AU691583B2 - Adhesive free topical pharmaceutical formulations - Google Patents

Description

WO 95/23596 PCT/EP95/00791 1 Adhesive free topical phMo tiGa fImu]1agTnc The present invention relates to novel topical pharmaceutical formulations, comprising a non-steroidal antiinflammatory drug (NSAID). The formulations may be used for the local treatment of pain and inflammation.

Topical formulations of NSAIDs, in the form of patches which are adhered to the skin, are known.

However, the removal of these patches may traumatise the skin and cause discomfort to the patient. In addition the drug may interact with the adhesive thus making it difficult to determine the actual dose received by the patient.

US 4,704,406 discloses sprayable preparations for the topical application of non-steroidal antiinflammatory agents comprising a) a volatile solvent which may be ethanol, propanol or isopropanol and b) a non-volatile solvent which may be a polyfunctional alcohol or a fatty acid ester of a mono- or polyfunctional alcohol, the weight ratio of a:b being from about 1:1 to 20:1. However, these formulations suffer from the disadvantage that NSAIDs are irritant if inhaled.

WO 92/05768 discloses the use of S(+)-flurbiprofen in the prevention or treatment of sunburn. On page 16 lines 15 to 21 it is stated that the drug may be applied topically in any fashion suitable for topical administration. A clothwipe and an impregnated bandage are listed as two, amongst many, typical topical preparations. No specific examples of such formulations are disclosed and the only assistance which the skilled reader is given is a reference to a textbook 1emington's Pharmaceutical Sciences, 17th Edition 1985.

~111 L_ P OI'iRitMWuoso 95 SPa -MI -2- However, this textbook gives no practical assistance in how to formulate a clothwipe or an impregnated bandage. Even with the incorporation of this reference the disclosure in WO 92/05768 is not enabling.

The present invention provides an adhesive-free topical pharmaceutical formulation suitable for use as a wipe having a first surface, to be placed in contact with the skin, comprising an absorbent material wherein the absorbent material is impregnated with a pharmaceutical composition comprising a solution of a non-steroidal anti-inflammatory drug in a C2-4 alcohol suitable and wherein the absorbent material has a second surface, opposite the first, provided with an impermeable backing layer of polyethylene.

The term adhesive-free means that the formulation does not contain an adhesive (for example a silicone based adhesive or an acrylate based adhesive) to hold the absorbent material in contact with the skin.

*Such formulations are particularly useful in the treatment *i of pain and inflammation associated with soft-tissue and musculo-skeletal injuries e.g. sports injuries. The formulations are also useful as a supportive treatment in localised arthritic, rheumatic and inflammatory conditions.

They are convenient to use, especially over large skin areas with a high density of hair and provide an immediate localised soothing and cooling effect due to evaporation of the alcohol as the drug begins to have its pharmacological effect.

:.The topical application of the pharmaceutical composition as a solution has the potential advantages of improved penetration and better physical and chemical stability due to the relatively small number of excipients required.

-I I L I I I I LC I I WO 95/23596 PCT/EP95/00791 3 Suitably the absorbent material may comprise any natural or synthetic material which is pharmaceutically acceptable. Preferably the absorbent material comprises lint, compressed cotton, paper, cotton wool, gauze, woven or unwoven fabric or fabric which has been spun.

More preferably, the absorbent material comprises compressed tissue paper, compressed cotton wool, polyester or a viscose/polyester mixture.

Suitable C 2 -4 alcohols are ethanol, propanol, isopropanol or n-butanol, isobutanol, sec-butanol or tert-butanol. Preferably ethanol is used. Suitably the C2-4 alcohol comprises 20-95% by weight of the pharmaceutical composition.

