Europaisches Patentamt s European Patent Office fin Publication number: 0 289 342 Office europeen des brevets A2

EUROPEAN PATENT APPLICATION

(5) Application number: 88303918.2 mt.ci.4: A 61 K 31/465 A 61 K 47/00, A 61 L 15/00 @ Date of filing: 29.04.88

© Priority: 01.05.87 IE 1119/87 17.07.87 IE 1946/87 Corish, John 49 Leopardstown Gardens (43) Date of publication of application: Leopardstown, Dublin 18 (IE) 02.11.88 Bulletin 88/44 Corrigan, Owen Ignatius 45 Evora Park @ Designated Contracting States: Howth County Dublin (IE) AT BE CH DE ES FR GB GR IT LI LU NL SE Geoghegan, Edward James Dunmhuire The Batteries © Applicant: ELAN TRANSDERMAL LIMITED Monksland Industrial Estate Athlone County Westmeath (IE) Athlone Westmeath County (IE) Masterson, Joseph G. Porterstown @ Inventor: Bannon, Yvonne Brigid Clonsilla Dublin 15 (IE) 35 Cherry Grove Kildare Naas County (IE) (74) Representative: Goldin, Douglas Michael et al J.A. KEMP & CO. 14, South Square Gray's Inn London WC1R5EU (GB)

@ Method for the treatment of withdrawal symptoms associated with smoking cessation and preparations for use in said method. (g) A preparation for the once-daily, percutaneous administra- tion of nicotine comprises nicotine uniformly distributed in a solid, semi-solid or mucilaginous medium which can be placed in intimate contact with the skin, the solid, semi-solid or mucilaginous medium is formed by adding a given amount of nicotine to a solution of a solidifying or gel-forming agent or mixture thereof in a suitable solvent or mixture of solvents and mixing or heating the mixture thereby obtained so as to form the solid, semi-solid or mucilaginous medium. CM The preparation can be used in a method of treating < withdrawal symptoms associated with smoking cessation and for combating the psychological dependence that occurs CM through frequent smoking. CO O) CO CM

Q_ LU

Bundesdruckerei Berlin 0 289 342 4 Description

METHOD FOR THE TREATMENT OF WITHDRAWAL SYMPTOMS ASSOCIATED WITH SMOKING CESSATION AND y PREPARATIONS FOR USE IN SAID METHOD

This invention relates to a method for the urge. Thus the objective for any smoking cessation treatment of withdrawal symptoms associated with 5 therapy involving nicotine administration would be smoking cessation with preparations containing the rapid attainment and maintenance of such nicotine and such preparations. plasma levels. Nicotine is the major alkaloid of tobacco and is the One of the approaches currently used in smoking most potent alkaloid in tobacco smoke. cessation therapy using nicotine is that employed by There is now strong evidence for regarding 10 a nicotine containing chewing gum sold under the smoking as a form of drug dependence, the drug, of Trade Mark NICORETTE. This gum contains a cation course, being nicotine. Measurements of the con- exchange resin containing 2 or 4 mg of nicotine. The centrations of nicotine, and its metabolite cotinine, in release rate of nicotine from this gum is dependent the blood of smokers have demonstrated the extent upon the duration and vigour of chewing. There can to which smoking is a drug taking activity. Rapid 15 be a considerable variation in absorption of nicotine absorption through the lungs enables the smoker to from gum depending upon how a person chews the get an intravenous-Iike shot of nicotine after each gum. To achieve adequate absorption of nicotine inhaled puff. By varying puff rate, puff volume and vigorous chewing is required. It has been reported depth of inhalation, smokers regulate their nicotine that normal chewing results in over 90% of nicotine intake and have literally finger-tip control over the 20 being released within 20 minutes. Thus the system concentrations of nicotine delivered to their brain. requires frequent administration by the smoker in an Nicotine has been shown to act as a primary attempt to maintain effective plasma levels and thus reinforcer in animals and many of its pharmacologi- curb the urge to smoke. The plasma levels achieved cal effects are potentially rewarding. It includes by the 2 mg gum fail to achieve the levels measured tolerances and smokers suffer from physical as well 25 after cigarette smoking and, therefore, the 4 mg gum as subjective effects when it is withdrawn. would be required by the smoker in most cases. Nicotine induces changes in the number of Because buccal absorption is pH dependent, a nicotinic cholinergic receptors and this is one buffer has been incorporated into the gum in an possible mechanism underlying tolerance. Besides attempt to maintain the buccal enviroment at its main direct action at nicotinic cholinergic recep- 30 constant pH. While it is intended that this buffer tor sites, through linkage of these sites with other maintain the pH in