US 20090191271A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0191271 A1 Brown et al. (43) Pub. Date: Jul. 30, 2009

(54) TOPICAL FORMULATIONS (86) PCT No.: PCT/GB2006/003408

(75) Inventors: Marc Barry Brown, Hertfordshire- § 371 (0X1), _ (GB); Stuart Allen Jones, London (2)’ (4) Date' Jul‘ 16’ 2008 (GB) (30) Foreign Application Priority Data

Sep. 14, 2005 (GB) ...... 05187695 Correspondence Address: _ _ _ _ GREENLEE WINNER AND SULLIVAN P C Publlcatlon classl?catlon 4875 PEARL EAST CIRCLE, SUITE 200 (51) In‘; C]_ BOULDER, CO 80301 (US) A61K 9/14 (2006.01) A61K 47/32 (2006.01) (73) Assignee; Med Pharm Limited, Surry (52) US. Cl...... 424/487; 514/772.4 Research Park,Guildford (GB) (57) ABSTRACT Saturated, monophasic of drug in a and (21) App1.No.: 12/067,004 propellant , together With a ?lm-forming agent, exhibit transderrnal diffusion ?uxes greater than those pre (22) PCT Filed: Sep. 14, 2006 dicted by Fick’s laW When applied topically.

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TOPICAL FORMULATIONS greatly to the epidermal permeability barrier, both to Water and to other permeates (Ting et al., 2004). [0005] In order for therapeutic quantities of drug to pen [0001] The present invention relates to formulations for etrate the skin, the barrier properties of the Stratum comeum topical drug delivery, and methods for their use and manufac must be overcome. The Stratum corneum exhibits selective ture. permeability and alloWs only relatively lipophilic compounds [0002] The administration of therapeutic compounds either With a molecular Weight beloW 400 Daltons to pass. HoWever, locally to the skin, or into the systemic circulation after pas Where a drug is very lipophilic, it may cross the Stratum sage through the skin, offers numerous potential advantages corneum, but diffusion is rapidly sloWed as it enters the more over oral or parenteral drug delivery. These include the avoid aqueous loWer regions of the epidermis in Which it is poorly ance of hepatic ?rst-pass metabolism, improved patient com soluble. Thus, as the diffusion of a very hydrophobic perme pliance and ease of access to the absorbing membrane, i.e. the ate proceeds into deeper layers of the skin, diffusion sloWs, skin. In addition, in the case of local delivery (i.e. delivery to and the gradient (from Stratum corneum doWn the super?cial layers of the skin) by directly administering the to the viable tissue) falls. The rate-determining step for spe drug to the pathological site, any adverse effects associated cies diffusing in this manner then becomes barrier clearance With systemic toxicity can be minimised. HoWever, the effec not barrier penetration. tive delivery of drugs into and through the skin is not trivial. [0006] In addition to their inability to penetrate into the [0003] Molecules can pass into and/or through the skin via deep layers of the epidermis, poorly Water soluble molecules passive diffusion. Passive diffusion can be described thermo are also notoriously dif?cult to formulate as they often exhibit dynamically by Fick’s ?rst laW: loW in numerous topical vehicles. A su?icient con centration of a topically applied therapeutic agent must be loaded into the vehicle to ensure an adequate concentration : KDmpp — Cree) [1] gradient betWeen the formulation and the skin, in order to attain adequate release of the drug into the skin. Topical formulations, such as ointments, Which can solubilise high Where (J) describes the steady state ?ux per unit area, (K) is of hydrophobic actives, are “heavy” and the partition of the drug betWeen the skin and the formulation “greasy”, thus making them cosmetically unacceptable. and (D) is the diffusion coe?icient through the diffusional HoWever, the loW solubility of hydrophobic compounds in path length (h). Since usually the concentration of the perme more cosmetically acceptable topical vehicles such as creams ate in the applied dose (capp) is so much higher than the and gels often precludes their use. concentration in the receptor phase (crec) this equation can be [0007] Methods of overcoming the barrier properties of the simpli?ed to: Stratum comeum may be divided into chemical, such as the use of occlusion, penetration enhancers and supersaturated JIkPCW [2] systems, and physical, such as iontophoresis, skin electropo Where kp is the