Title of Invention	"A SYSTEM FOR DISPENSING TOPICAL FORMULATIONS"
Abstract	The present invention relates to a pharmaceutical product comprising first and second active ingredient-containing formulations for topical administration to a patient, wherein said product includes storage means whereby said formulations are maintained separately prior to dispense, together with dispense means which permit said formulations to be dispensed from said storage means, wherein (i) an active ingredient in one or both of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based carrier bases having substantially the same lipophilicity. The invention also provides a dual or multi-chamber dispense system suitable for dispensing said formulations which is provided with a removable closure, e.g. a cap. This closure prevents the formulations from being accidentally dispensed from a dispensing orifice(s) and can also reduce exposure of these orifice(s) to the air. The products of the invention are particularly suitable for dispensing formulations for treating dermatological conditions such as acne, in particular formulations in which the active components have stability limitations when combined, e.g. those comprising oxidising antibacterials (e.g. benzoyl peroxide) and antibiotics.

Title of Invention

"A SYSTEM FOR DISPENSING TOPICAL FORMULATIONS"

Abstract

The present invention relates to a pharmaceutical product comprising first and second active ingredient-containing formulations for topical administration to a patient, wherein said product includes storage means whereby said formulations are maintained separately prior to dispense, together with dispense means which permit said formulations to be dispensed from said storage means, wherein (i) an active ingredient in one or both of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based carrier bases having substantially the same lipophilicity. The invention also provides a dual or multi-chamber dispense system suitable for dispensing said formulations which is provided with a removable closure, e.g. a cap. This closure prevents the formulations from being accidentally dispensed from a dispensing orifice(s) and can also reduce exposure of these orifice(s) to the air. The products of the invention are particularly suitable for dispensing formulations for treating dermatological conditions such as acne, in particular formulations in which the active components have stability limitations when combined, e.g. those comprising oxidising antibacterials (e.g. benzoyl peroxide) and antibiotics.