the mouth at approximately 8.5, neurotransmitter systems, nicotine has indirect there is no experimental data in the literature to effects on the release of most of the known support this conclusion. Such pH control is of neurotransmitters. Through its action on the locus considerable importance in relation to both the coeruleus it has a widespread effect on noradrener- 35 extent and variability of absorption of nicotine into gic activity throughout the brain. It also activates the bloodstream from this site of administration. ascending dopaminergic pathways thought to be Another feature of such oral nicotine administra- involved with the brainstem and hypothalamic re- tion is the susceptibility of the patient to gastrointes- ward systems. Its effect on dopaminergic activity tinal upsets. Also the poor taste qualities associated may link in with the lower incidence of Parkinson's 40 with oral nicotine administration makes such a Disease among cigarette smokers. Nicotine also method of smoking cessation unpopular with the stimulates cholinergic neurones in the nucleus patient and thus can lead to poor compliance, even basalis of Meynert which in turn project to all regions to the level of resumption of cigarette smoking. of the cortex. This and similar actions on nerve cells A major problem in maintaining continuous effec- in the septum, which project to the hippocampus, 45 tive therapeutic levels of nicotine in the bloodstream may be involved in the effect of nicotine on memory with the nicotine gum is the inability to self-adminis- processes and suggest that nicotine may be of ter during the time the patient is asleep, thus leading potential value in enhancing performance in people to low or even zero levels of nicotine in the morning with early Alzheimer's Disease. Nicotine also influen- and a return of the smoking urge. Even with ces serotonergic systems. 50 immediate administration of the nicotine gum, it can By smoking a cigarette, the smoker receives an take up to one hour before effective plasma levels of initial burst of nicotine into the bloodstream, which nicotine are again attained. then rapidly declines. The urge to smoke increases Additionally, the mode of administration of the as the nicotine level continues to fall below a given gum, in that it involves frequent dosage and point in the blood level, a point which can vary with 55 chewing, is a practice which is widely regarded as each smoker. However, it has been shown that the being socially unacceptable. Generally, gum will normal plasma trough level associated with usual have to be chewed at the same frequency as the smoking is approximately 5-15 ng/ml within one person's smoking pattern and usually every hour to hour of first smoking. At the time of smoking the achieve adequate plasma levels of nicotine. With plasma level is between 15 ng/ml and 30 ng/ml and 60 gum there is no assistance in breaking the smoking the natural urge to smoke is thereby suppressed. habit. When nicotine levels fall to a level of 15 ng/ml or less, Another aspect of oral nicotine administration in nicotine intake is required to suppress the smoking the gum form, is that there is now a suggestion of 0 289 342

the chance of contracting cancer of the mouth and mixture thereby obtained so as to form said solid, I" throat, as a result of frequent chewing of resin based semi-solid or mucilaginous medium. nicotine containing gum. Mouth ulcers have also The term solidifying agent as used herein also been observed in persons chewing nicotine gum. embraces thickening, hardening, setting, suspend- Another development has been the introduction 5 ing or like agents. of low-nicotine cigarettes. However, again with such Suitable materials for use as the solidifying or low-nicotine cigarettes there is no breaking of the gel-forming agent according to the invention in- smoking habit. clude, for example, plant extracts, vegetable oils, In a study by Jed E. Rose et al reported in Clin. gums, synthetic or natural polysaccharides, poly- Pharmacol. Ther. October 1985 a 30% aqueous 10 peptides, alginates, hydrocarbons, synthetic poly- solution of nicotine base was applied to intact skin mers, minerals and silicon compounds and mixtures under an opaque polyethylene patch. The purpose of thereof. the patch was to prevent subjects observing any Suitable plant extracts include agar, ispaghula, changes in skin colour such as redness. With such a psyllium, cydonia and ceratonia or a mixture thereof. solution immediate release of nicotine was ob- 15 A suitable vegetable oil is hydrogenated castor oil. served. However, painting on of a nicotine solution Examples of suitable gums include guar gum, as described by Jed E. Rose et al would not be acacia gum, ghatti gum, karaya gum