permeability coef?cient and equal to KD/h ration, ultrasound and poWder injection methods. For small (Hadgraft, 2004). According to Fick’s laW the most important organic molecules, chemical enhancement methods have sev factors that in?uence ?ux across the skin are the concentra eral advantages, in terms of their loW cost, lack of irritancy, tion gradient of the drug Within the skin, the partition coef? and simplicity, compared to physical methods. cient of the permeate and the diffusion coe?icient (Thomas [0008] Irrespective of their mode of action, penetration and Finnin, 2004; Hadgraft, 2004). In addition, the ?ux (J) of enhancers usually alter the barrier properties of the skin. a molecule across a membrane should increase linearly With Whether the structural alteration is reversible or not, the con concentration until ca p reaches the solubility limit i.e. at the centrations of penetration enhancers required to elicit an e?i point of saturation (i.e. a thermodynamic activity (TA) of 1. cacious response often causes skin irritation, unWanted side Assuming there is no interaction betWeen the drug and the effects, and/ or drug instability. Thus, Whilst many penetration delivery vehicle, then this means that, regardless of l) the enhancers are undoubtedly effective, they can often be di?i nature of the vehicle in the drug saturated formulation, and 2) cult to formulate and impractical to use. the quantity of a drug saturated formulation applied to the [0009] The Stratum corneum is only approximately 10 pm membrane at a TAIl, the ?ux/release of the drug Will remain thick When dry, but it sWells signi?cantly in the presence of the same. Thus, When a saturated drug formulation is applied Water. Hydration of the Stratum corneum softens the skin by to the skin, the drug Will be at its highest thermodynamic loosening the lipid packing Which makes it more easily tra activity, in accordance With Fick’s laW. In some instances TA versed by a lipid-like penetrant. Occlusion is a popular and can exceed 1 When supersaturated systems are formed. HoW simple Way to hydrate the skin and is commonly achieved by ever, such formulations are inherently unstable and as such either applying a patch or a very hydrophobic vehicle to are not suitable for use in vivo. prevent transepidermal Water loss. HoWever, as previously [0004] Human skin comprises three tissue layers: 1) the discussed, hydrophobic vehicles are cosmetically unaccept strati?ed, avascular, cellular epidermis; 2) the underlying der able and because of solubility issues most patches only mis of connective tissue; and 3) the subcutaneous fat beneath deliver about 10% of the total dose, With the subsequent 90% the dermis. The physiological function of the Stratum cor of the drug remaining in the patch being discarded. neum, the outermost and non-viable layer of the skin, is to act [0010] According to Fick’s ?rst laW, the ?ux of a drug as a protective barrier for the body. The Stratum comeum’s (assuming no interaction With the vehicle) is directly propor intercellular lipids comprise ceramides, cholesterols, choles tional to its thermodynamic activity in the formulation, Which terol esters, and free fatty acids, Whose organisation and is related to the degree of saturation. If a topical vehicle is unique create a high degree of Water supersaturated With a drug i.e. the maximum concentration of impermeability. It is these lipid lamellae that contribute drug that can be dissolved in a vehicle is increased using US 2009/0191271A1 Jul. 30, 2009

complimentary excipients and/or variations in the pH, tem perature, or the formulation vehicle, ?ux is increased as a TABLE 1 direct result of an increase in the thermodynamic activity Physical properties of CFC and HFA propellants. (Moser et al., 2001a). However, Whilst supersaturated sys tems are thermodynamically more active, they are typically BP KB 6 [i 6 0t thermodynamically unstable and crystallisation of the drug CFC II 23.8 60 7.6 0.46 2.3 9.5 often occurs With time, Which is not acceptable Within a CFC 12 —29.8 18 6.1 0.51 2.1 7.9 pharmaceutical product. CFC 114 3.6 12 6.4 0.50 2.3 8.5 HFA134a —25.8 8 6.6 2.06 9.5 5.4 [0011] One method to overcome the problem of the ther HFA 2276a —l7.3 10 6.6 0.93 4.1 5.8 modynamic instability Within supersaturated systems is to BI’: boiling point ° C.; create the supersaturation from subsaturated solutions imme KB: Kauri-Butanol value; diately before or during topical application. This can be 6: solubility parameter cal/ml; accomplished by Water uptake from the skin, evaporation of a u: dipole movement; 6: dielectric constant; volatile solvent, or using a mixed cosolvent system, Where the 0t: polarisability (adapted from Vervaet and Byron, 1999) vehicle changes are created prior to administration of the [0015] These differences are caused in part by the enhanced formula (Moser et al., 2001b). electronegativity of HFAs (?uorine is more electronegative [0012] Creating supersaturated systems using volatile sol than chlorine). The strong electron draWing potential of the vents is a very effective method of increasing thermodynamic ?uorine atoms minimises the intermolecular attraction in activity. HoWever, the volatile solvent must ideally be non these propellants Which leads to a loWer boiling point com toxic, non-combustible, have excellent solubility properties pared to structurally equivalent CFC propellants. In addition, for a Wide range of drugs, and be inert. In addition, the ?nal the asymmetrically positioned hydrogen atoms Within the supersaturated system should contain an anti-nucleating structure of HFAs creates a distinct dipole on the hydrogen agent to sloW doWn the process of crystallisation to retain carbon bonds in both propellants. The increased polarity of optimal thermodynamic activity. It has been shoWn that the the HFA propellants is re?ected in their larger dipole moment addition of polymers/plasticisers can be used to sloW the and dielectric constant compared to CFCs. process of recrystallisation. The folloWing polymers have [0016] Thus, Whilst HFA propellants are ideal in terms of previously been used to effectively prevent recrystallisation safety and volatility to use for topical sprays, their unique of a number of drugs in supersaturated solutions: Eudragit blend of hydrophobic and electronegative properties means R/S 100 L, HPMC phthalate, ethyl cellulose, methyl cellu that, unlike the hydrocarbons or the CFCs, they are incapable lose, cyclodextrin, hydroxypropyl cellulose, poly(vinyl pyr of solubilising a Wide range of both hydrophilic and hydro phobic therapeutic agents. Their lack of solubility for the rolidone) (PVP), poly (vinyl alcohol) (PVA), and carboxym majority of therapeutic compounds precludes their use alone ethyl cellulose. Supersaturated formulas are, generally, best stabilised by polymers having similar solubility parameters to as a volatile vehicle for topical sprays. [0017] In order to improve the solubility pro?le of HFA the drugs themselves, since those having higher values can propellants, co- can be used. HoWever, again the co have a destabilising effect. HoWever, matching solubility solvent system must display excellent topical tolerability, parameters is not yet a reliable method for predicting an should be volatile, acceptable as a pharmaceutical excipient optimal supersaturated formulation (Moser et al., 2001c). and be able to solubilise a Wide range of therapeutic agents. In [0013] At present, the majority of volatile topical sprays previous Work, in the investigation of MDIs, ethanol employ a short chain hydrocarbon such as butane, propane, has been used as a co-solvent (Brambilla, 1999). Ethanol n-butane, or a mixture thereof, as the delivery vehicle. These solubilises a Wide range of therapeutic agents and is accept solvents have been approved by the US Food and Drug able for use in therapeutic formulations. Administration (FDA) for topical use and are generally [0018] In US. Pat. No. 6,123,924, PVP is disclosed as a accepted as safe (GRAS listed by the FDA). HoWever, Whilst suspending agent to aid the of therapeutic agents hydrocarbon aerosol propellants are relatively inexpensive, for inhalable drug delivery. non-toxic, and environmentally friendly (since they are not [0019] In WO 95/15151, there is disclosed pharmaceutical damaging to the oZone layer and are not greenhouse gases) formulations for aerosol delivery and comprising the thera their use is limited by their ?ammability. Butane, especially, peutic agent in combination With a protective , Which is explosive and must only be handled in an explosion-proof may include PVA, and an HFA. room Which is equipped