Full Text	This .invention relates to systems for dispensing topical pharmaceutical and/or cosmetic formulations, in particular pharmaceutical formulations for the treatment of dermatoloqical conditions such as acne, rosacea, melasma (ci iloasma) , alopecia, fungal infections, bacterial infections, viral infections, psoriasis, eczema .an !:;ie like, and cosmetic formulations for treatiii' ; i.iiitions such as premature aging (e.g. wrinkli ;/j) oi. the skin. Such systems may also be, used for dispensing formulations for treating conditions which affect the mucosal membranes, e.g. the membranes of the genital area, such as vulvitis, balanitis, etc., and haemorrhoidal conditions. It has long been .the case that pharmaceutical formulations, typically in the form of creams or gels suitable for topical administration, have been used to combat f.kin disorders which are caused by the inflammation of sebaceous glands and/or skin follicles and which may result in conditions such as acne and rosacea. Acne is one of the most common skin disorders which is particularly common during puberty but which may pert1 is- for many years. The main factors which contribute to the pathogenesis of acne are comedogi-i'e;3.i..i, sebum production, inflammation of the sebaceou:- •.)lands arid the presence of the bacteria Propionibacterium acnes (P. acnes) . Many previous treatments for ouch skin disorders can be found in the literature and often comprise topically administrable organic peroxides, retinoids and/or ant3.biot.ics. Thus, for example, formulations for the treatment of skin disorders comprising benzoyl peroxide are described in US-A-3535422, US-A-4056611, US-A-4 H.I 8' comprising an antibiotic for the treatment of skin disorders such as acne and rosacea. US-A-3969516, for example, describes the use of the topical antibiotic clindamycin for the treatment of acne. Other antibiotic's which have been used in the treatment of skin disorders include erythromycin and tetracyclines. i Still further patents disclose the use of combination preparations which comprise actives having complementary but distinct mechanisms of action, for example formulations comprising a combination of an organic peroxide and an antibiotic for the treatment of Skin disorders. GB-A-2088717, US-A-4411893, US-A-4692329 and GB-A-1594314, for example, describe combin ' i c •• of the antibiotic erythromycin with various organj • i>. -o /xides as formulations for the treatment of acne o:. oi.ni-.-r skin disorders. UJ3-A-4607101 discloses a formulji,.U.n for the treatment of acne vulgaris comprislrK; a carbamide peroxide in combination with a topica i en :t ibiotic . It has been found that combinations of an antibiotic with an organic peroxide may be more effective in the treatment of skin disorders than either the antibiotic or the peroxide alone - see, for example, US-A-4497Y94. Benzoyl peroxide is an antibacterial, keratolytic and desquamating agent. Like other organic peroxides, it exerts an antibacterial effect via its strong oxidising properties. This chemical property of peroxides, nowever, can reduce the stability of such peroxide containing two ingredient formulations, since oxidative interaction with the second (e.g. antibiotic) ingredient may lead to loss of potency of both active ingredient .-.;, Benzamycin® (Dermik Lab.) is a topical gel for the treatment of acne comprising a combination of 3% erythromyciri, as a topical antibiotic, and 5% benzoyl peroxi,,. , ..-A.-..-, an antibacterial, ke.ratolyc.ic and desquamating agent. This combination, however, is unstable :i'c room temperature for the above reason, so that B- i ,-.. ini/cin'"' rapidly loses its pharmaceutical effect if scored at ambient temperature. Ii, -: i der to prolong the pharmaceutical effectiveness of Benzamycin® it must be formulated by a '; pharmacist" as and when required, thereafter being stored under refrigeration. However, this limits the product to being Bold in a pharmacy and may also lead to variation in the final composition. Thus the pharmacist is required firstly to dissolve the erythromycin in an alcohol and then to add the resulting solution to a gel containing the benzoyl peroxide, thereafter stirring the mixture until it is homogeneous in appearance. Accordingly, variations in the alcohol used for this purpose- may lead to variability^in the product; if the mixing is not complete, partially dissolved or undissolved drug aggregates may remain, which may lead the produel to feel gritty on application and, more important]y, to a partial loss of efficacy. Moreover, it may ne impractical for a patient: to store Benzamycin® in a refrigerator (for example, when the patient is travel! ing or does not have access to a refrigerator); the need for refrigeration may also reduce patient compliance, since the application of a cold topical formulation may well be unpleasant. Various attempts have been made to overcome the instability of formulations such as Benzamycin®. US-A-5446028, IIS- A-5767098 and US-A-60;.3637, for instance, disclose formulations further comprising a stabilising agent such as dioctyl sodium sulfosuccinate. US-A-5466446 discloses a method for preparing a reportedly stable formulation comprising clindamycin and benzoyl peroxide by controlling the ratio of each active ingredient.. The proprietor of this patent markets a product under the name Clindoxyl® Gel which contains benzoyl peroxide and clindamycin in the ratio of 5:1 and which has a shelf-life of 60 days at room temperature. The product is, however, required to be kept refrigerated prior to being dispensed, which is inconvenient as well as impractical. US-A-6L17843 discloses compositions wherein the ratio of organic peroxide to antibiotic is a factor in j achieving stability in the final composition. According to this patent a composition comprising benzoyl peroxide and clIndamvcin is prepared by a pharmacist by mixing an aqueou;: sc ] union, of clindamycin, typically having a pH of 5 to 6.B, with an aqueous suspension of benzoyl peroxide, typically having a pH of about 4 to 5. The benzoyl peroxide suspension preferably also contains a gelling agent with a pH-dependent viscosity, so that the viscosity of the product is increased when the two components are mixed. A gel composition is therefore obtained which is reported to be stable for around three months at room temperature. Be>u::icic] in® is the only FDA-approved combination of 1% clindamycin phosphate and 5% benzoyl peroxide gel. Although! this can be stored at room temperature (up to 25°C) , this is only stable for about two months. Ot.ijeM' attempts to overcome the stability problems of combined topical antibacterial/antibiotic formulations include presenting the components as separate formulations which may be: mixed in a controlled ratio on demand, e.g. immediately prior to, during or following application to the skin. For example, US-A-6462U25 discloses that separate antibiotic and benzoyl peroxide compositions may be packaged within and dispensed from a common dispenser such as a dual chamber storage device. In this way the active ingredients are kept apart during storage, being dispensed and mixed as required immediately prior to application to the skin; long shell life may thereby b.e achievable. Hcnvev-j , US-A-6462025 requires at least the antibiotic: to be: formulated in a "substantially anhydrous" composition comprising a polar solvent such as a polyo.l. arid a thickening agent which is a (meth)aery Lic acid polymer or a poly(meth)acrylamide. Other than water of hydration which may be present in the various components used to formulate the composition, no free water is added to the composition such that its water content is less than 5% by weight. It is suggested that the benzoyl peroxide may also be presented i.n a "substantially anhydrous" polar solvent-and thickening agent-containing composition; for reasons of "cosmetic elegance" this should preferably have a viscosity differing by no more than 25% from that of the antibiotic composition. Such thickened substantially anhydrous gels and like compositions are not, however, ideal medicaments for the treatment of skin disorders, since their use may lead to blockage of pores and/or the bases of hair follicles in a patient's skin, thereby potentially exacerh'-r-i iig conditions such as acne. The:: present invention is based on the finding that dual (or multi) formulation topical pharmaceutical products having significantly improved effects in the treatment of dermatological conditions such as acne may be obtained by using separate water-based (i.e. essentially "non-anhydrous") formulations for each active ingredient. The improvement is achieved by incorporating at least one of the active ingredients into a polymeric delivery system capable of delayed release- • ,i the active, e.g. a polymeric system comprising porous polymer particles, and by using water-based (in particular, aqueous) carrier bases with substantially the same lipophilicity in each of the formulations. Thus it has been found that the use of water-based or aqueous carriers optimises performance of polymeric delivery .-systems, both by ensuring slow continuous releas-' • • '? skin and development, of acne. The requirement for the formulations to comprise carrier bases with substantially the same lipophilicity is also uui important feature of the invention which may facilitate particularly ready, uniform and thermodynamically favourable mixing of the formulations. More importantly, it ensures consistent release of active ingredient from the polymeric delivery system or systems. The release properties of such systems are dependent on the physical proper-ties of the carrier in which they are dispersed, including pH and viscosity; thus, the degree of lipophilicity is particularly important, since it affects the partition coefficient of active ingredient between the polymer particles of the delivery system and the carrier and thus controls the rate ot: release of active ingredient from the particles into tli':' carrier and thus to the skin. By using carriers with substantially identical lipophilicity the products may be designed to ensure that a desired rate of release from the polymeric delivery system is consistently achieved after the formulations have been mixed and applied to the skin. Excellent storage stability (e.g. six months or more, preferably in excess of 12, 18 or even 24 months) may be achieved by presenting the active ingredients in separate rormulations which may be mixed immediately prior to, uuring or following application to the skin of a patient. In the case of systems involving oxidisingantibacterials such as benzoyl peroxide and antibiotics such as clindamycin, highly efficacious formulations with a storage life in excess of two years at ambient temperature may be prepared in this way. The principle may also be applied to any other topical pharmaceutical and/ or cosmetic formulations involving components which may potentially be mutually incompatible, e.g. as a result of chemical interaction. It is also generally applicable to dual and multi formulation topical pharmaceuticals and cosmetics in which at least one of the formulations involves a polymeric delivery system. STATEMENT OF THE INVENTION According to the present invention there is provided a system for dispensing topical formulations comprising first and second active ingredient-containing formulations for topical administration to a patient, said formulation being independently a pharmaceutical or a cosmetic product, comprising storage means (2) whereby the formulations are maintained separately prior to dispense, together with dispense means (4) (3a) (3b) which permit said formulations to be dispensed from said storage means (2), wherein (i) an active ingredient in one or both of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based carrier bases having substantially the same lipophilicity. Thus according to one aspect of the present invention there is provided a pharmaceutical and/ or cosmetic product comprising first and second active ingredient-containing formulations for topical administration to a patient, wherein said product included storage means whereby said formulations are maintained separately prior to dispense, together with dispense means which permit said formulations to be dispensed from said storage means; characterised in that (i) an active ingredient in at least one of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based (e.g. aqueous) carrier bases having substantially the same lipophilicity. It will be appreciated that the invention also embraces products comprising more than two formulations as defined above provided that these are each separately maintained in appropriate storage means prior to dispense, that all comprise water-based (for example, aqueous) carrier bases having substantially the same lipophilicity, and that at least one active ingredient is contained within a polymeric delivery system. The storage means within products of the invention may, for example, comprise separate chambers or compartments of a dual-or multi- chamber or compartment dispense device, for example side-by-side collapsible tubes, syringe barrels or other forms of container with approprial-i dispense valves, pistons, plungers or the like. A r>--oduct comprising two (or more) separate chambers (e.g. made from polypropylene) provided with two (or more) fixed dosing units in a single cap is particularly suitable. Alternatively the storage means may take I;tie form of -a pouch containing a single unit dose of each formulation; such unit dose pouches may, for example, be made of composite materials such as a metal (e.g. aluminium) foil having a plastics material (e.g. polyethylene or polyvinyl chloride) inner lining, with the pouch having separate parts for each formulae io;~i. Examples of suitable pouches from which the formul.it ions may be dispensed include those described in US - -A-6007264 and WO 01/91726, the entire contents of which are incorporated herein by reference. The dispense means are preferably such that the formulations are dispensable in a controllable (e.g. predetermined) ratio, for example in equal amounts or in other relative amounts as determined to optimise the efficacy o L: the combined formulation after mixing. In this way variations in the composition of the mixed product may be substantially reduced or eliminated. Thus, for example, side-by-side tube containers may be progressively emptied by turning a common winding key adapted to engage and roll up their distal ends, or the plungers of side-by-side syringes may be mutually linked together. It will be appreciated that the respective cross-Be..:L Lonal areas of such containers may be selected to ensur- • hat; the formulations are dispensed in the desired rai.Jo for a given movement of a linked dispen? -i ^ >n actuator. In the case of unit dose pouches, the ratio of the formulations is predetermined at the filling stage, so that the dispense means need comprise no more than corners or edges which may be cut off or torn off to permit the formulations to be squeezed out. In general it is convenient to dispense the formulations of a product of the invention in equal amounts, for example each in volumes in the range 1-5 ml, advantageously 1.5-3.5 ml, preferably 2-3 ml. In a preferred product according to the invention, first and second formulations are respectively presented in the chambers of a dual chamber dispense system of the type described in EP-A-0644129 and US-A-5356040, the conteiv r f which are incorporated herein by reference. Such a system has two side-by-side chambers, each equipped ••.-.'ith a dispense valve; these are operated by adjacent £>ctuators so as to dispense the formulations either .simultaneously or separately as desired. Suitable dispense systems, e.g. having chambers which are each capable of holding about 15 ml of formulation, are available from Maplast S.r.l., Via Pasublo 3, Tradate 21049 VA, Italy. The respective dimensions of the dispense means may be chosen to provide dispense of the respective formulations in a^ predetermined ratio. The product may include mixiag means such that the formulation;-.; are admixed during dispense. Thus, for example', the points of dispense for each of the storage means uic»y be connected to a single duct and/or nozzle outlet; this may, for example, be spirally grooved on its in1.-- Mrfc.ce ir ord-^r to enhance the efficiency of mixing. Alternatively the formulations may be dispensed separately and mixed by the patient. Thus, for example, a dispense system of the type described in the above-mentioned SP-A-0644129 may be fitted with separate duct/nozzle outlets for dispense of each formulation. Separate: operation of each actuator will deliver appropriate relative amounts of the formulations, e.g. onto the hand or directly onto an affected area of skin,-the formulations may then be mixed by the patient, e.g. by rubbing. It will be appreciated that such embodiment ,j may be preferred to products which include mixing mean;; ir. cases where the active ingredients are mutually \ ,active to the extent that they may generate toxic or otherwise undesirable by-products while residual mixed formulations stand in a common duct and/or nozzle between successive dispense operations. The; dispense means for use in the invention may comprise a dual- or multi-chamber dispense system as hereinbefore described which is provided with a removable closure (e.g. a cap). Preferably, in use, the closure prevents the formulations from being accidentally dispensed. For example, in the case of a system which comprises an actuator (e.g. a plunger) which must, be depressed to deliver the product, the closure nviy fit over the actuator thereby physically preventing this from being depressed when the dispense system ic iiot in use, e.g. when being carried in a handbag. The closure may also function to prevent exposure of the oririce (s) of the dispenser to the air when the product: is not in use. For example, this may act as a temporary cover or seal for the orifice(s) from which the individual components of the product are dispensed thus preventing (or, at least, reducing) exposure of these to the air. This function1of the closure is particularly important in the case of water-based or aqueous formulations as herein described which on exposure to the air have a tendency to evaporate and dry out. 5;.Li ice this can result in the formation of a caked layer or crust on the surface of any cream or lotion which i vUiia j no in the dispenser, exposure to the air should D<. minimised when the product is not in use. any drying out of cream or lotion within duct and external orifice dispenser may also reduce size orifices this turn affect amount dispensed given operation. some cases exposure to air even result> complete blockage of the duct(s) and/or dispense orifice (••) The closure for use in the invention may, for example, be provided with one or more (preferably, a plurality) of protrusions. These will generally correspond in number to the number of orifices provided in the dispenser. Typically, the closure may be provided with 1, 2 or 3 protrusions, preferably 2. When the closer- is in place on the dispenser these protrusions engage with the orifices of the dispenser. In order to provide a temporary seel, these protrusions will generally provide a close fit: with each orifice and, typically, will be shaped complimentarily to them. Thus, for example, where the orifices are circular in shape, the protrusions will have 5- circular cross-section, e.g. they will be generally cylindrical. One or more downward flanges (e.g. teeth) may also be provided 011 the sides of the closure for the purposes of alignment and final placement on-to the dispenser. The e!osure may be completely or partly (e.g. by pivoting, removed, from the dispenser prior to dispense of the iLI ..