and tragacanth socially acceptable. gum or a mixture thereof. Nicotine is known to show a high degree of Suitable synthetic and natural polysaccharides absorption by the percutaneous route. A method for 20 include alkylcelluloses, hydroxyalkylcelluloses, cellu- the percutaneous or transdermal administration of lose ethers, cellulose esters, nitro celluloses, dex- nicotine is known from U.S. Patent Specification trin, agar, carrageenan, pectin, furcellaran and No. 4,597,961. However, nicotine has not heretofore starch or starch derivatives and mixtures thereof. An been used commercially by the percutaneous or example of a preferred starch derivative is sodium transdermal route in a method of smoking cessation 25 starch glycolate. Especially preferred polysac- therapy. Various devices for the percutaneous or charides include agar and carrageenan. transdermal administration of nicotine are disclosed Suitable polypeptides include zein, gelatin, col- in U.S. Patent Specification No. 4,597,961. However, lagen and polygeline or a mixture thereof. these are clearly not commercial devices. U.S. Suitable alginates include alginic acid, propylene Patent Specification No. 4,597,961 refers to a dose 30 glycol alginate and sodium alginate or a mixture range of nicotine of 15 to 25 ng/l or 15 to 25 thereof. picograms/ml. However, as indicated above trough Preferred hydrocarbons include soft paraffin and plasma levels of nicotine are in the range 5-15 ng/ml hard paraffin, especially white petrolatum. and levels at the time of smoking rise to 15-30 ng/ml. An especially preferred synthetic polymer is a The transcutaneous devices disclosed in U.S. 35 carboxyvinyl polymer sold under the Trade Mark Patent Specification No. 4,597,961 have substantial CARBOMER. thickness viz 2 cm and hence are rather bulky. It is Suitable minerals include bentonite, hectorite, stated the onset of nicotine activity is in the range of aluminium magnesium silicate and magnesium sili- 1-2 minutes with a duration of action of from 30-45 cate or a mixture thereof. minutes. Hence, the device would have to be 40 Suitable compounds based on silicon include frequently applied, for example, hourly and even then colloidal silicon dioxide, silicones, polysiloxanes and it is doubtful whether adequate levels of nicotine silica gels or a mixture thereof. would be achieved having regard to the specified The term "agar" is used throughout the Specifica- dosage of 15 to 25 ng/l. tion and is synonymous with "agar-agar". It is an object of the present invention to provide a 45 The solvent used is preferably water. However, the method of administering nicotine in smoking cessa- solvent used may also suitably be an alcohol such as tion therapy, which on single daily application ethanol or stearyl alcohol, glycerol, propylene glycol, reproduces those plasma nicotine levels observed in polyethylene glycol or silicone or a mixture thereof, habitual smokers in a manner which decreases or including a mixture with water. eradicates nicotine dependence in humans, thus 50 The preparation when in the form of a solid or concomitantly leading to an eradication of the semi-solid preferably has a surface area in the harmful and undesirable health and social effects of range 2 to 15 cm2, more especially 5 to 10 cm2. smoking. It is also an object of the invention to The thickness of the preparation is in the range 0.5 provide a method and a preparation which will assist to 3 mm, more especially in the range 1 to 2 mm. in breaking the smoking habit. 55 The preparation according to the invention prefer- According to the invention there is provided a ably contains from 5 to 100 mg of nicotine or more preparation for the once-daily percutaneous admin- especially 10 to 50 mg of nicotine. istration of nicotine which comprises nicotine uni- The preparation according to the invention may formly distributed in a solid, semi-solid or mucilagin- also include an antimicrobial agent or a preservative. ous medium which can be placed in intimate contact 60 Suitable antimicrobial agents/preservatives include with the skin, said solid, semi-solid or mucilaginous benzalkonium chloride, cetrimide (cetyltrimethylam- medium being formed by adding a given amount of monium bromide), benzoic acid, benzyl alcohol, nicotine to a solution of a solidifying or gel-forming Parabens (Trade Mark for the methyl-, ethyl-, propyl- agent or mixture thereof in a suitable solvent or and butyl-esters of para-hydroxybenzoic acid) chlor- mixture of solvents and mixing or heating the 65 hexidine, chlorobutanol, phenylmercuric acetate, 0289 342 6 borate and nitrate, potassium sorbate, sodiumi a) The amount of nicotine in the preparation. benzoate, sorbic acid and thiomersal (mercurithio- b) The surface