Suitably the non-steroidal antiinflammatory drug comprises ibuprofen, S(+)-ibuprofen, flurbiprofen, flurbiprofen, R(-)-flurbiprofen, ketoprofen, ketoprofen, piroxicam, or naproxen, including pharmaceutically acceptable salts of each. Preferably the non-steroidal antiinflammatory drug is ibuprofen, S(+)-ibuprofen, flurbiprofen or S(+)-flurbiprofen. Most preferably S(+)-flurbiprofen is used.

Typically the non-steroidal antiinflammatory drug comprises 0.1-25% by weight of the pharmaceutical composition, for example 0.1-15%. Preferably the nonsteroidal drug comprises 1-15%, for example 1-10%, by weight of the pharmaceutical composition, more preferably 2.5 to 7.5% by weight and most preferably 4 to 6% by weight of the pharmaceutical composition.

Preferably the pharmaceutical composition comprises one or more co-solvents. The co-solvents are selected and optimised to achieve the desired consistency and skin-feel and to maximise the absorption of the active i I 1. I I Lh-~ I WO 95/23596 PCT/EP95/00791 4 ingredient. Suitable co-solvents are pharmaceutically acceptable excipients for the NSAID or salt thereof which are less-volatile than the C2- 4 alcohol and which prevent crystallisation of the NSAID despite evaporation of the C 2 4 alcohol. Suitable co-solvents are C 2 -4 alkanediols (for example 1,3-butanediol, 2,3-butanediol, 1,2-propanediol, 1,3-propanediol), benzyl alcohol, fatty acid esters (such as isopropyl palmitate or isopropyl myristate) or polyvinylpyrrolidone.

Suitably the co-solvent comprises 0.01 to 90% by weight of the composition. Preferred co-solvents are propylene glycol, benzyl alcohol, isopropyl palmitate, isopropyl myristate, or polyvinylpyrrolidone. Suitably benzyl alcohol comprises 1-15% by weight of the pharmaceutical composition and preferably comprises 2-10% by weight of the pharmaceutical composition.

Suitably propylene glycol comprises 1-25% by weight of the pharmaceutical composition and preferably comprises 10-20% by weight of the pharmaceutical composition.

A particularly preferred co-solvent is polyvinylpyrrolidone. Surprisingly polyvinylpyrrolidone has been found to form an amorphous matrix with NSAIDs, particularly with flurbiprofen or ibuprofen, or their respective S(+)-enantiomers, when an ethanolic solution is evaporated. An amorphous matrix may also be formed by mixing or melting the NSAID with polyvinylpyrrolidone. The optimum amount of polyvinylpyrrolidone required for each NSAID may be found by construction of a phase diagram, for example by plotting the melting point (using Differential Scanning Calorimetry) or solubility against the percentage weight of each of the components in the mixture, by methods known to those skilled in the art.

I IL I '-II II WO 95/23596 PCT/EP95/00791 5 Suitably the polyvinylpyrrolidone comprises 0.01 to by weight of the pharmaceutical composition.

Preferably the polyvinylpyrrolidone comprises 0.05 to by weight of the pharmaceutical composition and more preferably the polyvinylpyrrolidone comprises 0.25 to by weight of the pharmaceutical composition.

A preferred pharmaceutical composition comprises: 1-10% by weight of S(+)-flurbiprofen; 0.1-10% by weight of polyvinylpyrrolidone; and 80-98.9% by weight of ethanol.

Other particularly preferred co-solvents are fatty acid esters. The use of these co-solvents in high concentration, for example greater than 50% by weight of the pharmaceutical composition, produces an advantageous emollient effect and ;-duces undesirable drying of the skin. Suitably the fatty acid ester comprises 1 to by weight of the pharmaceutical composition. Preferably the weight of the fatty acid ester in the composition is greater than the weight of the C2- 4 alcohol. More preferably the fatty acid ester comprises 50 to 90% by weight of the pharmaceutical composition and most preferably comprises 50 to 70% by weight of the pharmaceutical composition. Preferred fatty acid esters are isopropyl palmitate and isopropyl myristate. More preferably the fatty acid ester is isopropyl palmitate.