-duet and readily fits (e.g. snaps) back into place once the product has been dispensed. The ciosure may be made of any suitable material but wil^ generally comprise a plastics material, e.g. polypropylene or polyethylene. Viewed from a further aspect the invention thus provides a closure (e.g. a cap) for a dual- or multi-chamber dispense system having one or more, preferably a plurality, e.g. 2, orifices from which separately stored formulations can be dispensed, wherein said closure comprises one or more, preferably a plurality, e.g. 2, protrusions which are complimentary in shape to said orifices. Preferably, the closure is further adapted such that in use this prevents the formulations from being dispensed. For example, this may be adapted to prevent depression of an actuator or plunger. More preferably, the closure is adapted to cover, e.g. to seal, che orifice or orifices of the dispenser when this is not in use. In another aspect the invention provides a dual or multi- chamber dispense system for dispensing separately stored formulations which comprises an actuator which causes dispense of said formulations from one or more (preferably a plurality, e.g. 2) orifices, wherein said system i s farther provided with a closure which prevents • depression of said actuator. Preferably, when in use, the cloi-jure also acts as a cover or seal to the orific«.: i,f.; of the dispenser. pr('-tY-rably, the dispense system and/or cap in accordance' with the invention have one or more of the advantageous features discussed above. P:•(•• rv-rred embodiments of these aspects of the invention are described with reference to the accompanying Figures, in which: Figaro LA shows a conventional multi-chamber dispenser; Figure IB shows a conventional multi-chamber-dispenser provided with a cap in. accordance with the invention; Figure 2 shows a cap in accordance with the invention,- and FJgntc.-; 3 shows a conventional multi-chamber dispenr-^ which is provided with a cap in accordance with tho -invention which is partially removed. W o... reference to Figure 1A, a container- I for a multi-component product has a body 2 within which are located :'" i rnt and second chambers (not shown) suitable for storing first and second formulations. Each chamber is provided with a duct (not shown) connecting it to an orifice 3a and 3b. There is further provided a dispensi ng mechanism which comprises an actuator 4 which is connected to a pumping mechanism of conventional design arid which is not discussed further herein. Depression of che actuator 4 delivers .appropriate amounts of the first and second formulations to the affected area of the skin via the orifices 3 a and 3b. The product of the invention is similar to that known in Un.- art but is additionally provided with, a cap 5. As 3h.own in Figure 2, cap 5 comprises a generally circulat , :l:irt 6 having a depending rim 7. At the front of the .->\ : ri: 6 and depending from the front portion is a novel cover 8 which on an inner face is provided with two pips 9a and 9b. These pips 9a and 9b are complimentary in shape to the orifices 3a and 3b of the container. The cap is additionally provided with four engagernent members or teeth 10 which depend from the rim 7. A notch 11 is also provided at the rear portion of the skire 6, In n«o, cap 5 engages with the top of the container 1 and qpMTf-rally fits over the actuator 4. The teeth 10 form an Interference fit between the actuator 4 and the body 2 OL t:he container 1 thereby -securing the cap 5 in place. The two pips 9a and 9b engage in the orifices 3a and 3b and function not only to prevent depression of the ad u-ii or 4 but also to seal the orifices 3a and 3b from the air. In operation, notch 11 at the rear of the cap 5 i ' ; ;h.t?d upv/ai^ds with the thumb for easy roniovi" of the cap I:i. Actuator 4 is depressed and the product is dispensed. The cap 5 is then simply replaced on the container i . In one class of preferred products according to the invention, the- first formulation is a water-based (e.g. aqueous) topical cream or gel carrier base containing an. antibactnrlal and/or keratolytic agent incorporated into a polymeric delivery system, and the second is a water-based (e.g. aqueous) carrier base having substantially the same 1ipophilicity and containing a topical antibio:-i Proff ired antibacterial agents include salicylic acid and organic peroxides, especially, benzoyl peroxide. y Combinations of aritibacterials, such as salicylic acid and organic peroxides, e.g. salicylic acid and benzoyl peroxide, may also be used. Salicylic acid is particularly suitable for use in treating acne, e.g. acne vulgaris, since it is both an antibacterial and a keratolyt. .i.c agent and may, for example, be present in such a I", . ct; formulation in an amount of 0.2-40% w/w, advantage:.>u.sly 1-30% w/w, preferably 2-10% w/w. For treating acne vulgaris, appropriate concentrations of salicylic acid may, for example, be 0.5% w/w or 2% w/w. Organic peroxides may, for example, be present in amounts cc. 0.2-40% w/w, advantageously 2-30% w/w, preferably 2.5-20% w/w. Combinations of salicylic acid and benzcyi peroxide may advantageously comprise 2% w/w salicylic acid in combination with 2.5% or 5% w/w benzoyl n-'-r-jxide. Othei Keratolytic agents which may be used include retinoids such as retiriol or ret-inoic acid and salts and esters thereof, for example in amounts of 0.01-2% w/w, advantageously 0.025-1% w/w, preferably 0.02-0.2% w/w. Preferred .retinoids include retinoic acid, isotretinoin, tretinoin, retiriol, retinyl palmitate, adapalene, tazaroterie and azelaic acid. When applied topically, azelaic acid helps to normalise keratinization, to reduce the proliferation of P. acnes and is effective agains1 ' • i r.cn-iul' lammatory and inflammatory acne lesions. its efficacy can be enhanced when used in combination with benzoyl peroxide, clindamycin, tretinoin or erythromycin/benzoyl peroxide. A oreferred combination of antibacterial and keratolytic agents which may be present in the first formulation is benzoyl peroxide together with retinoic acid or iretinol. It; will be appreciated that the amount of antibacterial and/or keratolytic agent (and of all other active ingredients) should be selected to give a desired end premier, concentration Hollowing the overall dilution • ' / of each ingredient which will occur when the formulations are mixed. Polymeric delivery systems useful in products of the in-, tiit ion will generally comprise a polymer or polymer';? in the form of particles (e.g. microparticles) , aggregate,'--, of particles (e.g. aggregates of microp; > 1 i ' les) or clusters of aggregates (agglomerates) of part id'./.-', (e.g. agglomerates of microparticles) which : are capahl e of entrapping any desired active for delayed release. The polymer particles will generally be porous (i.e. these have an open structure) and will also typical .ly be cross-linked, e.g. comprising a porous polymeric: mat.rix. Examples of polymeric delivery systems suitable for use in the invention include the Poly-Trap"1' (Cardinal Health, Inc.) and Poly-Pore'5' (Amcol International, Inc.) systems and, in particular, the Microsfyeri! ;• •' system (Advanced Polymer Systems, Inc.). Poly-Pore is a microparticl-e delivery system comprif-'i if i a I lyl methacrylate cross-polymer and is described, lor example, in US-A-5830960, US-A-5834577 and US--A-6.M 8849. It comprises spherical particles having a median particle size of about 30 p.m. The interior or: the Poly-Pore spheres comprises clusters of small spheres which are then agglomerated together to form a porous exterior surface and a hollow interior. Poly-Pore has the unique ability to adsorb both hydrophobia and hydrophilic liquids. The Poly-Trap family of compounds are made by a process which involves supsension polymerization of lauryl methacrylate and ethylene glycol dimethacrylate using a peroxide as a catalyst. The polymerization conditions lead to the formation of amorphous microaggregates or polymer particles. The size of these aggregates is about 25 /zm in diameter and within their structure .,.-.; a .nigh degree of cross-linking. The Poly-Trap po.viiit'is are extremely lipophilic and hydrophobia. As a resu.it, they are ideal carriers for lipophilic s actives and are also capable of controlling skin oiliness without dehydrating the skin. Poly-Trap polymers suitable for use in the products herein described are, for example, described in US-A-4962133 and US-A-4962170. Microsporige delivery systems can be made, for example, using either styrene and divinylbenzene, or methyl me;, hacrylate and ethylene glycol dimethyacrylate as start dug materials. The choice of monomers and cross-'linkers enable different families of compounds to be prepared. Whilst these both consist of porous micro-spheres their physical-chemical properties are quite ! ; 1'•• • -erii" . furthermore, the manufacturii nc process used to produce Microsponge products allows these to be produced v/ir:h a wide range of particle size, porosity (void volume), pore diameter (openings on. the surface) and surface area. With an almost unlimited number of variations, this permits customisation of the polymer to the active- ingredient to be entrapped. Specifically, this allows design and control of the required release rate and maximisation of beneficial effects on the skin. Microsponge systems useful in products of the invention may, for example, be as described in WO-A-88/10132, U3-A-4873091, US-A-4690825 and EP-A-0306236. Thus, for example, antibacterial agents such as benzoyl peroxide may be formulated in similar mariner to the product marketed in the USA under the tradename Exact® and by \:ht- present applicant in Turkey under the name Aksil®; benzoyl peroxide-containing Microsponges are described in, for example, US-A-5879716. Similar Microsponges containing retinoic acid are described in US-A-59553Oy. Loading of the active ingredient may take place via either a one-step or two-step process, e.g. as described in US-A-4690825 and US-A-5145675 respectively, whereafter the resulting Microsponges may be suspended in the desired carrier base (e.g. an aqueous carrier base). An advantage of the polymeric delivery systems herein described is that release of the antibacterial and/or keratolytic agent from the system (e.g. from the Micros; onucs) can be made to occur quite slowly, conveniently with onset being triggered by dispense and/or .••!]•.pi :i cation with rubbing of the formulations onto the skiii. The concentration of the agent in the carrier base ai. any time may consequently be low, minimising possibJ •:: .i. tritant side-effects whilst maintaining a therapevu: ically effective concentration. Similar advantages may accrue if the topical antibiotic is also contained within its own polymeric delivery system. The particles of the polymeric delivery system may be composed of a wide range of materials, including both synthetic polymers and natural substances such as cellulose or gelatin. The choice of material forming the poJymeric delivery system may depend upon the intended methods by which the en-trapped antibacterial or other aqe.Mi is to be released. Such methods are descril ->•] in J. Mioroencapsulation. (199.6), .13. (5), 575-588 and include but are not limited to diffusion, compression, dissolution or melting. Preferably, entrapped antibacterial and/or keratolytin agent is released from the polymeric delivery system by diffusion from the pores of the polymeric particles into the carrier. The rate of diffusion will depend on the partition coefficient of the antibacterial and/or keratolytic agent (and any other entrapped active ingredients) between the polymer forming the polymeric delivery system and the carrier. Porous particles containing agents such as benzoyl peroxide or retinoic acid will typically release sufficient of the agent into the carrier base during storage, dispense and/or application to provide a therapeut: ically effective initial concentration of agent in the i:01. ipu^ation as applied to the skin. Agents such as sal i :y":'i'"' acid, however, may not undergo such ready / initial t.c-lease fr:om a polymeric delivery system because of their d:i!:Eerent lipophilicity; it may therefore be advantageous to include a proportion of "free" active agent in the carrier base (e.g. up to 25% w/w of the total content of the agent) to provide the required initial therapeutically effective concentration and to further. Induce release of agent from the polymeric partic1es (c . g . microsponges) . The diameter of the porous particles which comprise the po 1 '.'Hi' i. -.c delivery system may, for example, be iri the range 1 to 1000 microns, e.g. 4 to 300 microns, such as 5 t>.: 1 ;'•(", ml crontj. It; is preferred, however, that the part id. ^ ;:;i::e is less than 30 microns, 'e..g. 10 to 25 micron;-;, :• ince- particles; larger than 30 microns can impart a 'gritty' feel to the formulation, which, may decrease patient compliance. The .surface area of the porous particles which comprise t tie micro sponge delivery system may, for example, i.ange from 1 to 500 m2/g, e.g. 20 to 200 m2/g; the total, pore volume may, for example, be in the range 0.3 to 4.0 omVg, e.g. 0.6 to 2.0 cm3/g and the pore diameter (i.e. the opening of the pores on the surface of the particle) may range from 0.001 to 1 micron, e.g. from 0.01 to 0.1 micron. Pore volume and, more importantly, pore diameter may have a significant effect on the rate of release of the entrapped antibacterial and/or Ke.- -t olytic agent, and may affect the migration of the agt.'bl £rom the polymeric delivery system into the carrier, in which the polymeric delivery system is dispersed. Thus the diameter (and hence volume) of the pores lias a diz^ect impact on the release of the agent, as well as on the amount of agent that can be entrapped within the delivery system. The polymeric delivery system may be made by suspension polymerisation, preferably crosslinking polymers such as polyolefins, for example polyethylene, polystyrene arid polydicyclopentadiene; polyacrylate / esters, for example optionally alkoxylated C1_w alkyl, cycloa'l k y'i aryl or aralkyl esters of polyacrylic or polymethacrylic acids; polyvinyl esters, for example polyvdr.vl :>oet,ate or polyvinyl laurate; polyvinyl ketone:', >' -r example polyviriylmethyl ketone; and polyviry.! •• theirs, for example polyvinyl propyl ether. The most o. nnmonly used crosslinking agents are divinylberr/.ene for polystyrene polymers and ethylene '; glycol dimethacrylate for polymethacrylates. It wJ.il be appreciated that the level of hardness of the particles of the polymeric delivery system may be varied widely by appropriate selection of the polymer composition, degree of crosslinking etc. It is desirable (hat the particles are elastically compressd b~\ e so that after application of the formulal:ion to an affected area, the application of gentle pressure, for example by rubbing, may induce release oi' the entrapped antibacterial 'and/or keratolytic agent into the carrier and thus to the skin. Ir. a-'{ Preferred topical antibiotics useful in the second formulai;j.L.Jij of the aforementioned class of preferred products include tetracyclines (e.g. formulated at concentrations of 0.2-20% w/w, advantageously 1-12% w/w, preferably 2-4% w/w), erythromyciii (e.g. formulated at concent rat. i.'ms of 2-30% w/w, advantageously 3-20% w/w, preferably :>-.LC% w/w), and clindamycin (e.g. formulated at concentrations of 0.02-20% w/w, advantageously 0.2- 10% w/w, preferably 1.6-5.2% w/w.) . Again allowance should be made for the overall dilution of individual active ingredients which will occur when the formulations a:~e mixed. Where appropriate, e.g. for solubility or distribution considerations, corresponding salts or esters, e.g. mineral acid addition salts such as clindoirr/ciri hydrochloride or phosphate, or carboxylic acid esi/t-r;. such as erythromycin propionate, stearate or ethylsiKvi;iate may also be used. Clindamycin phosphate > is particularly suitable for use in formulations used for adit-.- control (P. acnes is highly sensitive to clindamyc Li i; elindamycin is active in comedones from acne patients; it also reduces free fatty acids on the skin su t: IdU/e) . Tetraeyelines suitable for use in the second formulation include, in particular, tetracycline, doxycycline, miriocycline and lymecycline. The term '^water-based carrier" as used herein denotes any topical carrier in which water is present, preferably in ari amount in excess of 5% w/w, e.g. in excess ot, 10, 20, 30 or 40% w/w. The term "aqueous carrier base" is intended to denote any topical carrier base in which water is the major component, e.g. being present i.n amounts in excess of 50, 55,' 60, 65 or 70% w/w. Carrier bases contemplated for use in the invention include aqueous creams, gels, lotions or ointments, as well as oil-in-water and water-in-oil emulsions. Water-in-oil emulsions, for example, enable the delivery of hydrophilic ingredients from the polymeric delivery system. The carriers may, for example, include conventional formulating ingredients selected from lipophilic base materials (for example fatty (e.g. C10_30) alcohol esters of saturated or unsaturated fatty (e.g. C10_30) acids, such as cetyl ricinoleate; fatty acid esters of sterols such as cholesterol or lanosterol; emollient silicon oils, e.g. polysiloxanes such as dimethicone or cyclomeLhloone; or terpenes such as a-bisabolol), /- hydropl . . • ,x,.se tnatci iu 1.3 J or example polyethylene glycols, hereinafter referred to as PEGs), stabilisers and/or surfactants (for example fatty acids such as palmitic' or stearic acid; fatty alcohols such as cetyl or stearyl alcohol; amphiphilic fatty esters, e.g. fatty alcohol esters of mineral acids :such as sodium lauryl sulphate;, ratty acid esters of polyols such as glyceryl dilaurate or caprylic/capric triglyceride; PEGylated / fatty alcohols, e.g. PEG lauryl ethers such as laureth-4; PEGyLjiod sorbitan esters with Eatty acids such as oleic, iau"ic, palmitic or stearic acid, e.g. as in Tween(B1 surfactants; PEGylated sterols such as PEG-10 soya st:aroi; polysaccharides such as xanthan gum; proprietary products such as emulsifying wax; or thickeniuy polymeric stabilisers, e.g. polyacrylamide-based products such as Sepigels®), humectants (for example diola cr polyols such as propylene glycol or glycerol), viscosity modifiers C-for example saccharides such as sorbitcl), thickeners (for example colloidal or fumed si IJoa or silicates such as magnesium aluminium silicate), preservatives (for example antimicrobials or antifunga] :: such as methyl paraben, propyl paraben, benzyl alcohol, phenoxyethanol or germaben II; or antioxidauts such as vitamin E, ascorbyl palmitate or butylated hydroxytoluene), pH regulators (for example buffers, e.g. acid/salt combinations such as citric acid/sodLuh citrate; or bases such as triethanolamine), or ant J.-'.j,;.,, u I ants (for example disodium edetate) . As :ictv.