area of the preparation. salicylate) or a mixture thereof. As it is the skin itself that forms the rate t The preparation according to the invention may/ controlling barrier and not the dosage form compris- also include an antioxidant. Preferred antioxidants3 5 ing the preparation, the effect of nicotine loading will include sodium metabisulphite, butylated hydrox- only be observed in terms of systemic nicotine levels yanisole and butylated hydroxytoluene or a mixture3 below a threshold loading level. thereof. Below this threshold the amount of nicotine in the The preparation according to the invention may/ dosage form is the factor which determines the also include a pH-controlling agent. Preferred pH- 10 concentration gradient that in turn controls the rate controlling agents include citric acid and sodiumi of absorption. Above this threshold increasing drug citrate. loading has no effect on absorption as the ability of The preparation according to the invention may/ the skin to absorb nicotine is saturated. However, also include a plasticizer. Suitable plasticizers3 such drug loading does have the effect of prolonging include diethylphthalate, dibutylphthalate and tribu- 15 the time course of drug delivery by providing a larger tylcitrate or a mixture thereof. drug depot. In order to increase the extent of The preparation according to the invention may/ absorption above the threshold it is necessary to also include a surfactant. Suitable surfactants in- increase the area of absorption by increasing the clude sodium lauryl sulphate, diethylene glycolI surface area of the dosage form so that a larger area monostearate, propylene glycol monostearate, 20 of the skin is in contact with the nicotine. The effect polyethylene glycols as sold under the Trade Markc of changing the surface area for example at 4, 6, 8 MACROGOL, polysorbates and polyvinyl alcohol orr and 1 2 cm2 can be seen hereinafter in the Examples. a mixture thereof. The preparation according to the invention can be The preparation according to the invention mayI presented in a number of devices and dosage forms also include a penetration enhancer. Suitable pene- 25 for the percutaneous administration of nicotine. tration enhancers include dimethylsulphoxide, N,N- These devices and dosage forms may contain a dimethylacetamide, N.N-dimethylformamide, nicotine impermeable layer so as to cause unidirec- 2-pyrrolidone, N-methyl-2-pyrrolidone and 1-dodecylI tional administration of nicotine through the skin azacyclo-heptan-2-one or a mixture thereof. from the surface of the preparation in the device or The preparation according to the invention mayI 30 dosage form exposed to the skin. Such devices and also include a humectant. A particularly preferredi dosage forms include, but are not limited to, a device humectant is glycerol for use in a high humidityI known under name PANODERM and which is the environment. As indicated above glycerol may also) subject of our EP-A-0 117 027, a device known be used as a solvent in forming the preparation) under the name DERMAFLEX and which is the according to the invention and when used as suchi 35 subject of our EP-B-0 113 562, self adhesive will confer humectant properties on the preparation. patches, bandages and plasters, creams, gels, Further the preparation according to the inventioni jellies, mucilages, ointments and pastes. The term may also include a local anaesthetic. Suitable localI mucilaginous medium as used herein embraces anaesthetics include lidocaine, benzocaine, ligno- creams, gels, jellies, ointments and pastes. caine, methocaine, butylaminobenzoate and pro- 40 The preparation according to the invention may be caine or a mixture thereof. The preparation would1 adapted for reception in a receptacle of a device include a local anaesthetic mainly to suppress; which can be held in contact with the skin. irritation at the site of application thereof. Means for securing transdermal patches to the Additionally, the preparation according to the! body include, apart from adhesive means, straps, invention may include a rubefacient. Particularlyf 45 bracelets and like securing devices. preferred rubifacients include camphor and mentholI The present invention is also designed to provide, or a mixture thereof and other locally actingI through percutaneous administration by way of the peripheral vasodilators. said devices and dosage forms, a highly cosmetically The preparation according to the invention is> and aesthetically acceptable method of easily and preferably applied to the flexor surface of thei 50 discreetly administering nicotine in assisting the forearm, including the wrist, and also the ankle. Suchi smoker to overcome the smoking habit. sites of application show the greatest