composition of claim 18, wherein the ratio of n-butane and/or isobutane to dimethyl ether is in the range of 4:2 to 4:3 v/v.

24. The composition of claim 18, wherein the ratio of n-butane and/or isobutane to dimethyl ether is in the range of 4:2 to 1:1 v/v.

25. The composition of claim 1 comprising

(a) 0.00001-0.05% w/w vitamin D derivative or analogue,

(b) 0.0005-1% w/w corticosteroid,

(c) 5-55% w/w paraffin carrier, and

(d) 45-95% w/w propellant or mixture of propellants.

26. The composition of claim 25, comprising 10-50%, 15-45% or 20-40% w/w of the paraffin carrier.

27. A composition according to claim 25 which comprises 50-90% w/w or 55-70% w/w propellant or mixture of propellants.

28. The composition of claim 25, further comprising 0.1-10% w/w of the oil solvent of claim 6.

29. The composition of claim 25, further comprising 0.5-3% w/w of the oil solvent of claim 6.

30. The composition of claim 25, further comprising 1-2.5% w/w of the oil solvent of claim 6.

31. The composition of claim 25, further comprising 1.5-2% w/w of the oil solvent of claim 6.

32. The composition of claim 1, wherein the paraffin carrier comprises at least one paraffin selected from the group consisting of: from a polymer having a chain length of C₅To C₆₀Of a paraffin wax consisting of hydrocarbons having a peak chain length of C_14-16、C_18-22、C_20-22、C_20-26、C_28-40And C_40-44As determined by gas chromatography; or a lipophilic viscosity enhancing ingredient capable of imparting to the paraffin carrier a property of forming a semi-solid and occlusive layer on the skin after application and evaporation of the propellant, said lipophilic viscosity enhancing ingredient being selected from microcrystalline wax, silicone wax and hydrogenated castor oil or mixtures thereof; or an isoparaffin.

33. The composition of claim 32 wherein the isoparaffin is isohexadecane.

34. A pressurized container suitable for applying a topical composition to an affected skin area, the container comprising a container body containing a composition of any of claims 1-33 and a valve assembly containing an actuator for releasing the composition as a spray.

35. The container of claim 34, wherein the valve assembly comprises at least one orifice having a diameter of 0.05 to 1 mm.

36. The container of claim 34, wherein the actuator has a nozzle with a diameter of 0.3 to 1.5 mm.

37. The composition of any one of claims 1-33 for use in treating a skin disease or disorder.

38. The composition of claim 37, wherein the skin disease or disorder is selected from psoriasis, palmoplantar pustulosis, ichthyosis, dermatitis, rosacea, and acne.