With adequate safety Warning [0020] In US. Pat. No. 5,776,432 there is disclosed the use devices and explosion-proof equipment. of HFA and ethanol to solubilise a steroid. [0021] US 2003/0224053 discloses compositions Which [0014] Hydro?uoroalkane (HFA) solvents have been can form a ?lm in contact With skin and Which comprise a approved for human use in pressurised metered dose inhalers polymer, an active ingredient and a solvent to provide a patch (pMDIs) since the mid 1990’s (Vervaet and Byron, 1999). that can be peeled off and that Will deliver a useful amount of These solvents are highly volatile, like hydrocarbons, but are drug or cosmetic. There is no requirement that the composi non-combustible. HFAs Were developed speci?cally to tion be monophasic or that the active ingredient is saturated. replace chloro?uorocarbon (CFC) solvents, Which Were [0022] US 2003/0152611 discloses pharmaceutical com found to have damaging effects on the oZone layer. HoWever, positions for transderrnal administration comprising a cellu the boiling point, Kauri-Butanol value, dielectric constant, losic polymer matrix, an NSAID, an absorption promoter, dipole moment, polarisability and solubility parameters of Water and a solvent forming matrix. Monophasic saturated HFA and CFC propellants differ signi?cantly (c.f. table 1). solutions are not required. US 2009/01912711411 Jul. 30, 2009

[0023] US. Pat. No. 6,432,415 discloses bioadhesive gels [0035] The drug shouldbe present in a saturating amount in and aerosols comprising a Water-insoluble, pharmaceutically the formulation. In this respect, it Will be appreciated that a acceptable alkyl cellulose, a solvent system comprising a formulation held at a higher temperature Will require greater volatile solvent and Water, a solubilising agent and a pharma amounts of drug in order to be saturated, for most solvents. In ceutical. It is possible to incorporate a propellant. There is no this regard, the monophasic requirement remains important, suggestion that the preparations be either monophasic or satu but saturation may be determined by Whether the formulation, rated. When applied to a test membrane such as disclosed in the [0024] US. Pat. No. 6,325,990 provides lipophilic vita accompanying Examples, transcends Fick’s laW or only pro mins etc. in the absence of Water and in the presence of vides a ?ux at or beloW that predicted by Fick’s laW. adhesive polysiloxane, an absorption promoter and a volatile [0036] Thus, by saturated We also include substantially solvent, sprayable from an aerosol can. There is no suggestion saturated, Wherein at least 80% of that amount of the drug that the compositions should be either monophasic or satu needed to achieve saturation is present. This amount is pref rated. erably at least 90%, and more preferably 95%. At the tem [0025] WO 0/045795 provides medicinal spray composi perature of use, it is preferred that the formulation be as close tions comprising a medicament in a volatile vehicle and one to saturated as possible, While remaining monophasic. Super or more ?lm-forming polymers. There is no suggestion that saturated solutions are also included, but these are generally the compositions should be either monophasic or saturated. less preferred, as they are not generally stable, and have short [0026] WO 0/38658 discloses slimming compositions for shelf-lives before ceasing to be monophasic. dermal administration comprising a matrix Which forms a [0037] It is preferred that the amount of drug present be as soft ?lm after drying. There is no disclosure that the compo close to full saturation as possible, but many monophasic sitions should be either monophasic or saturated. solutions are not stable at such high concentrations. In such cases, the addition of antinucleating agents, such as are [0027] JP 08291050 discloses an aerosol composition hav ing foaming activity. The composition comprises an acrylic described beloW, may be advantageous, as may a slight drop in saturation, doWn as far as 80%, Which is considered to be a polymer, a plasticiser, a loWer alcohol, Water, a surfactant, a saturating amount for the purposes of the present invention. propellant and polyvalent alcohol. There is no suggestion that [0038] The advantage of the present invention lies in the the compositions should be either