-d above, the lipophilioity of a formulation affect. •- partition coefficient of active ingredieric contained vvit.hin a polymeric delivery system between the polymer particles and the carrier The requirement for the carriers within a particular product according to the invention to have substantially the same lipophilicity may therefore be tested and quantified by determining the partition coefficient in respect of each carrier base; the requirement is met if the partition / coefficients vary by no more than 10%, advantageously by no more than 5%, preferably by no more than 2.5%. It is also preferred that the individual water contents and viscositii -s of the formulations•within a particular produce very by no more than these limits, since thin may eii'lnnee ease and uniformity of mixing of the formulations during or after dispense. In a. preferred embodiment of the invention the individual formulations '> will hove substantially identical viscosities, e.g. varying by ao more than 10%, preferably by no more than 5%, more preferably by no more than 2.5%. In general the viscosities of the formulations may be up to 200,000 cps, preferably up to 100,000 cps, more preferably in the range 5,000 to 50,000 cps, yet more preferably 5,000 to 15,000 cps, e.g. about 10,000 cps. The use of formulations having lower viscosities, e.g. of the order of about 10,000 cps, is particularly preferred when dispensing these ^from systems having side-bv--H.ii.le chambers or compartments from which the produd i.;;• dispensed by the application of external pressure i:•• :ans. In particular, it has been found when using such systems that it is important to ensure that each formulation (e.g. cream, gel or lotion) should be free Lxowiuy to the extent that this essentially remains at the base of the container where the suction tube orificce is located. This orifice must be kept inside each formulation at all times otherwise air will enter the system causing inaccurate amounts of cream to be dispensed. On the other hand, it is important that the viscosJ ty of each formulation should not be too low since the liquid will not stick to the skin. The use of low viscosity formulations has the added advantage that non-pressurized systems may be used to dispense these. Such systems are more environmentally friendly than those which utilise an inert gas to force gels into the intake tubes of the pump. These are also more cost effective to manufacture. / The farriers within a particular product may advantageously contain essentially the same ingredients or close analogues, homologues or equivalents thereof, in amounts appropriate to ensure the desired levels of lipophi 1i c:ity ate. Where it is desired substantially to match the viscosities of the formulations within a product, at; will be appreciated that the presence of polymer particles (e.g. microsponges) in a formulation may have a significant viscosity increasing effect, particularly if the content of the polymer particle is relatively high (for example as may be required if the level or. entrapment of active ingredient in the polymer partic.les is relatively low) . It may therefore be desirable to increase the relative amounts of viscosity enhanc.i M-J iqen'is (e.g. polysacchazides such as xanthari gum or thickening agents such as silica or silicates) and/or to reduce the amount of relatively low viscosity components such as glycerol or sx:rbitol in a corresponding non-polymeric particle (e.g non-Microsponge) formulation in order to compensate for this. Alternatively, both formulations may include polymer particles (e.g. Microsponges) in order to match the viscosity levels. Whilst the invention is primarily described herein in terms of systems comprising oxidising antibacterials (e.g. benzoyl peroxide) and antibiotics, as noted above the invention is more generally applicable to any topical pharmaceutical and/or cosmetic preparation which involve:- tv/o or more formulations, at least one of which involve:, -, polymeric delivery system. Such preparations need net .necessarily involve components which have stability limitations when combined. For example, the product herein described may be suitable for use with any conventional dermatological-preparation, e.g. any topical anti-acne compositions. Such compositions may include, for example, one or more of the following active oomponants: organic peroxides (e.g. benzoyl peroxide), re'.;i.noids (such as retinoic acid, retinol, tretinoiri, isocretinoin, adapaler.e and tarazotene, e.g. at a concentration of 0.001-1% w/w, preferably 0.025-1% w/w, morn preferably 0.05-1% w/w), other comedolytic agents ft;.9. azelaic acid and salicylic acid), sulfur, resorc:i no I , zinc, anti- inflammatory steroids (such as corticosteroids, e.g. hydrocortisone, which may be present, in concentrations in the range 0.25-2.5% w/w), 'i antibiotics (e.g. clindamycin, erythromycin, tetracy 'LI in-, doxycycline, rniriocycline, lyrneeye.line) , anti-fungal agents (e.g. undecilenic acid, miconazole (base and nitrate), ketoconazole, iconazole, clotrimazule arid metronidazole) , alpha-hydroxy acids (e.g. glyaolic acid, lactic acid, ko j ic acid), vitamin K, hair growth promotion agents (such as minoxidil, e.g. present in a concentration of 1-5% w/w), depigmenting agents (such as hydroquinone, e.g. at a concentration of 1-10% w/w), antiviral agents (e,jg. acyclovir, valacyclovir and the like or a combination thereof), anaesti: •• ; agents (e.g. lidocaine, benzocaiiie, priloc.-t i iu-', pramoxine, benzyl alcohol, dibucaine) , counter .; i .: i tant agents (e.g. menthol, camphor, phenol and the Like or a combination of these), antiseptic/microbicidal agents (e.g. benzalkoriium chloride, boric acid, cetylpyridinium chloride, benzethoniurn chloride, resorcinol, chloroxyenol and the like), antibacterial and/or antitrichomonal agents (e.g. metronidazole, tinidazole, ornidazole and the like), astringents (e.g. bismuth subgallate, zinc oxide, witch hazel c-md the like), wound healing agents (e.g. cod liver oil, shark liver oil, sucralfate and the like), protectants (e.g. dimethicone, aluminium hydroxide gel, aluminium acetate, mineral oil, cocoa butter, glycerine, kaolin, petrolatum, lanolin oil, peruvian balsam, calamine, titanium dioxide, etc.), hormones (e.g. conjugated estrogens, estriol and the like), vitamins (Table Removed) * signifies presence in a polymeric delivery system, preferably in a Microsponge system . Particularly preferred combinations of actives for use in products of the invention include: salicylic acid and Clindamycin (e.g. Clindamycin phosphate); benzoyl peroxide and clliidamycin; benzoyl peroxide and salicylic acid; arid rr-tinoic acid (or a derivative thereof) and an antibiotic- i.e.g. Clindamycin). In these particular combinations, either of the actives may 'entrapped1, i.e. present in a polymeric deliA^ery system, preferably in a Microsponge system. However, preferably it will be the first listed active which will be 'entrapped1. Combinations of retinoic acid (or a derivative thereof) either in 'entrapped' or 'free1 form together with an 'entrapped1 form of an antibiotic, benzoyl peroxide.- or' salicylic acid are a],so preferred for use in the invent 1 on . 'The pharmaceutical formulations in products of the present ; n /erition may be manufactured by methods convent .1 on. u ly known for the manufacture of pharmaceutical creams or gels. One suitable method of manufacture includes the steps of preparing an aqueous solution of. the water-soluble ingredients, mixing this solution together with the hydrophobia ingredients, homogenising the resulting mixture and thereafter adding the active ingredient (e.g. antibacterial agent or antibiotic) . The resulting cream or gel may then be filled into the appropriate storage means of the product. To use a product of the present invention, a patient may simply activate the dispense means (e.g. by depressing a pump or plunger) and collect the formulation (s) dispensed, e.g. in his hand. If necessary, the patient may then mix the formulations to obtain ; -<. mhination product which is applied to the area f :- be treated. formulations dispensed from pro-ducts of invention are preferably on a regular basis for example once or twice daily.> Although much of the discussion and examples presented herein pertain to products primarily designed for the treatment of acne conditions, it will be clear to those of ordinary skill in the art that similar considerations and formulation strategies are equally applicable to the treatment of a wide range of other skin conditions. For example, the products of the invention may be used in treating other dermatological condition;-;, such as fungal infections, various dermatitis (e.g. eczema, psoriasis and the like), rosace,j, -aelasma (chloasma) and alopecia. Such products also find use in non-medical, e.g. cosmetic, applications such as in treating or preventing wrinkles, in treating rough skin, hyperpigmented spots (e.g. liver spots) and other manifestations of aging skin, cellulite, stretch marks, etc., and in promoting or suppressing hair growth. The products herein described may also be used in treating dermarological conditions and conditions affecting mucosal surfaces (e.g. skin & mucosal & oral membranes) and its appendices, such as pseudofolliculitis barbae, fungal infections, bacterial infections, viral infections, allergic and/or atopic dermat.1 t:i;; (eczema) such as seborrheic dermatitis, diaper ra;;h and the like, conditions related to wounds, burns, T» • '"P '; njur ies, 'insect hi'en sunburn i:/;' "h like, ,:i,-.i we-11 as infectious and non-infectious condition!.; affecting skin & mucosal membranes of the genital area such as vulvitis, balanitis and the like, and hemorrhoidal conditions. The contents of all publications, patents or otherwj.se, mentioned hereinbefore are herein incorporat.ed by reference. The -invention will now be described in more detail by way of the following non-limiting Examples: Example 1. - Benzoyl Peroxide/Salicylic Acid Lotion in Double Container (Standard Strength Formulation) 5% Benzoyl Peroxide Lotion: (Table Removed) Preparat: ioi.: 1. D.i .•:.; compone K:- "'>, 4, 5, 6 and 7 with mixing. 2. Propele a premix of component 8 and add to above with mixin-v; . 3. Add components 9-14 with slow mixing. 4. Add component 15 with mixing. The Benxoy.i. Peroxide and Salicylic Acid B'ormulations are subsequently transferred to a dual-chamber dispense system .such as that described in EP-A-0644129 which may be provided with a suitable cap as herein described. Example ?, - Benzoyl Peroxide/Salicylic Acid Lotion in Double Container (Extra Strength Formulation) (Table Removed) Prepaiv 1. D: ;:;p>-r i'Fie component 2 in deionised water and add component..-. '--:,, 4, 5, 6 arid 7 with mixing. 2. Prepare a premix of component 8 and add to above with mixiri :j. 3. Add components 9-13 with slow mixing. 4. Add component 14 with mixing. The Clindeuuycin formulation may be used in combination with any or the Benzoyl Peroxide and Salicylic Acid formulations according to Examples 1 and 2 or with a 0.05 wt% Retinoic Acid formulation. The components are presented in a dual-chamber dispense system such as that, described in KP-A-0644129 and which may be provided with a suitable cap as herein described. A suitable retinoic acid lotion formulation may be prepared b/ substituting Retinoic Acid in place of the Salicy . . ..u in Liie J !; balicyc_L^.i: ACJ.Q Lotion 01. Example 1 (hereinafter referred to as "reference formulation"). The active ingredient would then be Retinoic Acid with a total concentration of 0.2% which would be diluted after mixing with the second component upon dispensing and mixing to obtain the desired 0.1% final concentration. 1/5 of this amount (i.e. 0.2/5 = 0.04%) would be substituted for thf; 'free1 form of Salicylic Acid in the reference formulation and the remaining -!/L> of 0.2% (i.e. 0.16%) would be 'entrapped1. To obtain :;0% entrapment, 0.16/0.3 = 0.53% Retinoic Acid would need to be substituted for the 'entrapped1 Salicylic Acid ingredient in the reference formulation. Suitable adjustment of the water content of the formula would neon to be made to take the total amount of ingred'i ent: s up to 100%. For a noil-entrapped or 'free1 version of the Retinoic Acid formulation, the total of 0.2% should be substituted directly into the Salicylic Acid lotion formula and the water adjustment made for the difference. ') For formulas requiring lower concentrations of Retinoic Acid such ,:K:; 0.075%, 0.05% and 0.01% total active, the same ca 1 cu ! ations should be carried out taking into account t'n • dilution, entrapment and ratio of 'free' to ' entrap; u> • oroduct . It will be appreciated that the invention can be embodied in other specific forms without departing from the spirit or essential character thereof and that the scope of the invention is not limited to the disclosed embodimentH. Those of ordinary skill in the art could readily produce other combinations of actives suitable for use with the dispensing system herein described. We Claim: 1. A system for dispensing topical formulations comprising first and second active ingredient-containing formulations for topical administration to a patient, said formulation being independently a pharmaceutical or a cosmetic product, comprising storage means (2) whereby the formulations are maintained separately prior to dispense, together with dispense means (4) (3a) (3b) which permit said formulations to be dispensed from said storage means (2), wherein (i) an active ingredient in one or both of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based carrier bases having substantially the same lipophilicity. 2. A system for dispensing topical formulations as claimed in claim 1, wherein an active ingredient in one of said formulations or both of said formulation is contained within a porous polymeric delivery system. 3. A system for dispensing topical formulations as claimed in any one of claim 1 or 2, wherein the dispense means are such as to permit dispense of the both said formulation in a predetermined amount. 4. A system for dispensing topical formulations as claimed in any one of claim 1 to 3, wherein the dispense means are such as to permit dispense of the both said formulation in equal amounts between 1 to 5 ml. 5. A system for dispensing topical formulations as claimed in any of claims 1 to 4, wherein the storage means comprise a first chamber and a second chamber each equipped with an orifice (3a)(3b), said formulation being dispensed by adjacently disposed actuators (4). 6. A system for dispensing topical formulations as claimed in any one of claims 1 to 5, wherein the storage means comprise a unit dose pouch having separate parts for each formulation. 7 A system for dispensing topical formulations as claimed in any one of the claims 1 to 6, wherein the dispense means are adapted to dispense said formulation separately. 8. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7, wherein, in the first formulation, the active ingredient is an antibacterial or a keratolytic agent or a mixture thereof; and is contained within a polymeric delivery system comprising porous polymer particles; said first formulation comprises a water based carrier base that is selected from an aqueous topical cream or gel carrier base; and in the second formulation the active ingredient is a topical antibiotic? 9. A system for dispensing topical formulations as claimed in claim 8, wherein said keratolytic agent is a retinoid, preferable retinoic acid. 10. A system for dispensing topical formulations as claimed in claim 8, wherein said antibacterial agent is selected from a group consisting of salicylic acid and organic peroxide being preferably benzoyl peroxide. 11. A system for dispensing topical formulations as claimed in any of claim 8, wherein said antibiotic is selected from a group consisting of erythromycin, clindamycin and tetracycline. 12. A system for dispensing topical formulations as claimed in claim 8, wherein said antibacterial agent is benzoyl peroxide and said antibiotic is clindamycin. 13. A system for dispensing topical formulations as claimed in claim 8, wherein said topical antibiotic is contained within a polymeric delivery system. 14. A system for dispensing topical formulations as claimed in claims 1 to 7, which comprises as active ingredients of first and second formulations, an anti-fungal agent and a retinoid, any one or both of which is incorporated into a polymeric delivery system. 15. A system for dispensing topical formulations as claimed in claim 14, wherein the antifungal agent is undecilenic acid, miconazole (base or nitrate), ketoconazole, iconazole, clotrimazole and the retinoid is either retinol or retinoic acid. 16. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7„ which comprises as active ingredients of first and second formulations a depigmenting agent and a keratolytic agent, any one or both of which is incorporated into a polymeric delivery system. 17.A system for dispensing topical formulations claimed in any one of the claims 1 to 7, comprising a depigmenting agent and a retinoid, as active ingredients any one or both of which is incorporated into a polymeric delivery system. 18. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7, which comprises as active ingredients of first and second formulations, a corticosteroid and a retinoid, any one or both of which is incorporated into a polymeric delivery system. 19. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7, which comprises as active ingredients of first and second formulations, a hair growth promoter and a retinoid or other keratolytic agent, any one or both of which is incorporated into a polymeric delivery system. 20. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein, the difference in the water content of said first and second formulations is 0 to 10%, preferably 0 to 5%, more preferably 0 to 2.5 %. 21. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein, said first and second formulation have viscosity of upto 40,000 cps, preferably upto 30,000 cps, more preferably upto 20,000 cps, most preferably upto 10,000 cps. 22. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein the difference in the viscosity of said first and second formulation is 0 to 10 %, preferably 0 to 5%, more preferably 0 to 2.5 %. 23. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein, the difference in the lipophilicities of said first and second formulations is 0 to 10%, more preferably 0 to 5%, still more preferably 0 to 2.5 %. 24. A system for dispensing topical formulations as claimed in any one of the preceding claims which comprises a dual chamber dispense system provided with an actuator which causes dispense of said formulations from one or more orifices, characterized in that said system is further provided with a closure which prevents depression of said actuator. 25. A system for dispensing topical formulations as claimed in claim 24, wherein said closure is adapted to cover or seal the orifice(s) of the dispenser. 26. A system for dispensing topical formulations as claimed in claim 24, wherein said closure is provided with one or more protrusions which are complementary in shape to said orifices. provided with one or more protrusions which are complementary in shape to said orifices. 27. A system for dispensing topical formulations substantially as hereinbefore described with reference to the foregoing examples and accompanying drawings.