A preferred pharmaceutical composition comprises: 1-10% by weight of S(+)-flurbiprofen; 1-10% by weight of benzyl alcohol; 50-70% by weight of isopropyl palmitate; and 10-48% by weight of ethanol.

Optionally the pharmaceutical composition comprises one or more penetration enhancers for example an I LL I WO 95/23596 PCT/EP95/00791 6 aromatic oil (for example peppermint oil or eucalyptus oil), a dialkyl sulphoxide, an amide of the cyclic amine, polyoxyethylene oleyl ether (available from ICI Surfactants under the trade name BRIJ 92), a fatty acid (for example oleic acid), a fatty alcohol (for example lauryl alcohol), methyl salicylate, diethylene glycol or a surfactant. Suitably the penetration enhancer comprises 0.1-10% by weight of the pharmaceutical composition and preferably comprises to 5% by weight of the pharmaceutical composition.

Optionally the pharmaceutical composition may contain a thickener, such as hydroxypropyl cellulose (available from Aqualon under the trade name Klucel).

Suitably the thickener comprises 0.1 to 25% by weight of the pharmaceutical composition, preferably 0.1-5% by weight.

Optionally the pharmaceutical composition may contain a stabiliser to reduce esterification reactions between the C 2 -4 alcohol and the NSAID where the NSAID is a carboxylic acid. Water is a suitable stabiliser when it comprises 5 to 30% by weight of the pharmaceutical composition.

Optionally the pharmaceutical composition may comprise a pharmaceutically acceptable rubefacient to provide a localised warming effect. Suitably the rubefacient comprises 0.01-10% by weight of the composition. Preferably the rubefacient comprises eucalyptus oil by weight), capsaicin (0.01-0.1% by weight), or methyl salicylate by weight), ethyl nicotinate (0.01 1% by weight) or nicotinic acid (0.01-1% by weight).

u IIII I la WO 95/23596 PCTIEP95/00791 7 Optionally the pharmaceutical composition may comprise a film forming agent such as cetostearyl alcohol. Suitably the film former comprises 0.1 to by weight of the pharmaceutical composition and preferably comprises 0.5 to 5% by weight of the pharmaceutical composition.

Optionally the pharmaceutical composition may also comprise a topically acceptable steroid, for example prednisolone, hydrocortisone, prednisone, dexamethasone, triamcinilone, betamethasone, beclomethasone, desoxymethasone, diflucorolone, fluclorolone, fluocinolone and fluorcinonide. It will be appreciated by those skilled in the art that esters or other pharmaceutically acceptable derivatives of the above steroids may also be used. Suitably the steroid comprises 0.001 to 5.0% by weight of the pharmaceutical composition, preferably 0.01 to 2.5% by weight and more preferably 0.02 to 0.5% by weight of the pharmaceutical composition.

In another aspect the present invention comprises a process for the preparation of a pharmaceutical composition, as described above, comprising combining the NSAID or a salt thereof with the C2- 4 alcohol and optional ingredients, for example the co-solvent, with suitable mixing. Any mixing method known to those skilled in the art may be employed, for example stirring, shaking or other methods of mechanical agitation.

The pharmaceutical compositions may additionally comprise other components well known to those skilled in the art. Such additional ingredients may comprise one or more of the following and/or any mixtures thereof: sequestrants (for example tetra sodium ethylene diamine

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WO 95/23596 PCT/EP95/00791 8 tetra acetate dihydrate), anti-oxidants (for example DLa tocopherol acetate and/or butylated hydroxytoluene), preservatives (for example bronopol, sodium dehydroacetate, polyhexamethylenebiguanide hydrochloride, isothiazolonediazolidinylurea, and/or 2phenoxyethanol), colouring agents (for example pharmaceutically acceptable and/or food desirable colorants and/or dyes), emollients (for example mineral oils, polymethylsiloxane, dimethicone, volatile silicone fluid, sweet almond oils, petroleum jellys and/or triglycerides of fatty acids [such as lauric triglyceride, capric/caprylic triglyceride, and/or mixed triglycerides]), moisturisers (for example D-panthenol), perfumes (for example pharmaceutically and/or cosmetically acceptable sweet smelling oils) and humectants to improve the feel of the composition on the skin.