consistencyi With the present invention, it is possible to affix from individual to individual in terms of nicotines one of the said devices or dosage forms to the skin, absorption relative to other sites for administrationi so as to provide constant absorption of nicotine because of the amount of tissue at such sites. BloodI 55 through the skin directly into the bloodstream, vessels are found close to the surface of the skin att maintaining regular levels of nicotine in the blood. such sites which facilitates the uptake of nicotine: Therefore, the need to smoke a cigarette to obtain into the systemic circulation. nicotine is eliminated, thereby eliminating ingestion On contact of the preparation according to thei of smoke and tar and thus breaking the smoking invention with the skin, the nicotine starts to migratei 60 habit. The fact that this can be achieved with a rapidly from the preparation to the humid interface att device or dosage form which is administered only the point of contact and then through the skin andI once every 24 hours provides for an additional aid to into the bloodstream. The rate and extent of this; smoking cessation therapy in that it assists the percutaneous absorption is dependent on severalI smoker to overcome the psychological dependency factors including: 65 associated with the habit of smoking on a frequent 0 289 342 8

basis. Commercially available products such as manufacture of a medicament for use in the r nicotine containing gum need to be administered on once-daily, percutaneous administration of nicotine a frequent basis, (practically every hour), throughout in a method for the treatment of withdrawal the course of any one day. This is a direct symptoms associated with smoking cessation and in substitution for a similar smoking regimen and while, 5 which the nicotine is administered in an amount to a certain degree, the gum provides replacement sufficient to maintain plasma levels of nicotine plasma nicotine levels, it also serves to maintain the substantially equivalent to trough plasma levels habit of frequent administration which can itself lead resulting from intermittent smoking. to a psychological dependence on the gum, thus The invention also provides a method of treating rendering it even more difficult for the smoker to 10 withdrawal symptoms associated with smoking overcome the pharmacological and physiological cessation, which method comprises administering dependence effects of nicotine. The present inven- once-daily, percutaneously to a person an amount of tion thus tackles both the physiological and psycho- nicotine sufficient to maintain in said person plasma logical dependency parameters associated with levels of nicotine substantially equivalent to trough smoking. By employing a succession of lower . 15 plasma levels resulting from intermittent smoking. strengths of nicotine over several weeks or months, Preferably, the amount of nicotine administered is the nicotine level in the blood is gradually lowered, sufficient to achieve a plasma nicotine concentration thus reducing nicotine dependency. As the skin is in excess of 2 ng/ml, more especially 5 ng/ml, the rate controlling membrane in nicotine absorp- within 1 hour after administration. tion, it is also possible in accordance with the 20 Also the amount of nicotine administered is invention, by varying the concentration of nicotine in preferably sufficient to achieve a plasma nicotine said devices and dosage forms, and furthermore by concentration in the range 2 to 100 ng/ml, more varying the surface area of the nicotine containing especially 5 to 30 ng/1 , over a period of from 1 to 24 portion of the said devices and dosage forms hours. directly in contact with the skin, to adjust the extent 25 Further, preferably, the amount of nicotine admin- of absorption of the nicotine and thereby mimic istered is progessively lowered over a period of time, blood levels associated with virtually any level of such that the plasma level of nicotine is gradually smoking and achieve such levels over a 24 hour lowered, thereby reducing nicotine dependency. period with a single administration. This allows the The invention also provides use of nicotine for the smoker to effectively titrate the dosage in line with 30 manufacture of a medicament for use in the the extent of the smoking habit and/or urge. once-daily, percutaneous administration of nicotine In some individuals, it may be desirable to remove in a method for combating the psychological the device or dosage form which is affixed to the dependence that occurs through frequent smoking skin, in the evening before retiring to bed, and in and in which the nicotine is administered in an these cases, appreciable morning trough levels of 35 amount