Full Text

This .invention relates to systems for dispensing topical pharmaceutical and/or cosmetic formulations, in particular pharmaceutical formulations for the treatment of dermatoloqical conditions such as acne, rosacea, melasma (ci iloasma) , alopecia, fungal infections, bacterial infections, viral infections, psoriasis, eczema .an !:;ie like, and cosmetic formulations for treatiii' ; i.iiitions such as premature aging (e.g. wrinkli ;/j) oi. the skin. Such systems may also be, used for dispensing formulations for treating conditions which affect the mucosal membranes, e.g. the membranes of the genital area, such as vulvitis, balanitis, etc., and haemorrhoidal conditions.
It has long been .the case that pharmaceutical formulations, typically in the form of creams or gels suitable for topical administration, have been used to combat f.kin disorders which are caused by the inflammation of sebaceous glands and/or skin follicles and which may result in conditions such as acne and rosacea. Acne is one of the most common skin disorders which is particularly common during puberty but which may pert1 is- for many years. The main factors which contribute to the pathogenesis of acne are comedogi-i'e;3.i..i, sebum production, inflammation of the sebaceou:- •.)lands arid the presence of the bacteria Propionibacterium acnes (P. acnes) .
Many previous treatments for ouch skin disorders can be found in the literature and often comprise topically administrable organic peroxides, retinoids and/or ant3.biot.ics. Thus, for example, formulations for the treatment of skin disorders comprising benzoyl peroxide are described in US-A-3535422, US-A-4056611,
US-A-4 H.I 8' comprising an antibiotic for the treatment of skin disorders such as acne and rosacea. US-A-3969516, for example, describes the use of the topical antibiotic clindamycin for the treatment of acne. Other antibiotic's which have been used in the treatment of
skin disorders include erythromycin and tetracyclines.
i Still further patents disclose the use of
combination preparations which comprise actives having complementary but distinct mechanisms of action, for example formulations comprising a combination of an organic peroxide and an antibiotic for the treatment of Skin disorders. GB-A-2088717, US-A-4411893, US-A-4692329 and GB-A-1594314, for example, describe combin ' i c •• of the antibiotic erythromycin with various organj • i>. -o /xides as formulations for the treatment of acne o:. oi.ni-.-r skin disorders. UJ3-A-4607101 discloses a formulji,.U.n for the treatment of acne vulgaris comprislrK; a carbamide peroxide in combination with a topica i en :t ibiotic .
It has been found that combinations of an antibiotic with an organic peroxide may be more effective in the treatment of skin disorders than either the antibiotic or the peroxide alone - see, for example, US-A-4497Y94.
Benzoyl peroxide is an antibacterial, keratolytic and desquamating agent. Like other organic peroxides, it exerts an antibacterial effect via its strong oxidising properties. This chemical property of peroxides, nowever, can reduce the stability of such peroxide containing two ingredient formulations, since oxidative interaction with the second (e.g. antibiotic) ingredient may lead to loss of potency of both active ingredient .-.;,
Benzamycin® (Dermik Lab.) is a topical gel for the
treatment of acne comprising a combination of 3%
erythromyciri, as a topical antibiotic, and 5% benzoyl peroxi,,. , ..-A.-..-, an antibacterial, ke.ratolyc.ic and desquamating agent. This combination, however, is unstable :i'c room temperature for the above reason, so that B- i ,-.. ini/cin'"' rapidly loses its pharmaceutical effect if scored at ambient temperature.
Ii, -: i der to prolong the pharmaceutical effectiveness of Benzamycin® it must be formulated by a
';
pharmacist" as and when required, thereafter being stored under refrigeration. However, this limits the product to being Bold in a pharmacy and may also lead to variation in the final composition. Thus the pharmacist is required firstly to dissolve the erythromycin in an alcohol and then to add the resulting solution to a gel containing the benzoyl peroxide, thereafter stirring the mixture until it is homogeneous in appearance. Accordingly, variations in the alcohol used for this purpose- may lead to variability^in the product; if the mixing is not complete, partially dissolved or undissolved drug aggregates may remain, which may lead the produel to feel gritty on application and, more important]y, to a partial loss of efficacy. Moreover, it may ne impractical for a patient: to store Benzamycin® in a refrigerator (for example, when the patient is travel! ing or does not have access to a refrigerator); the need for refrigeration may also reduce patient compliance, since the application of a cold topical formulation may well be unpleasant.
Various attempts have been made to overcome the instability of formulations such as Benzamycin®. US-A-5446028, IIS- A-5767098 and US-A-60;.3637, for instance, disclose formulations further comprising a stabilising agent such as dioctyl sodium sulfosuccinate. US-A-5466446 discloses a method for preparing a reportedly stable formulation comprising clindamycin and benzoyl peroxide by controlling the ratio of each active
ingredient.. The proprietor of this patent markets a product under the name Clindoxyl® Gel which contains benzoyl peroxide and clindamycin in the ratio of 5:1 and which has a shelf-life of 60 days at room temperature. The product is, however, required to be kept refrigerated prior to being dispensed, which is inconvenient as well as impractical.
US-A-6L17843 discloses compositions wherein the ratio of organic peroxide to antibiotic is a factor in
j
achieving stability in the final composition. According to this patent a composition comprising benzoyl peroxide and clIndamvcin is prepared by a pharmacist by mixing an aqueou;: sc ] union, of clindamycin, typically having a pH of 5 to 6.B, with an aqueous suspension of benzoyl peroxide, typically having a pH of about 4 to 5. The benzoyl peroxide suspension preferably also contains a gelling agent with a pH-dependent viscosity, so that the viscosity of the product is increased when the two components are mixed. A gel composition is therefore obtained which is reported to be stable for around three months at room temperature.
Be>u::icic] in® is the only FDA-approved combination of 1% clindamycin phosphate and 5% benzoyl peroxide gel. Although! this can be stored at room temperature (up to 25°C) , this is only stable for about two months.
Ot.ijeM' attempts to overcome the stability problems of combined topical antibacterial/antibiotic formulations include presenting the components as separate formulations which may be: mixed in a controlled ratio on demand, e.g. immediately prior to, during or following application to the skin. For example, US-A-6462U25 discloses that separate antibiotic and benzoyl peroxide compositions may be packaged within and dispensed from a common dispenser such as a dual chamber storage device. In this way the active ingredients are kept apart during storage, being dispensed and mixed as required immediately prior to application to the skin;
long shell life may thereby b.e achievable.
Hcnvev-j , US-A-6462025 requires at least the antibiotic: to be: formulated in a "substantially anhydrous" composition comprising a polar solvent such as a polyo.l. arid a thickening agent which is a (meth)aery Lic acid polymer or a poly(meth)acrylamide. Other than water of hydration which may be present in the various components used to formulate the composition, no free water is added to the composition such that its water content is less than 5% by weight. It is suggested that the benzoyl peroxide may also be presented i.n a "substantially anhydrous" polar solvent-and thickening agent-containing composition; for reasons of "cosmetic elegance" this should preferably have a viscosity differing by no more than 25% from that of the antibiotic composition.
Such thickened substantially anhydrous gels and like compositions are not, however, ideal medicaments for the treatment of skin disorders, since their use may lead to blockage of pores and/or the bases of hair follicles in a patient's skin, thereby potentially exacerh'-r-i iig conditions such as acne.
The:: present invention is based on the finding that dual (or multi) formulation topical pharmaceutical products having significantly improved effects in the treatment of dermatological conditions such as acne may be obtained by using separate water-based (i.e. essentially "non-anhydrous") formulations for each active ingredient. The improvement is achieved by incorporating at least one of the active ingredients into a polymeric delivery system capable of delayed release- • ,i the active, e.g. a polymeric system comprising porous polymer particles, and by using water-based (in particular, aqueous) carrier bases with substantially the same lipophilicity in each of the formulations.
Thus it has been found that the use of water-based
or aqueous carriers optimises performance of polymeric
delivery .-systems, both by ensuring slow continuous releas-' • • '?
skin and development, of acne.
The requirement for the formulations to comprise carrier bases with substantially the same lipophilicity is also uui important feature of the invention which may facilitate particularly ready, uniform and thermodynamically favourable mixing of the formulations. More importantly, it ensures consistent release of active ingredient from the polymeric delivery system or systems. The release properties of such systems are dependent on the physical proper-ties of the carrier in which they are dispersed, including pH and viscosity; thus, the degree of lipophilicity is particularly important, since it affects the partition coefficient of active ingredient between the polymer particles of the delivery system and the carrier and thus controls the rate ot: release of active ingredient from the particles into tli':' carrier and thus to the skin. By using carriers with substantially identical lipophilicity the products may be designed to ensure that a desired rate of release from the polymeric delivery system is consistently achieved after the formulations have been mixed and applied to the skin.
Excellent storage stability (e.g. six months or more, preferably in excess of 12, 18 or even 24 months) may be achieved by presenting the active ingredients in separate rormulations which may be mixed immediately prior to, uuring or following application to the skin of a patient. In the case of systems involving oxidisingantibacterials such as benzoyl peroxide and antibiotics such as clindamycin, highly efficacious formulations with a storage life in excess of two years at ambient temperature may be prepared in this way. The principle may also be applied to any other topical pharmaceutical and/ or cosmetic formulations involving components which may potentially be mutually incompatible, e.g. as a result of chemical interaction. It is also generally applicable to dual and multi formulation topical pharmaceuticals and cosmetics in which at least one of the formulations involves a polymeric delivery system.
STATEMENT OF THE INVENTION
According to the present invention there is provided a system for dispensing topical formulations comprising first and second active ingredient-containing formulations for topical administration to a patient, said formulation being independently a pharmaceutical or a cosmetic product, comprising storage means (2) whereby the formulations are maintained separately prior to dispense, together with dispense means (4) (3a) (3b) which permit said formulations to be dispensed from said storage means (2), wherein (i) an active ingredient in one or both of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based carrier bases having substantially the same lipophilicity.
Thus according to one aspect of the present invention there is provided a pharmaceutical and/ or cosmetic product comprising first and second active ingredient-containing formulations for topical administration to a patient, wherein said product included storage means whereby said formulations are maintained separately prior to dispense, together with dispense means which permit said formulations to be dispensed from said storage means; characterised in that (i) an active ingredient in at least one of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based (e.g. aqueous) carrier bases having substantially the same lipophilicity.
It will be appreciated that the invention also embraces products comprising

more than two formulations as defined above provided that these are each separately maintained in appropriate storage means prior to dispense, that all comprise water-based (for example, aqueous) carrier bases having substantially the same lipophilicity, and that at least one active ingredient is contained within a polymeric delivery system.
The storage means within products of the invention may, for example, comprise separate chambers or compartments of a dual-or multi- chamber or compartment dispense device, for example side-by-side collapsible
tubes, syringe barrels or other forms of container with approprial-i dispense valves, pistons, plungers or the like. A r>--oduct comprising two (or more) separate chambers (e.g. made from polypropylene) provided with two (or more) fixed dosing units in a single cap is particularly suitable. Alternatively the storage means may take I;tie form of -a pouch containing a single unit dose of each formulation; such unit dose pouches may, for example, be made of composite materials such as a metal (e.g. aluminium) foil having a plastics material (e.g. polyethylene or polyvinyl chloride) inner lining, with the pouch having separate parts for each formulae io;~i. Examples of suitable pouches from which the formul.it ions may be dispensed include those described in US - -A-6007264 and WO 01/91726, the entire contents of which are incorporated herein by reference.
The dispense means are preferably such that the formulations are dispensable in a controllable (e.g. predetermined) ratio, for example in equal amounts or in other relative amounts as determined to optimise the efficacy o L: the combined formulation after mixing. In this way variations in the composition of the mixed product may be substantially reduced or eliminated. Thus, for example, side-by-side tube containers may be progressively emptied by turning a common winding key adapted to engage and roll up their distal ends, or the plungers of side-by-side syringes may be mutually linked together. It will be appreciated that the respective cross-Be..:L Lonal areas of such containers may be selected to ensur- • hat; the formulations are dispensed in the desired rai.Jo for a given movement of a linked dispen? -i ^ >n actuator.
In the case of unit dose pouches, the ratio of the formulations is predetermined at the filling stage, so that the dispense means need comprise no more than corners or edges which may be cut off or torn off to permit the formulations to be squeezed out.
In general it is convenient to dispense the formulations of a product of the invention in equal amounts, for example each in volumes in the range 1-5 ml, advantageously 1.5-3.5 ml, preferably 2-3 ml.
In a preferred product according to the invention, first and second formulations are respectively presented in the chambers of a dual chamber dispense system of the type described in EP-A-0644129 and US-A-5356040, the conteiv r f which are incorporated herein by reference. Such a system has two side-by-side chambers, each equipped ••.-.'ith a dispense valve; these are operated by adjacent £>ctuators so as to dispense the formulations either .simultaneously or separately as desired. Suitable dispense systems, e.g. having chambers which are each capable of holding about 15 ml of formulation, are available from Maplast S.r.l., Via Pasublo 3, Tradate 21049 VA, Italy. The respective dimensions of the dispense means may be chosen to provide dispense of the respective formulations in a^ predetermined ratio.
The product may include mixiag means such that the formulation;-.; are admixed during dispense. Thus, for example', the points of dispense for each of the storage means uic»y be connected to a single duct and/or nozzle outlet; this may, for example, be spirally grooved on its in1.-- Mrfc.ce ir ord-^r to enhance the efficiency of mixing.
Alternatively the formulations may be dispensed separately and mixed by the patient. Thus, for example, a dispense system of the type described in the above-mentioned SP-A-0644129 may be fitted with separate duct/nozzle outlets for dispense of each formulation. Separate: operation of each actuator will deliver appropriate relative amounts of the formulations, e.g. onto the hand or directly onto an affected area of skin,-the formulations may then be mixed by the patient, e.g. by rubbing. It will be appreciated that such embodiment ,j may be preferred to products which include
mixing mean;; ir. cases where the active ingredients are mutually \ ,active to the extent that they may generate toxic or otherwise undesirable by-products while residual mixed formulations stand in a common duct and/or nozzle between successive dispense operations.
The; dispense means for use in the invention may comprise a dual- or multi-chamber dispense system as hereinbefore described which is provided with a removable closure (e.g. a cap). Preferably, in use, the closure prevents the formulations from being accidentally dispensed. For example, in the case of a system which comprises an actuator (e.g. a plunger) which must, be depressed to deliver the product, the closure nviy fit over the actuator thereby physically preventing this from being depressed when the dispense system ic iiot in use, e.g. when being carried in a handbag.
The closure may also function to prevent exposure of the oririce (s) of the dispenser to the air when the product: is not in use. For example, this may act as a temporary cover or seal for the orifice(s) from which the individual components of the product are dispensed thus preventing (or, at least, reducing) exposure of these to the air. This function1of the closure is particularly important in the case of water-based or aqueous formulations as herein described which on exposure to the air have a tendency to evaporate and dry out. 5;.Li ice this can result in the formation of a caked layer or crust on the surface of any cream or lotion which i vUiia j no in the dispenser, exposure to the air should D<. minimised when the product is not in use. any drying out of cream or lotion within duct and external orifice dispenser may also reduce size orifices this turn affect amount dispensed given operation. some cases exposure to air even result> complete blockage of the duct(s) and/or dispense orifice (••)
The closure for use in the invention may, for example, be provided with one or more (preferably, a plurality) of protrusions. These will generally correspond in number to the number of orifices provided in the dispenser. Typically, the closure may be provided with 1, 2 or 3 protrusions, preferably 2. When the closer- is in place on the dispenser these protrusions engage with the orifices of the dispenser. In order to provide a temporary seel, these protrusions will generally provide a close fit: with each orifice and, typically, will be shaped complimentarily to them. Thus, for example, where the orifices are circular in shape, the protrusions will have 5- circular cross-section, e.g. they will be generally cylindrical. One or more downward flanges (e.g. teeth) may also be provided 011 the sides of the closure for the purposes of alignment and final placement on-to the dispenser.
The e!osure may be completely or partly (e.g. by pivoting, removed, from the dispenser prior to dispense of the iLI ..-duet and readily fits (e.g. snaps) back into place once the product has been dispensed.
The ciosure may be made of any suitable material but wil^ generally comprise a plastics material, e.g. polypropylene or polyethylene.
Viewed from a further aspect the invention thus provides a closure (e.g. a cap) for a dual- or multi-chamber dispense system having one or more, preferably a plurality, e.g. 2, orifices from which separately stored formulations can be dispensed, wherein said closure comprises one or more, preferably a plurality, e.g. 2, protrusions which are complimentary in shape to said orifices. Preferably, the closure is further adapted such that in use this prevents the formulations from being dispensed. For example, this may be adapted to prevent depression of an actuator or plunger. More