The partitioning potential of the pharmacologically active ingredient from the pharmaceutical composition may be optimised by examining the solubility of the active ingredient in the residual pharmaceutical composition which is obtained after evaporation of the

C

2 -4 alcohol. In order to obtain maximum skin penetration it is believed that the active ingredient should be in solution at near-saturation in the residual pharmaceutical composition. Preferably the active ingredient should be at saturation in the residual pharmaceutical composition and most preferably the active ingredient should be at super-saturation in the residual pharmaceutical composition. Therefore, for optimal absorption, the excipients and their proportions must be adjusted to achieve the desired level of saturation of the active ingredient on the skin after the evaporation of the volatile components.

LI M -0 I 1__1 II WO 95/23596 PCT/EP95/00791 9 An initial optimisation may be carried out by adjusting the relative amounts of the excipients and then applying the pharmaceutical composition to a glass slide. After a suitable time interval the composition is examined under a microscope for signs of crystallisation of the active.

Alternatively the relative amounts of volatile and non-volatile components may be adjusted and the solubility of the active ingredient determined. Using these results phase diagrams may be constructed which may be used to obtain the optimum level of saturation required for maximum skin penetration Skin penetration may be further optimised by examining the penetration of the active ingredient from test compositions or formulations through a suitable membrane, for example human cadaver skin [see Int.J.Pharm. 87, 261-264 (1992)], or hairless mouse skin [see J.Pharm.Pharmacol, 40, 525-529 (1987)3,in a diffusion cell.

Suitably a horizontal diffusion cell may be used with the membrane being placed as a barrier between two halves (a donor compartment and a receptor compartment) of the diffusion cell. A specified amount of the formulation is applied to one side (the donor compartment) of the membrane which is maintained at a suitable temperature e.g. 32 0 C. The donor compartment contains a suitable receptor solution continuously agitated and maintained at the desired temperature.

After application of the test composition or test formulation the receptor medium in the receptor compartment is sampled at specific time points, optionally replacing the medium as required. The samples are analysed for content of the active 9 4 I Y s ~I WO 95/23596 PCTIEP95100791 10 ingredient using appropriate qualitative analytical techniques, for example HPLC. Using the assay results, taking into account the area available for diffusion, the volume of the receptor compartment, the receptor sample volumes, the amount of active ingredient absorbed per unit area and the percentage of the initial dose which has permeated can be calculated, and absorption profiles constructed. A suitable number of replicates should be performed.

Suitably the pharmaceutical formulation may be in the form of a disposable wipe. The wipe may be contained in a suitable impermeable pouch to prevent evaporation on storage. As the name suggests, the wipe is wiped over the affected area so that the drug dose is applied to the skin in solution, the wipe being discarded after use. If desired the wipe may be held in contact with the affected area of the skin by any suitable means, for example by hand or by means of a bandage. Optionally rn impermeable backing layer may be present on one side of the wipe. Use of an impermeable backing layer reduces hand-drug contact. The formulation should provide high penetration rates, since the NSAID or salt thereof remains in solution in the cosolvent on the skin, and a cooling effect. The impermeable backing layer may be joined to the absorbent material at the edges or all over the surface.

Optionally the impermeable backing layer may be provided with pockets. The purpose of the pockets is to receive the thumb and fingers of the person applying to wipe to facilitate administration and minimise hand-drug contact.