monophasic or saturated. combined high saturation levels and the use of propellant. The [0028] JP 01230514 provides an aerosol type patch com propellant is typically a highly volatile liquid With a loW prising a ?lm forming polymer, a solvent, a propellant and boiling point, such as a CFC or HFA, and particularly HFA drug. There is no suggestion that the compositions should be (hydro?uoroalkane), such that it can force the formulation either monophasic or saturated. from a dispenser. Evaporation is almost instantaneous and the [0029] WO 88/09185 discloses a dressing comprising a boiling during transfer from the dispenser to the site of admin ?lm-forming polymer Which contains the active ingredient, a istration has the effect of causing the evaporation of a sub liquid polymer matrix Which forms the ?exible ?lm on hard stantial amount of the solvent, Which are as de?ned beloW, but ening, and a solvent controlling release of the active ingredi is typically ethanol or isopropyl alcohol. Thus, the solvent is ent, together With a solvent for the matrix, and a propellant. preferably a volatile solvent, and is preferably more volatile The compositions are not monophasic and concentration is than Water and Will often be organic, and the almost explosive not a signi?cant factor. decompression of the propellant causes the disruption and [0030] AU 198664695 provides a pesticide composition loss of solvent by evaporation. This loss can be up to 50% and comprising a ?lm-forming polymer, a solvent and an active even higher. material. A clear solution is described as being desirable for [0039] The effect of the loss of solvent is to drive the use as an aerosol, but saturation is not suggested or required. remaining solution toWards supersaturation. It is for this rea [0031] GB 2188844 discloses an anti-psoriatic composi son that saturation levels of at least 80% are necessary, as tion comprising a liquid formulation of ?lm forming poly levels much beloW this tend to result in saturated solutions mers together With anti-psoriatic compounds. There is no rather than supersaturated solutions, and little advantage is to disclosure that the compositions should be either monophasic be seen. At 80% and above, levels of supersaturation of up to or saturated. 2.5 times saturation may be achieved, With the concomitant [0032] Surprisingly, We have noW discovered that satu ability to drive permeation across the Stratum corneum. rated, monophasic solutions of drug in a solvent and propel LoWer levels of saturation require greater loss of solvent lant mixture, together With a ?lm-forming agent, exhibit pas before supersaturation is achieved. sive diffusion ?uxes greater than those predicted by Fick’s [0040] The pharmaceutical may be any substance for Which laW. it is desired to achieve penetration into and/or through the skin, and such substances Will generally also be referred to [0033] Thus, in a ?rst aspect, the present invention provides herein as ‘drugs’. Suitable drugs for use in accordance With a pharmaceutical formulation capable of forming a ?lm on topical administration, said formulation comprising a prepa the present invention include, but are not limited to, those in the folloWing Table, either individually or in combination: ration of a pharmaceutical, a solvent therefor, a ?lm-forming agent, and a propellant, Wherein the formulation is monopha sic and the pharmaceutical is present in a saturating amount therein, under conditions of use. Type Of Drug [0034] The term ‘monophasic’ is used to indicate that the Local antipruritics Crotalniton formulation does not contain undissolved drug, and also that Doxepin hydrochloride there is only the one liquid phase, and not a colloid or micro Mesulphen colloid, for example. There is only one phase, and that phase Polidocanol is liquid. US 2009/0191271Al Jul. 30, 2009

-c0ntinued -continued