preferably, the closure is adapted to cover, e.g. to seal, che orifice or orifices of the dispenser when this is not in use.
In another aspect the invention provides a dual or multi- chamber dispense system for dispensing separately stored formulations which comprises an actuator which causes dispense of said formulations from one or more (preferably a plurality, e.g. 2) orifices, wherein said system i s farther provided with a closure which prevents • depression of said actuator. Preferably, when in use, the cloi-jure also acts as a cover or seal to the orific«.: i,f.; of the dispenser.
pr('-tY-rably, the dispense system and/or cap in accordance' with the invention have one or more of the advantageous features discussed above.
P:•(•• rv-rred embodiments of these aspects of the invention are described with reference to the accompanying Figures, in which:
Figaro LA shows a conventional multi-chamber dispenser;
Figure IB shows a conventional multi-chamber-dispenser provided with a cap in. accordance with the invention;
Figure 2 shows a cap in accordance with the invention,- and
FJgntc.-; 3 shows a conventional multi-chamber dispenr-^ which is provided with a cap in accordance with tho -invention which is partially removed.
W o... reference to Figure 1A, a container- I for a multi-component product has a body 2 within which are located :'" i rnt and second chambers (not shown) suitable for storing first and second formulations. Each chamber is provided with a duct (not shown) connecting it to an orifice 3a and 3b. There is further provided a dispensi ng mechanism which comprises an actuator 4 which is connected to a pumping mechanism of conventional design arid which is not discussed further herein.

Depression of che actuator 4 delivers .appropriate amounts of the first and second formulations to the affected area of the skin via the orifices 3 a and 3b.
The product of the invention is similar to that known in Un.- art but is additionally provided with, a cap 5. As 3h.own in Figure 2, cap 5 comprises a generally circulat , :l:irt 6 having a depending rim 7. At the front of the .->\ : ri: 6 and depending from the front portion is a novel cover 8 which on an inner face is provided with two pips 9a and 9b. These pips 9a and 9b are complimentary in shape to the orifices 3a and 3b of the container. The cap is additionally provided with four engagernent members or teeth 10 which depend from the rim 7. A notch 11 is also provided at the rear portion of the skire 6,
In n«o, cap 5 engages with the top of the container 1 and qpMTf-rally fits over the actuator 4. The teeth 10 form an Interference fit between the actuator 4 and the body 2 OL t:he container 1 thereby -securing the cap 5 in place. The two pips 9a and 9b engage in the orifices 3a and 3b and function not only to prevent depression of the ad u-ii or 4 but also to seal the orifices 3a and 3b from the air. In operation, notch 11 at the rear of the cap 5 i ' ; ;h.t?d upv/ai^ds with the thumb for easy roniovi" of the cap I:i. Actuator 4 is depressed and the product is dispensed. The cap 5 is then simply replaced on the container i .
In one class of preferred products according to the invention, the- first formulation is a water-based (e.g. aqueous) topical cream or gel carrier base containing an. antibactnrlal and/or keratolytic agent incorporated into a polymeric delivery system, and the second is a water-based (e.g. aqueous) carrier base having substantially the same 1ipophilicity and containing a topical antibio:-i Proff ired antibacterial agents include salicylic

acid and organic peroxides, especially, benzoyl peroxide.
y
Combinations of aritibacterials, such as salicylic acid and organic peroxides, e.g. salicylic acid and benzoyl peroxide, may also be used. Salicylic acid is particularly suitable for use in treating acne, e.g. acne vulgaris, since it is both an antibacterial and a keratolyt. .i.c agent and may, for example, be present in such a I", . ct; formulation in an amount of 0.2-40% w/w, advantage:.>u.sly 1-30% w/w, preferably 2-10% w/w. For treating acne vulgaris, appropriate concentrations of salicylic acid may, for example, be 0.5% w/w or 2% w/w. Organic peroxides may, for example, be present in amounts cc. 0.2-40% w/w, advantageously 2-30% w/w, preferably 2.5-20% w/w. Combinations of salicylic acid and benzcyi peroxide may advantageously comprise 2% w/w salicylic acid in combination with 2.5% or 5% w/w benzoyl n-'-r-jxide.
Othei Keratolytic agents which may be used include retinoids such as retiriol or ret-inoic acid and salts and esters thereof, for example in amounts of 0.01-2% w/w, advantageously 0.025-1% w/w, preferably 0.02-0.2% w/w. Preferred .retinoids include retinoic acid, isotretinoin, tretinoin, retiriol, retinyl palmitate, adapalene, tazaroterie and azelaic acid. When applied topically, azelaic acid helps to normalise keratinization, to reduce the proliferation of P. acnes and is effective agains1 ' • i r.cn-iul' lammatory and inflammatory acne lesions. its efficacy can be enhanced when used in combination with benzoyl peroxide, clindamycin, tretinoin or erythromycin/benzoyl peroxide.
A oreferred combination of antibacterial and keratolytic agents which may be present in the first formulation is benzoyl peroxide together with retinoic acid or iretinol.
It; will be appreciated that the amount of antibacterial and/or keratolytic agent (and of all other active ingredients) should be selected to give a desired

end premier, concentration Hollowing the overall dilution
*• ' /
of each ingredient which will occur when the formulations are mixed.
Polymeric delivery systems useful in products of the in-, tiit ion will generally comprise a polymer or polymer';? in the form of particles (e.g. microparticles) , aggregate,'--, of particles (e.g. aggregates of microp; > 1 i ' les) or clusters of aggregates (agglomerates) of part id'./.-', (e.g. agglomerates of microparticles) which : are capahl e of entrapping any desired active for delayed release. The polymer particles will generally be porous (i.e. these have an open structure) and will also typical .ly be cross-linked, e.g. comprising a porous polymeric: mat.rix. Examples of polymeric delivery systems suitable for use in the invention include the Poly-Trap"1' (Cardinal Health, Inc.) and Poly-Pore'5' (Amcol International, Inc.) systems and, in particular, the Microsfyeri! ;• •'* system (Advanced Polymer Systems, Inc.).
Poly-Pore is a microparticl-e delivery system comprif-'i if i a I lyl methacrylate cross-polymer and is described, lor example, in US-A-5830960, US-A-5834577 and US--A-6.M 8849. It comprises spherical particles having a median particle size of about 30 p.m. The interior or: the Poly-Pore spheres comprises clusters of small spheres which are then agglomerated together to form a porous exterior surface and a hollow interior. Poly-Pore has the unique ability to adsorb both hydrophobia and hydrophilic liquids.
The Poly-Trap family of compounds are made by a process which involves supsension polymerization of lauryl methacrylate and ethylene glycol dimethacrylate using a peroxide as a catalyst. The polymerization conditions lead to the formation of amorphous microaggregates or polymer particles. The size of these aggregates is about 25 /zm in diameter and within their structure .,.-.; a .nigh degree of cross-linking. The Poly-Trap po.viiit'is are extremely lipophilic and hydrophobia.

As a resu.it, they are ideal carriers for lipophilic
s
actives and are also capable of controlling skin oiliness without dehydrating the skin. Poly-Trap polymers suitable for use in the products herein described are, for example, described in US-A-4962133 and US-A-4962170.
Microsporige delivery systems can be made, for example, using either styrene and divinylbenzene, or methyl me;, hacrylate and ethylene glycol dimethyacrylate as start dug materials. The choice of monomers and cross-'linkers enable different families of compounds to be prepared. Whilst these both consist of porous micro-spheres their physical-chemical properties are quite ! ; 1'•• • -erii" . furthermore, the manufacturii nc process used to produce Microsponge products allows these to be produced v/ir:h a wide range of particle size, porosity (void volume), pore diameter (openings on. the surface) and surface area. With an almost unlimited number of variations, this permits customisation of the polymer to the active- ingredient to be entrapped. Specifically, this allows design and control of the required release rate and maximisation of beneficial effects on the skin.
Microsponge systems useful in products of the invention may, for example, be as described in WO-A-88/10132, U3-A-4873091, US-A-4690825 and EP-A-0306236. Thus, for example, antibacterial agents such as benzoyl peroxide may be formulated in similar mariner to the product marketed in the USA under the tradename Exact® and by \:ht- present applicant in Turkey under the name Aksil®; benzoyl peroxide-containing Microsponges are described in, for example, US-A-5879716. Similar Microsponges containing retinoic acid are described in US-A-59553Oy. Loading of the active ingredient may take place via either a one-step or two-step process, e.g. as described in US-A-4690825 and US-A-5145675 respectively, whereafter the resulting Microsponges may be suspended in the desired carrier base (e.g. an aqueous carrier

base).
An advantage of the polymeric delivery systems herein described is that release of the antibacterial and/or keratolytic agent from the system (e.g. from the Micros; onucs) can be made to occur quite slowly, conveniently with onset being triggered by dispense and/or .••!]•.pi :i cation with rubbing of the formulations onto the skiii. The concentration of the agent in the carrier base ai. any time may consequently be low, minimising possibJ •:: .i. tritant side-effects whilst maintaining a therapevu: ically effective concentration. Similar advantages may accrue if the topical antibiotic is also contained within its own polymeric delivery system.
The particles of the polymeric delivery system may be composed of a wide range of materials, including both synthetic polymers and natural substances such as cellulose or gelatin. The choice of material forming the poJymeric delivery system may depend upon the intended methods by which the en-trapped antibacterial or other aqe.Mi is to be released. Such methods are descril ->•] in J. Mioroencapsulation. (199.6), .13. (5), 575-588 and include but are not limited to diffusion, compression, dissolution or melting.
Preferably, entrapped antibacterial and/or keratolytin agent is released from the polymeric delivery system by diffusion from the pores of the polymeric particles into the carrier. The rate of diffusion will depend on the partition coefficient of the antibacterial and/or keratolytic agent (and any other entrapped active ingredients) between the polymer forming the polymeric delivery system and the carrier.
Porous particles containing agents such as benzoyl peroxide or retinoic acid will typically release sufficient of the agent into the carrier base during storage, dispense and/or application to provide a therapeut: ically effective initial concentration of agent in the i:01. ipu^ation as applied to the skin. Agents such

as sal i :y":'i'"' acid, however, may not undergo such ready
/ initial t.c-lease fr:om a polymeric delivery system because
of their d:i!:Eerent lipophilicity; it may therefore be advantageous to include a proportion of "free" active agent in the carrier base (e.g. up to 25% w/w of the total content of the agent) to provide the required initial therapeutically effective concentration and to further. Induce release of agent from the polymeric partic1es (c . g . microsponges) .
The diameter of the porous particles which comprise the po 1 '.'Hi' i. -.c delivery system may, for example, be iri the range 1 to 1000 microns, e.g. 4 to 300 microns, such as 5 t>.: 1 ;'•(", ml crontj. It; is preferred, however, that the part id. ^ ;:;i::e is less than 30 microns, 'e..g. 10 to 25 micron;-;, :• ince- particles; larger than 30 microns can impart a 'gritty' feel to the formulation, which, may decrease patient compliance.
The .surface area of the porous particles which comprise t tie micro sponge delivery system may, for example, i.ange from 1 to 500 m2/g, e.g. 20 to 200 m2/g; the total, pore volume may, for example, be in the range 0.3 to 4.0 omVg, e.g. 0.6 to 2.0 cm3/g and the pore diameter (i.e. the opening of the pores on the surface of the particle) may range from 0.001 to 1 micron, e.g. from 0.01 to 0.1 micron. Pore volume and, more importantly, pore diameter may have a significant effect on the rate of release of the entrapped antibacterial and/or Ke.- -t olytic agent, and may affect the migration of the agt.'bl £rom the polymeric delivery system into the carrier, in which the polymeric delivery system is dispersed. Thus the diameter (and hence volume) of the pores lias a diz^ect impact on the release of the agent, as well as on the amount of agent that can be entrapped within the delivery system.
The polymeric delivery system may be made by suspension polymerisation, preferably crosslinking polymers such as polyolefins, for example polyethylene,