Suitably the surface of the wipe for application to the skin has an area in the range 5-500cm 2 preferably in the range 5-100 cm 2 and more preferably in the range o I I WO 95/23596 PCT/EP95/00791 11 10-40 cm 2 The dosage of the non-steroidal antiinflammatory drug applied to the skin is in the range of 0.5 mg to 10 mg per cm 2 of absorbent material in contact with the skin. Preferably the dosage is in the range 1-5 mg per cm 2 and more preferably the dosage is in the range 2-4 mg per cm 2 The shape of the wipe is unimportant but preferably it is square, circular or rectangular, or dumb-bell shaped. Suitably the density of the absorbent material used lies in the range of 20-300 g/m 2 for example 40-200 g/m 2 preferably in the range 30-200 g/m 2 for example 50-120 g/m 2 and most preferably the density lies in the range of 60-180 g/m 2 for example 60-100 g/m 2 Alternatively, the formulation may be provided in the form of a wrap-around tissue which may be applied to joints, for example knees, ankles or elbows. The wrap around tissue allows the active drug solution to remain in contact with the skin for a longer period.

Optionally an impermeable backing layer may be present on one side of the tissue. The fabric is wrapped around the affected area, for example a joint, and optionally may be secured by an additional bandage (such as Setonet), such that the impermeable backing layer is in contact with the bandage, and removed after a period of time.

Suitably the surface of the wrap-around tissue for application to the skin has an area in the range 100-500 cm 2 and preferably in the range 200-300 cm 2 The dosage ranges of non-steroidal anti-inflammatory drugs per cm 2 of absorbent material are as described for the wipe. Suitably the density of the absorbent material used lies in the range of 20-300 g/m 2 for example 40-200 g/m 2 preferably in the range 30-200 g/m 2 for example 50-120 g/m 2 and most preferably Ip ?1#PIIII WO 95/23596 PCT/EP95100791 12the density lies in the range of 60-,,0 g/m 2 for example 60-100 g/m 2 The shape of the wrap-around is suitably circular, square, rectangular or shaped to facilitate comfortable application to a joint for example a butterfly shape or a dumb-bell shape. Preferably the wrap-around is shaped for easy application to a knee, ankle, elbow, wrist, finger or toe joint.

Suitable impermeable backing material comprises a flexible polymer which is impermeable to the solvents used in the pharmaceutical compositions such as polyethylene or polypropylene. Preferably the backing material is polyethylene.

The pharmaceutical formulations are prepared by cutting the absorbent material to an appropriate size, providing the material with an impermeable backing if desired and then contacting the absorbent material ";ith the pharmaceutical composition such that the pharmaceutical composition is absorbed into the material (the latter two steps may also be carried out before cutting the absorbent material to size). Contact may be made by dipping the material into the pharmaceutical composition, spraying the pharmaceutical composition onto the material or spreading the pharmaceutical composition over the material. Alternatively the absorbent material may be placed in an impermeable pouch which is open at one end and the pharmaceutical composition added. The pouch is then sealed. The pouch may be formed from a material which is impermeable to the pharmaceutical composition for example metal foil or a flexible polymer.

I

WO 95/23596 PCT/EP95/00791 13 One preferred embodiment according to the present invention comprises an absorbent material, without adhesive, suitable for use as wipe having a first surface, to be placed in contact with the skin, with an area in the range of 10-40 cm 2 wherein the absorbent material is impregnated with a pharmaceutical composition comprising 2.5-7.5% by weight of a solution of S(+)-flurbiprofen in ethanol containing 0.1-10% of a co-solvent such that the effective dose is in the range 0.5 to 10 mg per cm 2 of absorbent mnaterial in contact with the skin and wherein the absorbent material has a second surface, opposite the first, provided with an impermeable backing layer of polyethylene, and further wherein the absorbent material is sealed in an impermeable pouch.