Type Of Drug Type OfDrug Local anaesthetics Amethocaine (Hydrochloride in solutions Polyphloroglucinol Phosphate (Treatment or creams, base in gels or ointments) ofWounds and pruritic skin disorders) Amylocaine (Hydrochloride) Sodium pidolate (humectant, applied as BenZocaine cream/lotion for dry skin disorders) Bucricaine (hydrochloride) Sulphur (mild anti?mgal/antiseptic) Butacaine Sulphate Sulphurated Lime (For acne, scabies, Butyl AminobenZoate Picrate seborrhoeic dermatitus) Cincocaine (base, hydrochloride or Sulphurated Potash (Acne) benZoate) Minoxidil (hair groWth) Dimethisoquin Hydrochloride Topical retinoids and related Adapalene Dyclocaine Hydrochloride preparations for acne Isotretinoin Ethyl Chloride Polyprenoic acid Lidocaine Tretinoin Lignocaine Other topical preparations Nicotinamide Myrtecaine for acne OXethaZaine (OXetacaine) Topical antibacterials Amphomycin Prilocaine Bacitracin/Bacitracin Zinc Propanocaine Hydrochloride Bekanamycin Sulphate Tetracaine Chloramphenicol Antihistamines AntaZoline Chlorquinaldol ChlorcycliZine Hydrochloride Chlortetracycline Dimethindene Maleate Framycetin sulphate Diphenhydramine Fusidic Acid Histapyrrodine Halquinol Isothipendyl Hydrochloride Mupirocin Mepyramine Mupirocin Mepyramine Maleate Neomycin sulphate Tolpropamine Hydrochloride Polymyxins (Polymyxin B Sulphate) Tripelennamine Hydrochloride Silver sulphadiaZine (sulfadiazine) Triprolidine Hydrochloride Sulphanilamide Corticosteroids Alclometasone dipropionate Sulphasomidine Beclomethasone dipropionate SulphathiaZole (sulfathiazole) Sodium Betamethasone valerate Topical antifungals BenZoyl peroxide Clobetasol propionate Amorol?ne Clobetasone butyrate BenZoic acid Desoximetasone Bifonazole Di?ucortolone valerate Bromochlorosalicylanilide FludroXycortide/Flurandrenolone Buclosamide Fluocinolone acetonide Butena?ne Hydrochloride Hydrocortisone ChlormidaZole Hydrochloride Hydrocortisone acetate Chlorphenesin Hydrocortisone butyrate Ciclopirox Olamine Topical preparations Calcipotriol Clotrimazole for psoriasis Coal tar CroconaZole Hydrochloride Dithranol EberconaZole 5-Fluouracil EconaZole nitrate Ciclosporin Fenticlor Fumeric acid FenticonaZole Nitrate Lonapalene Flutrimazole Methotrexate Haloprogin Methoxsalen Ketoconazole Salicylic acid Mepartricin Tacalcito MiconaZole nitrate Tacrolimus Nafti?ne Hydrochloride Pimecrolimus Natamycin TaZarotene NeticonaZole Hydrochloride Topical preparations AZelaic acid Nystatin for acne BenZoyl peroxide OmoconaZole Nitrate Dithiosalicylic acid OXiconaZole Nitrate Motretinide Pyrrolnitrin Resorcinol Sertaconazole Nitrate Topical antibacterials Clindamycin Sodium Propionate for acne Erythromycin Sulbentine ‘Dermatological drugs’ Becaplermin (Diabetic skin ulcers) SulconaZole nitrate Bentoquatum (prevents allergic contact SulconaZole Nitrate dermatitis caused by poison ivy) Terbina?ne Gamolenic acid TioconaZole Glycolic acid (Photodamaged skin) Tolciclate Hydroquinone/Mequinol (Depigmenting Tolnaftate agents) Triacetin Ichthammol Undecenoates/Undecanoic Acid Keluamid (seborrhoeic dermatitis) Antiviral preparations 1-Docosanol Lithium succinate Aciclovir MonobenZone (vitiligo) Brivudine US 2009/0191271141 Jul. 30, 2009

permeation of the drug. Thus, a ?lm-forming agent that is -continued capable of forming a hydrogel is preferred. In this respect, PVP and PVA are preferred. Other, suitable, ?lm forming Type Of Drug agents include; acrylic polymers or copolymers, methacry Edoxudine late polymers and copolymers, poly (vinyl acetate), and cel Ibacitabine lulose based polymers and co-polymers. Idoxuridine [0046] The ?lm-forming agent typically also serves the role Idoxuridine in dimethyl sulfoxide Imiquimod of anti-nucleating agent as the formulation grows more con Penciclovir centrated once it has been dispensed. However, it may be Vidarabine desired to further inhibit nucleation of the drug, in which case Parasiticidal preparations BenZyl benZoate a further component may be added to the formulation for this Carbaryl Malathion purpose, always provided that the formulation is monophasic Permethrin and saturated with drug under conditions of use. Suitable Phenothrin anti-nucleating agents are well known in the art, and may Preparations for minor Cetrimide include PVA when PVP is used as the ?lm-forming agent. cuts and abrasions Collodion Magnesium sulphate Other suitable anti nucleating agents include methyl cellu Pro?avine lose, ethyl cellulose, hydroxyalkylcelluloses, such as hydrox Topical circulatory Heparinoid ypropylmethylcellulose and hydroxypropylcellulose, glycol preparations esters, polyacrylic acid, and derivatives thereof. Transdermal drugs Ibuprofen Diclofenac [0047] Plasticisers may also usefully be added to the for Glyceryl trinitrate mulation, where the resulting ?lm would be