sufficient to maintain plasma levels of plasma nicotine in the range of 5 to 12 ng/ml are nicotine substantially equivalent to trough plasma achieved. This ability to sustain residual plasma levels resulting from intermittent smoking. levels of nicotine for 8-10 hours after the device or The invention also provides a method for combat- dosage form has been removed from contact with ing the psychological dependence that occurs the skin is another unique feature of the present 40 through frequent smoking, which method comprises invention. administering once-daily, percutaneously to a per- In certain cases such as: when the smoker is son an amount of nicotine sufficient to maintain in applying the preparation according to the invention said person plasma levels of nicotine substantially in the said device or dosage form for the first time or, equivalent to trough plasma levels resulting from when the individual is applying another dose after 45 intermittent smoking. having detached the previous one some hours Preferably, the amount of nicotine administered is previously or, when an individual who has a particu- sufficient to achieve a plasma nicotine concentration larly high nicotine requirement is replacing the in excess of 2 ng/ml, more especially 5 ng/m1, existing dose, an initial 'burst' or priming dose of within 1 hour after administration. nicotine may be required to achieve rapid effective 50 Also the amount of nicotine administered is plasma levels to curb the nicotine craving or preferably sufficient to achieve a plasma nicotine smoking urge. Such can be supplied by applying a concentration in the range 2 to 100 ng/ml, more device or dosage form in which an amount of especially 5 to 30 ng/ml, over a period of from 1 to 24 nicotine is included in a layer of adhesive which is hours. used to affix the said device or dosage form to the 55 Further, preferably, the amount of nicotine admin- skin. Such a priming dose of nicotine may be istered is progressively lowered over a period of included in a layer of adhesive material defining the time, such that the plasma level of nicotine is skin contacting surface of the preparation and which gradually lowered, thereby reducing nicotine de- layer is freely permeable to the nicotine contained in pendency. the solid, semi-solid or mucilaginous agar medium of 60 In order to form the preparation according to the said preparation. Alternatively, the priming dose of invention the thickening, hardening, setting, gelling, nicotine may be included in a peripheral layer of suspending or solidifying agent or a mixture of such adhesive defining part of the skin-contacting surface agents is added to the solvent(s) at a concentration of the preparation. that will result in a suitably mucilaginous, semi-solid The invention also provides use of nicotine for the 65 or solid mass. The mixture is mixed and/or heated, 9 0 289 342 10 depending on the agent used, so as to produce a Q7-2218) Part B was then added and the mixture uniform medium. The nicotine is added to produce a was further agitated to ensure uniformity. The concentration suitably in the range 0.5% to 25%, mixture was cured overnight to ensure proper gel and preferably in the range 1% to 10%. Any other formation. 0.6 g portions of the gel, equivalent to 20 inactive ingredients and additional ingredients as mg of nicotine, were weighed into a preformed hereinbefore specified are now added and the entire circular device, sold under the Trade Mark PAN- mixture is mixed to uniformity. This mixture is now ODERM of internal diameter 3.2 cm giving a surface used to form the final dosage form which may be any area of 8 cm2. of the following: The plasma nicotine levels for the above Example a) a solid or semi-solid disc or patch formed 10 ranged from about 12 ng/ml to about 22 ng/ml over a by moulding, cutting, punching or slicing of the 24 hour period. mixture. b) a cream. Example 4 c) a mucilage. To 100 g of water was added 10 g of powdered d) a gel. 15 gelatin and 10 g of dextrin. The mixture was heated e) a paste. to boiling. While mixing, the following were also f) a jelly. added, 0.01 g of benzalkonium chloride, 0.1 g of g) an ointment. sodium metabisulphite, 4.8 g of nicotine. The hot The dosage form may now be incorporated into liquid was poured onto glass plates as described in any suitable device for attachment to the skin as 20 Example 1 . After setting the gel was cut into discs indicated above. 