A second preferred embodiment comprises an absorbent material, without adhesive, suitable for use as a wrap-around having a first surface, to be placed in contact with the skin, with an area in the range of 200-300 cm 2 wherein the absorbent material is impregnated with a pharmaceutical composition comprising a 2.5-7.5% by weight of a solution of S(+)-flurbiprofen in ethanol containing 0.1-10% of a co-solvent such that the effective dose is in the range 0.5 to 10 mg per cm 2 of absorbent material in contact with the skin and wherein the absorbent material has a second surface, opposite the first, provided with an impermeable backing layer of polyethylene, and further wherein the absorbent material is sealed in an impermeable pouch. Preferably the backing layer is provided with pockets.

The invention is illustrated by way of example only in Figures 1-8.

WO 95/23596 PCT/EP95/00791 Fig.1 Fig.2 Fig.3 4 Fig.6 7 Fig.8 14 shows a plan view of a rectangular wipe with pockets; shows a cross-sectional view about the axis shown in Fig.l; show alternative shapes of wipes with pockets; shows a wipe in use; show examples of a wrap-around and product; shows a cross-section of a wrap around product.

Figure 2 shows a wipe comprising an absorbent layer with an impermeable backing layer provided with pockets for insertion of the thumb and fingers as shown in Figure Figure 8 shows a cross-section of a wrap-around product comprising an absorbent layer and an impermeable backing layer The invention is illustrated by the following nonlimitative Examples.

The NSAID's used in this invention are commercially available or may be prepared by known methods. For example racemic ibuprofen, racemic flurbiprofen, S(+)-ibuprofen and S(+)-flurbiprofen may be obtained from the Boots Company PLC. S(+)-Ibuprofen and flurbiprofen may also be obtained by resolving the racemic acids by methods known to those skilled in the art, for example using a-methylbenzylamine.

III III~ WO 95/23596 WO 9523596PCT/E P95/00791

COMPOSITIONS,

Com-Position 1

%W/W

S )-Flurbiprofen Benzyl Alcohol Cetostearyl Alcohol 2 Denatured Ethanol to 100% Composition 2

W/W

S(+)-Flurbiprof en Eenzyl Alcohol 2 Cetostearyl Alcohol 2 Denatured Ethanol to 100% Composition 3 w/w S )-Flurbiprof en Benzyl Alcohol Propylene Glycol 1 Denatured Ethanol to 100% Composition 4 w/w S -Flurbiprofen Propylene Glycol Benzyl Alcohol Ethanol to 100% WO 95/23596 PCT/EP95/00791 16 Composition w/w S(+)-Flurbiprofen Benzyl Alcohol Cetostearyl Alcohol 2 Ethanol to 100% The cetostearyl alcohol was dissolved in most of the ethanol. Benzyl alcohol was added to the mixture. The flurbiprofen was dissolved in the mixture. The mixture was made up to weight with ethanol.

Composition 6 w/w S(+)-Flurbiprofen Propylene Glycol Isopropyl Palmitate 3 Ethanol to 100% Composition 7 w/w S(+)-Flurbiprofen Polyvinylpyrrolidone (K30) 1 Isopropyl Myristate 3 Ethanol to 100% Composition 8 w/w S(+)-Flurbiprofen Polyvinylpyrrolidone (K30) Volatile Silicone Ethanol to 100%

ILI

WO 95/23596 WO 9523596PCTIEP95OO791 17 Composition 9

W/W

S -Flurbiprof en Propylene Glycol Benz yl Alcohol Ethanol to 100% CoMposition w/w S -Flurbiprof en Brij 92 3 Propylene Glycol Ethanol to 100% Composition 11 w/W S(+)-Flurbiprofen Polyvinylpyrrolidone (K90) 1 Ethanol to 100% Comp~osition 12 w/w S(+)-Flurbiprof en Polyvinylpyrrolidone (K90) 0.56 Ethanol to 100% Comosition 13 w/w S(+)-Flurbiprofen Polyvinylpyrrolidone (K90) 0.26 Ethanol to 100% WO 95123596 WO 9523596PCTE-P95J00791I 18 Composition 14 %w/w S -Flurbiprof en Polyvinylpyrrolidone (K(90) 0.1 Ethanol to 100% Composition w/w S )-Flurbiprof en Polyvinylpyrrolidone (K(30) 0.56 Ethanol to 100% The flurbiprof en and po lyvinylpyrrol idone were formed into a clear, amorphous, mass with some of the ethanol.