polystyrene arid polydicyclopentadiene; polyacrylate
/
esters, for example optionally alkoxylated C1_w alkyl, cycloa'l k y'i aryl or aralkyl esters of polyacrylic or polymethacrylic acids; polyvinyl esters, for example polyvdr.vl :>oet,ate or polyvinyl laurate; polyvinyl ketone:', >' -r example polyviriylmethyl ketone; and polyviry.! •• theirs, for example polyvinyl propyl ether. The most o. nnmonly used crosslinking agents are divinylberr/.ene for polystyrene polymers and ethylene
';
glycol dimethacrylate for polymethacrylates.
It wJ.il be appreciated that the level of hardness of the particles of the polymeric delivery system may be varied widely by appropriate selection of the polymer composition, degree of crosslinking etc. It is desirable (hat the particles are elastically compressd b~\ e so that after application of the formulal:ion to an affected area, the application of gentle pressure, for example by rubbing, may induce release oi' the entrapped antibacterial 'and/or keratolytic agent into the carrier and thus to the skin.
Ir. a-'{ Preferred topical antibiotics useful in the second formulai;j.L.Jij of the aforementioned class of preferred products include tetracyclines (e.g. formulated at concentrations of 0.2-20% w/w, advantageously 1-12% w/w, preferably 2-4% w/w), erythromyciii (e.g. formulated at concent rat. i.'ms of 2-30% w/w, advantageously 3-20% w/w, preferably :>-.LC% w/w), and clindamycin (e.g. formulated at concentrations of 0.02-20% w/w, advantageously 0.2-

10% w/w, preferably 1.6-5.2% w/w.) . Again allowance should be made for the overall dilution of individual active ingredients which will occur when the formulations a:~e mixed. Where appropriate, e.g. for solubility or distribution considerations, corresponding salts or esters, e.g. mineral acid addition salts such as clindoirr/ciri hydrochloride or phosphate, or carboxylic acid esi/t-r;. such as erythromycin propionate, stearate or
ethylsiKvi;iate may also be used. Clindamycin phosphate
>
is particularly suitable for use in formulations used for adit-.- control (P. acnes is highly sensitive to clindamyc Li i; elindamycin is active in comedones from acne patients; it also reduces free fatty acids on the skin su t: IdU/e) .
Tetraeyelines suitable for use in the second formulation include, in particular, tetracycline, doxycycline, miriocycline and lymecycline.
The term '^water-based carrier" as used herein denotes any topical carrier in which water is present, preferably in ari amount in excess of 5% w/w, e.g. in excess ot, 10, 20, 30 or 40% w/w. The term "aqueous carrier base" is intended to denote any topical carrier base in which water is the major component, e.g. being present i.n amounts in excess of 50, 55,' 60, 65 or 70% w/w. Carrier bases contemplated for use in the invention include aqueous creams, gels, lotions or ointments, as well as oil-in-water and water-in-oil emulsions. Water-in-oil emulsions, for example, enable the delivery of hydrophilic ingredients from the polymeric delivery system.
The carriers may, for example, include conventional formulating ingredients selected from lipophilic base materials (for example fatty (e.g. C10_30) alcohol esters of saturated or unsaturated fatty (e.g. C10_30) acids, such as cetyl ricinoleate; fatty acid esters of sterols such as cholesterol or lanosterol; emollient silicon oils, e.g. polysiloxanes such as dimethicone or

cyclomeLhloone; or terpenes such as a-bisabolol),
/-
hydropl . . • ,x,.se tnatci iu 1.3 J or example polyethylene glycols, hereinafter referred to as PEGs), stabilisers and/or surfactants (for example fatty acids such as palmitic' or stearic acid; fatty alcohols such as cetyl or stearyl alcohol; amphiphilic fatty esters, e.g. fatty alcohol esters of mineral acids :such as sodium lauryl sulphate;, ratty acid esters of polyols such as glyceryl dilaurate or caprylic/capric triglyceride; PEGylated
/
fatty alcohols, e.g. PEG lauryl ethers such as laureth-4; PEGyLjiod sorbitan esters with Eatty acids such as oleic, iau"ic, palmitic or stearic acid, e.g. as in Tween(B1 surfactants; PEGylated sterols such as PEG-10 soya st:aroi; polysaccharides such as xanthan gum; proprietary products such as emulsifying wax; or thickeniuy polymeric stabilisers, e.g. polyacrylamide-based products such as Sepigels®), humectants (for example diola cr polyols such as propylene glycol or glycerol), viscosity modifiers C-for example saccharides such as sorbitcl), thickeners (for example colloidal or fumed si IJoa or silicates such as magnesium aluminium silicate), preservatives (for example antimicrobials or antifunga] :: such as methyl paraben, propyl paraben, benzyl alcohol, phenoxyethanol or germaben II; or antioxidauts such as vitamin E, ascorbyl palmitate or butylated hydroxytoluene), pH regulators (for example buffers, e.g. acid/salt combinations such as citric acid/sodLuh citrate; or bases such as triethanolamine), or ant J.-'.j,;.,, u I ants (for example disodium edetate) .
As :ictv.-d above, the lipophilioity of a formulation affect. •- partition coefficient of active ingredieric contained vvit.hin a polymeric delivery system between the polymer particles and the carrier The requirement for the carriers within a particular product according to the invention to have substantially the same lipophilicity may therefore be tested and quantified by determining the partition coefficient in respect of each

carrier base; the requirement is met if the partition
/
coefficients vary by no more than 10%, advantageously by no more than 5%, preferably by no more than 2.5%. It is also preferred that the individual water contents and viscositii -s of the formulations•within a particular produce very by no more than these limits, since thin may eii'lnnee ease and uniformity of mixing of the formulations during or after dispense. In a. preferred embodiment of the invention the individual formulations
'>
will hove substantially identical viscosities, e.g. varying by ao more than 10%, preferably by no more than 5%, more preferably by no more than 2.5%.
In general the viscosities of the formulations may be up to 200,000 cps, preferably up to 100,000 cps, more preferably in the range 5,000 to 50,000 cps, yet more preferably 5,000 to 15,000 cps, e.g. about 10,000 cps. The use of formulations having lower viscosities, e.g. of the order of about 10,000 cps, is particularly preferred when dispensing these ^from systems having side-bv--H.ii.le chambers or compartments from which the produd i.;;• dispensed by the application of external pressure i:•• :ans. In particular, it has been found when using such systems that it is important to ensure that each formulation (e.g. cream, gel or lotion) should be free Lxowiuy to the extent that this essentially remains at the base of the container where the suction tube orificce is located. This orifice must be kept inside each formulation at all times otherwise air will enter the system causing inaccurate amounts of cream to be dispensed. On the other hand, it is important that the viscosJ ty of each formulation should not be too low since the liquid will not stick to the skin. The use of low viscosity formulations has the added advantage that non-pressurized systems may be used to dispense these. Such systems are more environmentally friendly than those which utilise an inert gas to force gels into the intake tubes of the pump. These are also more cost

effective to manufacture.
/ The farriers within a particular product may
advantageously contain essentially the same ingredients or close analogues, homologues or equivalents thereof, in amounts appropriate to ensure the desired levels of lipophi 1i c:ity ate. Where it is desired substantially to match the viscosities of the formulations within a product, at; will be appreciated that the presence of polymer particles (e.g. microsponges) in a formulation may have a significant viscosity increasing effect, particularly if the content of the polymer particle is relatively high (for example as may be required if the level or. entrapment of active ingredient in the polymer partic.les is relatively low) . It may therefore be desirable to increase the relative amounts of viscosity enhanc.i M-J iqen'is (e.g. polysacchazides such as xanthari gum or thickening agents such as silica or silicates) and/or to reduce the amount of relatively low viscosity components such as glycerol or sx:rbitol in a corresponding non-polymeric particle (e.g non-Microsponge) formulation in order to compensate for this. Alternatively, both formulations may include polymer particles (e.g. Microsponges) in order to match the viscosity levels.
Whilst the invention is primarily described herein in terms of systems comprising oxidising antibacterials (e.g. benzoyl peroxide) and antibiotics, as noted above the invention is more generally applicable to any topical pharmaceutical and/or cosmetic preparation which involve:- tv/o or more formulations, at least one of which involve:, -, polymeric delivery system. Such preparations need net .necessarily involve components which have stability limitations when combined. For example, the product herein described may be suitable for use with any conventional dermatological-preparation, e.g. any topical anti-acne compositions. Such compositions may include, for example, one or more of the following

active oomponants: organic peroxides (e.g. benzoyl peroxide), re'.;i.noids (such as retinoic acid, retinol, tretinoiri, isocretinoin, adapaler.e and tarazotene, e.g. at a concentration of 0.001-1% w/w, preferably 0.025-1% w/w, morn preferably 0.05-1% w/w), other comedolytic agents ft;.9. azelaic acid and salicylic acid), sulfur, resorc:i no I , zinc, anti- inflammatory steroids (such as corticosteroids, e.g. hydrocortisone, which may be present, in concentrations in the range 0.25-2.5% w/w),
'i
antibiotics (e.g. clindamycin, erythromycin,
tetracy 'LI in-, doxycycline, rniriocycline, lyrneeye.line) ,
anti-fungal agents (e.g. undecilenic acid, miconazole
(base and nitrate), ketoconazole, iconazole, clotrimazule arid metronidazole) , alpha-hydroxy acids
(e.g. glyaolic acid, lactic acid, ko j ic acid), vitamin K, hair growth promotion agents (such as minoxidil, e.g. present in a concentration of 1-5% w/w), depigmenting agents (such as hydroquinone, e.g. at a concentration of 1-10% w/w), antiviral agents (e,jg. acyclovir, valacyclovir and the like or a combination thereof), anaesti: •• ; agents (e.g. lidocaine, benzocaiiie, priloc.-t i iu-', pramoxine, benzyl alcohol, dibucaine) , counter .; i .: i tant agents (e.g. menthol, camphor, phenol and the Like or a combination of these), antiseptic/microbicidal agents (e.g. benzalkoriium chloride, boric acid, cetylpyridinium chloride, benzethoniurn chloride, resorcinol, chloroxyenol and the like), antibacterial and/or antitrichomonal agents (e.g. metronidazole, tinidazole, ornidazole and the like), astringents (e.g. bismuth subgallate, zinc oxide, witch hazel c-md the like), wound healing agents (e.g. cod liver oil, shark liver oil, sucralfate and the like), protectants (e.g. dimethicone, aluminium hydroxide gel, aluminium acetate, mineral oil, cocoa butter, glycerine, kaolin, petrolatum, lanolin oil, peruvian balsam, calamine, titanium dioxide, etc.), hormones (e.g. conjugated estrogens, estriol and the like), vitamins