0.95 mm thick and 3.2 cm in diameter, each weighing The invention will be further illustrated by the 0.65 g with a surface area of 8 cm2 and each following Examples. containing 25 mg of nicotine. The above-prepared discs yielded plasma nicotine Example 1 25 levels ranging from about 15 ng/ml to about 25 ng/ml To 20 g of water was added 0.5 g of carrageenan. over 24 hours. This mixture was heated to boiling and then allowed to cool gradually. While still in its liquid state 1 .04 g of Example 5 nicotine was added and the mixture was agitated to A product was made as per Example 1 with 0.05 g ensure uniformity. The liquid mixture was then 30 of methylparaben added to the hot water/carragee- poured onto several 20 cm x 20 cm glass plates nan mixture. equipped with TEFLON (TEFLON is a Trade Mark) dividers approximately 0.75 mm in height. A second Example 6 similar glass plate was placed over the liquid 50 g of stearyl alcohol and 50 g of white petrolatum supported by the TEFLON dividers. The liquid was 35 were melted by heating to 75° C. 0.05 g of methyl- allowed to cool to room temperature and solidified paraben, 0.3 g of propylparaben, 2 g of sodium lauryl into a sheet of uniform thickness, (approximately sulphate, 24 g of propylene glycol and 8 g of nicotine 0.75 mm). The sheet was then cut into square were dissolved in 84 g of water. The aqueous patches 2 cm x 2 cm, each weighing approximately solution was heated to 75° C and added to the 0.3 g with a surface area of 4 cm2 and each 40 melted stearyl alcohol/ petrolatum mixture. The containing 15 mg of nicotine. The patches were entire mixture was allowed to cool with constant wrapped in aluminium foil to prevent dehydration. stirring and congealed into a uniform cream. 0.5 g In-vivo studies established that plasma nicotine portions of the cream, equivalent to 20 mg of levels over a 24 hour period following the application nicotine, were weighed into circular transdermal of a single patch prepared according to the above 45 delivery devices sold under the Trade Mark PAN- Example ranged from about 7 ng/ml to about 15 ODERM of internal diameter 2.75 cm giving a surface ng/ml. area of 6 cm2. The plasma nicotine levels for this cream ranged Example 2 from about 21 ng/ml to about 33 ng/ml over 24 Patches were prepared as per Example 1, except 50 hours. that 0.693 g of nicotine was added to the water/car- rageenan mixture and the sheet was cut into circular Example 7 discs (0.75 mm thick) of diameter 3.2 cm, each A product was made as per Example 1 except that weighing approximately 0.6 g, with a surface area 1 .4 g of nicotine was added to the water/carragee- of 8 cm2 and each containing 20 mg of nicotine. 55 nan mixture and the patch was cut into rectangular The plasma nicotine levels for the above-prepared patches measuring 3x4 cm, each weighing 0.9 g disc ranged from about 12 ng/ml to about 24 ng/ml with a surface area of 12 cm2. over a 24 hour period. The plasma nicotine levels for this patch ranged from about 8 ng/ml to about 16 ng/ml over 24 hours. Example 3 60 To 50 g of Silicone Gel (Dow Corning Q7-2218) Example 8 Part A was added 25 g of a 2o% solution of nicotine To 20 g of water was added 0.8 g of agar. This in water, 5 g camphor, 2.5 g of dimethylsulphoxide mixture was heated and allowed to cool gradually, and 2.5 g of glycerol. The ingredients were mixed to while still in its liquid state 0.6664 ml of nicotine was uniformity. 65 g of Silicone Gel (Dow Corning 65 added and the mixture was agitated to ensure 11 0 289 342 12 t uniformity. The liquid mixture was then poured onto by 1 cm of aluminium foil. The disc so prepared was several 20 cm x 20 cm glass plates equipped with then sealed by a coated foil circular seal edged by 1 TEFLON (TEFLON is a Trade Mark) dividers approxi- cm of adhesive. On removal of the seal the disc mately 1.31 mm in height. A second similar glass selectively adhered to the adhesive side of the plate was placed over the liquid supported by the 5 device and the aluminium die in which the disc was TEFLON dividers. The liquid was allowed to cool to formed was discarded. The device so prepared room temperature and solidified into a sheet of provides excellent skin contact in use. uniform thickness (approximately 1.31 mm in thick- ness). The sheet was then cut into discs, each Example 12 weighing approximately 0.76 g with a surface area of 10 A device was prepared as in Example 9 with 0.05 g 5.3 cm2 and each containing 25 mg of nicotine. The of methylparaben added to the hot water: agar patches were wrapped in aluminium foil to prevent mixture. dehydration. Over a 24 hour period, the above-prepared disc Example 13 produced plasma nicotine levels ranging from 15 A device was prepared as in Example 10 with a about 8 ng/ml to about 26 ng/ml. 15:5 (w/w) mixture of water: PEG (polyethylene glycol) 400 in place of water and glycerol. Example 9 To 20 g of water was added 0.8 g of agar. This Example 14 mixture was heated and allowed to cool gradually, 20 A device was prepared as in Example 9 having a while still in its liquid state 0.6664 ml of nicotine was nicotine concentration of 25 mg/g with a surface added and the liquid agitated to ensure uniformity. area of 7.64 cm2 and thickness of 1.31 mm. The mixture, while still in the liquid state, was then poured into a formed coated aluminium die resulting Example 15 in a disc of gel of 1.31 mm in thickness and surface 25 500 g of water was heated to boiling. 