The mass was made up to weight with the remaining ethanol.

Composition 16 %W/w -Flurbiprofen Polyvinylpyrrolidone (K(30) 0.26 Ethanol to 100% Composition 17 W/w S -Flurbiprof en Polyvinylpyrrolidone (K(30) 0.1 Ethanol to 100% WO 95/23596 PCT/EP95/00791 19 Composition 18 w/w S(+)-Flurbiprofen Propylene Glycol Ethanol to 100% Composition 19 w/w S(+)-Flurbiprofen Isopropyl Palmitate Eucalyptus Oil 3 Benzyl Alcohol Brij 92 3 Ethanol to 100% Composition w/ S(+)-Flurbiprofen Benzyl Alcohol Isopropyl Palmitate Ethanol to 100% The flurbiprofen and isopropyl palmitate were mixed and agitated to form a suspension. Benzyl alcohol was added to dissolve most of the flurbiprofen. The mixture was made up to weight with the ethanol.

Composition 21 W/w S(+)-Flurbiprofen Benzyl Alcohol 3 Isopropyl Palmitate 56 Brij 92 3 Eucalyptus Oil 3 Ethanol to 100% L- I I L WO 95/23596 PCT/EP95/00791 20 The flurbiprofen and isopropyl palmitate were mixed and agitated to form a suspension. Benzyl alcohol and Brij 92 were added to completely dissolve the flurbiprofen, followed by the eucalyptus oil. The mixture was made up to weight with ethanol.

Composition 22 w/w S(+)-Flurbiprofen Klucel GF Propylene Glycol 2 Brij 92 1 Purified Water Ethanol to 100% The Brij 92, propylene glycol and ethanol were mixed.

Flurbiprofen was dissolved into the mixture. The Klucel was added and mixed until homogenous. The water was added slowly and stirred until a homogenous solution was obtained. Finally the solution was made up to weight with ethanol.

Composition 23 w/w S(+)-Flurbiprofen Benzyl Alcohol BP Eucalyptus Oil BP 3 Klucel GF 0.3 PVP 2 Dimethicone 1 Ethanol to 100% In Compositions 1-23 the ingredients were mixed together to form a solution, unless otherwise stated.

n WO 95/23596( PCT/EP95/00791 21 Additional Examples are prepared by replacing flurbiprofen by S(+)-ibuprofen, S(+)-ketoprofen, racemic flurbiprofen, racemic ibuprofen or racemic ketoprofen each of which may be present in amounts of 3%, 9% or 10% by weight. Similar amounts of S(+)-flurbiprofen may also be used.

Example 1 (Wipe) A circular piece of unwoven fabric which had a diameter of approximately 5 cm and a density of 80 g/m 2 was placed in a foil pouch open at one end. Composition 1 (1 ml) was added to the pouch and the pouch was sealed.

Example 2 (Wrap-Around) A paper tissue, in which the surface area of the side to be placed on a joint was 250 cm 2 and the density of the material was 23 g/m 2 was placed in a foil pouch open at one end. Composition 1 (2 ml) was added and the pouch was sealed.