less ?exible than Oxybutynin desirable. Plasticisers are well known in the art, and include Nicotine Ethinylestradiol + norelgestronin water, glycerol, oleic acid, citric acid, phosphate esters, fatty Griseofulvin acid esters, glycol derivatives, hydrocarbons and hydrocar Hyoscine bon derivatives, adipic acid/butanediol polyesters, epoxi Alfentanil dised soya oils, diethyl phthalate, dibutyl phthalate, citric acid Fentanyl esters such as triethyl citrate and the like, castor oil, triacetin Remifentanil Testosterone and chlorinated paraf?ns. Oestro gen [0048] Components other than the drug, solvent, propellant Methylphenidate hydrochloride and ?lm-forming agent are also referred to herein as excipi Prednisolone Methyl prednisolone ents. Antiperspirants Aluminium chloride [0049] It will be appreciated that the formulation will be Glycopyrronium bromide saturated with drug and be monophasic under conditions of use. In this respect, these requirements relate to the formula [0041] Other suitable drugs include the non-steroidal anti tion immediately prior to dispensing, such as when in an in?ammatories (NSAIDs), actinic keratosis treatments, and aerosol canister. capsaicin, as well as such other substances as menthol. It will [0050] We have established that it is extremely important be appreciated that the pharmaceutical may be suitable either that the drug be present in saturating concentrations in the for local or systemic application. formulation, at the time of use, and that the formulation be [0042] Topical administration will generally include any monophasic. It is especially surprising that formulations con exposed position on the body where it may be advantageous taining differing amounts of all of the same components, but to administer a formulation of the invention. The highly vola wherein the drug is in a higher, but not saturating concentra tile nature of the propellant will normally restrict such admin tion, perform considerably worse than those having a lower, istration to intact skin, including contusions and bruises, but but saturated concentration. the invention also envisages, in a less preferred aspect, the [0051] The propellant may be an HFA, as illustrated above. administration of formulations to any topical membrane, and The HFA will normally play more of a part than a merely to lesions or wounds. neutral and unreactive diluent, and will generally act as a [0043] The formulations of the invention are capable of cosolvent, albeit a poor one, for the most part. For purposes of forming a ?lm on topical administration, typically to the skin. convenience, it will also be appreciated that the propellant In particular, the majority of the propellant component of the will normally be added last. Thus, as is demonstrated in the formulation will normally evaporate almost immediately, accompanying Examples, where ethanol is used as the pri thereby concentrating the remainder of the formulation. The mary solvent, for example, and the ?nal concentration of ?lm-forming component may be such as to form a ?lm sub ethanol is 10% in relation to the ?nal composition, then PVP stantially in the absence of the propellant or, more preferably, as a ?lm-forming agent can only be added to a ?nal concen after the evaporation of a portion of the solvent. tration of no more than about 2% if a drug such as beclom [0044] The ?lm-forming component may suitably be a ethasone dipropionate (BDP) is used. In such a formulation, polymer approved for topical administration, such as polyvi the HFA will form around 87-88% of the formulation. nyl pyrrolidone (PVP) or polyvinyl alcohol (PVA), for [0052] However, where the amount of HFA that is added to example. precisely the same pre-mix is such that the ?nal amount of [0045] Without being restricted by theory, it is believed that ethanol is 20% rather than 10%, then the resulting formula the formation of a ?lm serves to occlude the skin, and to tion will not be saturated for BDP. encourage the retention of water in the skin. This has the [0053] It will be appreciated that where HFA is referred to advantage that water in the skin may continue to interact with herein, then this includes reference to any suitable propellant the drug after evaporation of the solvents, thereby to continue unless otherwise indicated. It will also be appreciated that