(Table Removed)
* signifies presence in a polymeric delivery system, preferably in a Microsponge system .
Particularly preferred combinations of actives for use in products of the invention include: salicylic acid and Clindamycin (e.g. Clindamycin phosphate); benzoyl peroxide and clliidamycin; benzoyl peroxide and salicylic acid; arid rr-tinoic acid (or a derivative thereof) and an antibiotic- i.e.g. Clindamycin). In these particular
combinations, either of the actives may 'entrapped1, i.e. present in a polymeric deliA^ery system, preferably in a Microsponge system. However, preferably it will be the first listed active which will be 'entrapped1.
Combinations of retinoic acid (or a derivative thereof) either in 'entrapped' or 'free1 form together with an 'entrapped1 form of an antibiotic, benzoyl peroxide.- or' salicylic acid are a],so preferred for use in the invent 1 on .
'The pharmaceutical formulations in products of the present ; n /erition may be manufactured by methods convent .1 on. u ly known for the manufacture of pharmaceutical creams or gels. One suitable method of manufacture includes the steps of preparing an aqueous solution of. the water-soluble ingredients, mixing this solution together with the hydrophobia ingredients, homogenising the resulting mixture and thereafter adding the active ingredient (e.g. antibacterial agent or antibiotic) . The resulting cream or gel may then be filled into the appropriate storage means of the product.
To use a product of the present invention, a patient may simply activate the dispense means (e.g. by depressing a pump or plunger) and collect the formulation (s) dispensed, e.g. in his hand. If necessary, the patient may then mix the formulations to obtain ; -<. mhination product which is applied to the area f :- be treated. formulations dispensed from pro-ducts of invention are preferably on a regular basis for example once or twice daily.> Although much of the discussion and examples presented herein pertain to products primarily designed for the treatment of acne conditions, it will be clear to those of ordinary skill in the art that similar considerations and formulation strategies are equally applicable to the treatment of a wide range of other
skin conditions. For example, the products of the invention may be used in treating other dermatological condition;-;, such as fungal infections, various dermatitis (e.g. eczema, psoriasis and the like), rosace,j, -aelasma (chloasma) and alopecia. Such products also find use in non-medical, e.g. cosmetic, applications such as in treating or preventing wrinkles, in treating rough skin, hyperpigmented spots (e.g. liver spots) and other manifestations of aging skin, cellulite, stretch marks, etc., and in promoting or suppressing hair growth.
The products herein described may also be used in treating dermarological conditions and conditions affecting mucosal surfaces (e.g. skin & mucosal & oral membranes) and its appendices, such as
pseudofolliculitis barbae, fungal infections, bacterial infections, viral infections, allergic and/or atopic dermat.1 t:i;; (eczema) such as seborrheic dermatitis, diaper ra;;h and the like, conditions related to wounds, burns, T» • '"P '; njur ies, 'insect hi'en sunburn i:/;' "h like, ,:i,-.i we-11 as infectious and non-infectious condition!.; affecting skin & mucosal membranes of the genital area such as vulvitis, balanitis and the like, and hemorrhoidal conditions.
The contents of all publications, patents or otherwj.se, mentioned hereinbefore are herein incorporat.ed by reference.
The -invention will now be described in more detail by way of the following non-limiting Examples:
Example 1. - Benzoyl Peroxide/Salicylic Acid Lotion in Double Container (Standard Strength Formulation)
5% Benzoyl Peroxide Lotion:
(Table Removed)
Preparat: ioi.:
1. D.i .•:.; compone K:- "'>, 4, 5, 6 and 7 with mixing.
2. Propele a premix of component 8 and add to above
with mixin-v; .
3. Add components 9-14 with slow mixing.
4. Add component 15 with mixing.
The Benxoy.i. Peroxide and Salicylic Acid B'ormulations are subsequently transferred to a dual-chamber dispense system .such as that described in EP-A-0644129 which may be provided with a suitable cap as herein described.
Example ?, - Benzoyl Peroxide/Salicylic Acid Lotion in Double Container (Extra Strength Formulation)
(Table Removed)
Prepaiv
1. D: ;:;p>-r i'Fie component 2 in deionised water and add
component..-. '--:,, 4, 5, 6 arid 7 with mixing.
2. Prepare a premix of component 8 and add to above
with mixiri :j.
3. Add components 9-13 with slow mixing.
4. Add component 14 with mixing.
The Clindeuuycin formulation may be used in combination with any or the Benzoyl Peroxide and Salicylic Acid formulations according to Examples 1 and 2 or with a 0.05 wt% Retinoic Acid formulation. The components are presented in a dual-chamber dispense system such as that, described in KP-A-0644129 and which may be provided with a suitable cap as herein described.
A suitable retinoic acid lotion formulation may be prepared b/ substituting Retinoic Acid in place of the Salicy . . ..u in Liie J !; balicyc_L^.i: ACJ.Q Lotion 01. Example 1 (hereinafter referred to as "reference formulation"). The active ingredient would then be Retinoic Acid with a total concentration of 0.2% which would be diluted after mixing with the second component upon dispensing and mixing to obtain the desired 0.1% final concentration. 1/5 of this amount (i.e. 0.2/5 = 0.04%) would be substituted for thf; 'free1 form of Salicylic Acid in the reference formulation and the remaining -!/L> of 0.2% (i.e. 0.16%) would be 'entrapped1. To obtain :;0% entrapment, 0.16/0.3 = 0.53% Retinoic Acid
would need to be substituted for the 'entrapped1 Salicylic Acid ingredient in the reference formulation. Suitable adjustment of the water content of the formula would neon to be made to take the total amount of ingred'i ent: s up to 100%. For a noil-entrapped or 'free1 version of the Retinoic Acid formulation, the total of 0.2% should be substituted directly into the Salicylic Acid lotion formula and the water adjustment made for the difference.
')
For formulas requiring lower concentrations of Retinoic Acid such ,:K:; 0.075%, 0.05% and 0.01% total active, the same ca 1 cu ! ations should be carried out taking into account t'n • dilution, entrapment and ratio of 'free' to ' entrap; u> • oroduct .
It will be appreciated that the invention can be embodied in other specific forms without departing from the spirit or essential character thereof and that the scope of the invention is not limited to the disclosed embodimentH. Those of ordinary skill in the art could readily produce other combinations of actives suitable for use with the dispensing system herein described.

We Claim:
1. A system for dispensing topical formulations comprising first and second active ingredient-containing formulations for topical administration to a patient, said formulation being independently a pharmaceutical or a cosmetic product, comprising storage means (2) whereby the formulations are maintained separately prior to dispense, together with dispense means (4) (3a) (3b) which permit said formulations to be dispensed from said storage means (2), wherein (i) an active ingredient in one or both of said formulations is contained within a polymeric delivery system and (ii) both of said formulations comprise water-based carrier bases having substantially the same lipophilicity.
2. A system for dispensing topical formulations as claimed in claim 1, wherein an active ingredient in one of said formulations or both of said formulation is contained within a porous polymeric delivery system.
3. A system for dispensing topical formulations as claimed in any one of claim 1 or 2, wherein the dispense means are such as to permit dispense of the both said formulation in a predetermined amount.
4. A system for dispensing topical formulations as claimed in any one of claim 1 to 3, wherein the dispense means are such as to permit dispense of the both said formulation in equal amounts between 1 to 5 ml.
5. A system for dispensing topical formulations as claimed in any of claims 1 to 4, wherein the storage means comprise a first chamber and a second chamber each equipped with an orifice (3a)(3b), said formulation being dispensed by adjacently disposed actuators (4).

6. A system for dispensing topical formulations as claimed in any one of claims 1 to 5, wherein the storage means comprise a unit dose pouch having separate parts for each formulation.
7 A system for dispensing topical formulations as claimed in any one of the claims 1 to 6,
wherein the dispense means are adapted to dispense said formulation separately.
8. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7,
wherein, in the first formulation, the active ingredient is an antibacterial or a keratolytic agent or a
mixture thereof; and is contained within a polymeric delivery system comprising porous polymer
particles;
said first formulation comprises a water based carrier base that is selected from an aqueous topical
cream or gel carrier base; and
in the second formulation the active ingredient is a topical antibiotic?
9. A system for dispensing topical formulations as claimed in claim 8, wherein said keratolytic agent is a retinoid, preferable retinoic acid.
10. A system for dispensing topical formulations as claimed in claim 8, wherein said antibacterial agent is selected from a group consisting of salicylic acid and organic peroxide being preferably benzoyl peroxide.
11. A system for dispensing topical formulations as claimed in any of claim 8, wherein said
antibiotic is selected from a group consisting of erythromycin, clindamycin and tetracycline.
12. A system for dispensing topical formulations as claimed in claim 8, wherein said antibacterial
agent is benzoyl peroxide and said antibiotic is clindamycin.

13. A system for dispensing topical formulations as claimed in claim 8, wherein said topical
antibiotic is contained within a polymeric delivery system.
14. A system for dispensing topical formulations as claimed in claims 1 to 7, which comprises as active ingredients of first and second formulations, an anti-fungal agent and a retinoid, any one or both of which is incorporated into a polymeric delivery system.
15. A system for dispensing topical formulations as claimed in claim 14, wherein the antifungal agent is undecilenic acid, miconazole (base or nitrate), ketoconazole, iconazole, clotrimazole and the retinoid is either retinol or retinoic acid.
16. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7„ which comprises as active ingredients of first and second formulations a depigmenting agent and a keratolytic agent, any one or both of which is incorporated into a polymeric delivery system.
17.A system for dispensing topical formulations claimed in any one of the claims 1 to 7, comprising a depigmenting agent and a retinoid, as active ingredients any one or both of which is incorporated into a polymeric delivery system.
18. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7, which comprises as active ingredients of first and second formulations, a corticosteroid and a retinoid, any one or both of which is incorporated into a polymeric delivery system.
19. A system for dispensing topical formulations as claimed in any one of the claims 1 to 7, which comprises as active ingredients of first and second formulations, a hair growth promoter and a retinoid

or other keratolytic agent, any one or both of which is incorporated into a polymeric delivery system.
20. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein, the difference in the water content of said first and second formulations is 0 to 10%, preferably 0 to 5%, more preferably 0 to 2.5 %.
21. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein, said first and second formulation have viscosity of upto 40,000 cps, preferably upto 30,000 cps, more preferably upto 20,000 cps, most preferably upto 10,000 cps.
22. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein the difference in the viscosity of said first and second formulation is 0 to 10 %, preferably 0 to 5%, more preferably 0 to 2.5 %.
23. A system for dispensing topical formulations as claimed in any one of the preceding claims wherein, the difference in the lipophilicities of said first and second formulations is 0 to 10%, more preferably 0 to 5%, still more preferably 0 to 2.5 %.
24. A system for dispensing topical formulations as claimed in any one of the preceding claims
which comprises a dual chamber dispense system provided with an actuator which causes dispense of
said formulations from one or more orifices, characterized in that said system is further provided with a
closure which prevents depression of said actuator.
25. A system for dispensing topical formulations as claimed in claim 24, wherein said closure is adapted to cover or seal the orifice(s) of the dispenser.
26. A system for dispensing topical formulations as claimed in claim 24, wherein said closure is provided with one or more protrusions which are complementary in shape to said orifices.

provided with one or more protrusions which are complementary in shape to said orifices.
27. A system for dispensing topical formulations substantially as hereinbefore described with reference to the foregoing examples and accompanying drawings.

Documents:

3315-DELNP-2005-Abstract-(02-09-2008).pdf

3315-DELNP-2005-Abstract-(21-08-2008).pdf

3315-delnp-2005-abstract.pdf

3315-DELNP-2005-Claims-(02-09-2008).pdf

3315-DELNP-2005-Claims-(16-09-2008).pdf

3315-DELNP-2005-Claims-(21-08-2008).pdf

3315-delnp-2005-claims.pdf

3315-delnp-2005-complete specification (granted).pdf

3315-DELNP-2005-Correspondence-Others-(02-09-2008).pdf

3315-delnp-2005-correspondence-others-(16-09-2008).pdf

3315-delnp-2005-Correspondence-Others-(18-03-2011).pdf

3315-DELNP-2005-Correspondence-Others-(21-08-2008).pdf

3315-delnp-2005-correspondence-others.pdf

3315-delnp-2005-description (complete)-(16-09-2008).pdf

3315-delnp-2005-description (complete)-02-09-2008.pdf

3315-delnp-2005-description (complete)-16-09-2008.pdf

3315-delnp-2005-description (complete)-21-08-2008.pdf

3315-delnp-2005-description (complete).pdf

3315-DELNP-2005-Drawings-(21-08-2008).pdf

3315-delnp-2005-drawings.pdf

3315-DELNP-2005-Form-1-(02-09-2008).pdf

3315-DELNP-2005-Form-1-(21-08-2008).pdf

3315-delnp-2005-form-1.pdf

3315-delnp-2005-form-13-(02-09-2008).pdf

3315-delnp-2005-form-13.pdf

3315-delnp-2005-form-18.pdf

3315-DELNP-2005-Form-2-(02-09-2008).pdf

3315-DELNP-2005-Form-2-(21-08-2008).pdf

3315-delnp-2005-form-2.pdf

3315-DELNP-2005-Form-26-(21-08-2008).pdf

3315-delnp-2005-form-26.pdf

3315-delnp-2005-Form-27-(18-03-2011).pdf

3315-DELNP-2005-Form-3-(21-08-2008).pdf

3315-delnp-2005-form-3.pdf

3315-delnp-2005-form-5.pdf

3315-delnp-2005-pct-101.pdf

3315-delnp-2005-pct-304.pdf

3315-delnp-2005-pct-401.pdf

3315-delnp-2005-pct-402.pdf

3315-delnp-2005-pct-409.pdf

3315-delnp-2005-pct-416.pdf

3315-DELNP-2005-Petition-137-(21-08-2008).pdf

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Patent Number

224122

Indian Patent Application Number

3315/DELNP/2005

PG Journal Number

44/2008

Publication Date

31-Oct-2008

Grant Date

29-Sep-2008

Date of Filing

26-Jul-2005

Name of Patentee

EDKO TRADING AND REPRESENTATION CO. LTD.

Applicant Address

ESKI BUYUKDERE CADDESI, TAHIRAOA CESME SOKAK, AYAZAOA TICARET MARKEZI, NO: 11 KAT: 1, MASLAK, 34398 ISTUNBUL, TURKEY.

Inventors:

#	Inventor's Name	Inventor's Address
1	EMBIL, KORAL	ESKI BUYUKDERE CADDESI, TAHIRAOA CESME SOKAK, AYAZAOA TICARET MARKEZI, NO: 11 KAT: 1, MASLAK, 34394 ISTUNBUL, TURKEY.
2	NACHT, SERGIO	RILEY-NACHT, LLC, 10375 DESIGNATA AVENUE, LAS VEGAS, NV 89135, U.S.A.

PCT International Classification Number

A61K 9/06

PCT International Application Number

PCT/GB2004/000288

PCT International Filing date

2004-01-23

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0301577.3	2003-01-23	U.K.