A fabric suitable for use in the above formulations comprises non-woven wet-laid fabric composed of wood pulp/viscose fibres bonded with ethyl vinyl acetate binder having the following specification: Weight: 43 47 gsm Thickness: 200 240 microns Tensile Strength Dry MD 1200 1500 N/M (Newtons/Metre) CD 800 1100 N/M Wet MD 500 800 N/M CD 350 600 N/M 22 Stretch Dry MD 7 CD 8 13% Wet MD 12 CD 15 22% Absorption capacity.250 g/m 2 Sheet Size: 230 x 250 mm 5 mm J-folded Sheet Count: 20 nominal Other suitable fabrics include viscose (density g/m 2 chemically bonded viscose (density 40 g/m 2 a mixture of viscose and polyester (density 65 g/m 2 and polyester (density 171 g/m 2 SThroughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

o 0 i

Claims (5)

1. An adhesive-free topical pharmaceutical formulation comprising an absorbent material wherein the absorbent material is impregnated with a pharmaceutical composition comprising a solution of a non-steroidal anti-inflammatory drug in a C 2 -4 alcohol.

2. A formulation according to claim 1 wherein the non- steroidal anti-inflammatory drug is ibuprofen, ibuprofen, flurbiprofen, S(+)-flurbiprofen, 10 flurbiprofen, ketoprofen, S(+)-ketoprofen, piroxicam, or naproxen, including pharmaceutically acceptable salts of o each and comprises 0.1-25% by weight of the pharmaceutical composition. 1V 3. A formulation according to either claim 1 or claim 15 2 wherein the C 2 4 alcohol is selected from ethanol, propanol, isopropanol or n-butanol, isobLtanol, sec- butanol or tert-butanol and comprises 20-95% by weight of the pharmaceutical composition.

4. A formulation according to any previous claim wherein the pharmaceutical composition further comprises 0.01-90% by weight of a co-solvent selected from propylene glycol, benzyl alcohol, isopropyl palmitate, isopropyl myristate, or polyvinylpyrrolidone. A formulation according to claim 4 wherein the co- solvent is polyvinylpyrrolidone and comprises 0.01 to by weight of the pharmaceutical composition. WO 95/23596 PCTEP95/00791 24

6. A formulation according to claim 5 wherein the pharmaceutical composition comprises: 1-10% by weight of S(+)-flurbiprofen; 0.1-10% by weight of polyvinylpyrrolidone; and

80-98.9% by weight of ethanol. 7. A formulation according to claim 4 wherein the co- solvent is isopropyl palmitate and comprises greater than 50% by weight of the pharmaceutical composition. 8. A formulation according to claim 7 wherein the pharmaceutical composition comprises: 1-10% by weight of S(+)-flurbiprofen; 1-10% by weight of benzyl alcohol; 50-70% by weight of isopropyl palmitate; and 10-48% by weight of ethanol. 9. A formulation as claimed in claim 1 suitable for use as wipe having a first surface, to be placed in contact with the skin, with an area in the range of cri, wherein the absorbent material is impregnated with a pharmaceutical composition comprising 2.5-7.5% by weight of a solution of S(+)-flurbiprofen in ethanol containing 0.1-10% of a co-solvent such that the effective dose is in the range 0.5 to 10 mg per cm 2 of absorbent material in contact with the skin and wherein the absorbent material has a second surface, opposite the first, provided with an impermeable backing layer of polyethylene, and further wherein the absorbent material is sealed in an impermeable pouch. R 25 A formulation as claimed in claim 1 suitable for use as a wrap-around having a first surface, to be placed in contact with the skin, with an area in the range of 200-300 cm 2 wherein the absorbent material is impregnated with a pharmaceutical composition comprising a 2.5-7.5% by weight of a solution of S(+)-flurbiprofen in ethanol containing 0.1-10% of a co-solvent such that the effective dose is in the range 0.5 to 10 mg per cm 2 of absorbent material in contact with the skin and wherein the absorbent material has a second surface, opposite the first, provided with an impermeable backing layer of polyethylene, and further wherein the absorbent material is sealed in an impermeable pouch. I. 11. A formulation as claimed in claim 1 substantially as hereinbefore described with reference to the Examples. S* DATED this 16th day of December 1997 The Boots Company PLC by DAVIES COLLISON CAVE Patent Attorneys for the Applicants