25 g of area of 5.3 cm2 following solidification and edged carrageenan was added and the mixture was boiled around the circumference by 1 cm of aluminium foil. for approximately 5-10 minutes. The solution was The disc so prepared was then sealed by a coated allowed to cool to between 50 and 60° C. 33 g of foil circular seal edged by 1 cm of adhesive. On nicotine was added and allowed to dissolve. The removal of the seal the disc selectively adhered to 30 solution was diluted to 1,000 g with water. The the adhesive side of the device, and the aluminium mixture while still in its liquid state was poured die in which the disc was formed was discarded. The (0.9091 g) into a formed coated aluminium die. The device so prepared provides excellent skin contact resulting solidified disc had a thickness of 1.30 mm, in use. a surface area of 7.0 cm2 and contained 30 mg of 35 nicotine. The formed disc was sealed by a circle of Example 10 aluminium coated with an impervious membrane and To a 20 g 15:5 (w/w) mixture of water and glycerol a coat of gelatin. On removal of the seal, the disc was added 0.8 g of agar. This mixture was heated selectively adhered to the gelatin side of the and allowed to cool gradually. While still in its liquid aluminium seal. Adhesive tape was used to secure form 0.6664 ml of nicotine was added and the liquid 40 the disc to the skin. The disc so prepared produces agitated to ensure uniformity. The mixture while still plasma nicotine levels ranging from about 3 ng/ml to in the liquid state, was poured into a formed coated about 16 ng/ml over a 24 hour period. aluminium die resulting in a disc of gel of 1.31 mm in thickness and surface area of 5.3 cm2 upon In-Vivo Studies solidification and edged around the circumference 45 All of the foregoing in-vivo studies were per- by 1 cm of aluminium foil. The disc so prepared was formed in healthy habitually smoking volunteers who then sealed by a coated foil circular seal edged by I had abstained from smoking for 36 hours before the cm of adhesive. On removal of the seal the disc study and for the duration of the study itself. The selectively adhered to the adhesive side of the study site was a non-smoking environment which device and the aluminium die in which the disc was 50 was nicotine free. The subjects were not permitted formed was discarded. The device so prepared to consume tea, coffee or Cola during the study. The provides excellent skin contact in use and produces average number of volunteers for the various studies plasma nicotine levels ranging from about 11 ng/ml was six. Pre-study physical examinations and elec- to about 34 ng/ml over 24 hours. trocardiogram (ECG) were normal and pre and post 55 study haematology, blood biochemistry and urina- Example 11 lysis were also normal in all subjects. Blood samples To a 20 g 90:10 (w/w) water: ethanol mixture was (10 ml) were obtained at 0 hours immediately before added 0.8 g agar. This mixture was heated and the dosage form was applied onto the skin and at allowed to cool gradually, while still in its liquid form specific times thereafter. Plasma was obtained by 0.6664 ml of nicotine was added and the mixture 60 centrifugation of the blood samples at 2°C and agitated to ensure uniformity. The mixture while still plasma nicotine levels were measured by a capillary in the liquid state was poured into a formed coated gas chromatography method. The Examples tested aluminium die resulting in a disc of gel of 1.31 mm in above demonstrate plasma nicotine levels which thickness and surface area of 5.3 cm2 upon simulate those obtained with usual smoking. solidification and edged around the circumference 65 The discs prepared according to Example 15 were 13 0 289 342 14 1 evaluated in a quit-rate study. When compared to antioxidant, a pH-controlling agent, a plas- subjects receiving placebo patches, the application ticizer, a surfactant, a penetration enhancer, a of the nicotine-containing patches resulted in a humectant, a local anaesthetic, or a mbefacient positive reduction in cigarette smoking. or a mixture thereof. it is a unique feature of the present invention that 9. A preparation according to any preceding the development and evaluation of the in-vivo claim, characterised in that it includes a priming performance of the system or systems is based dose of nicotine a) in a layer of adhesive solely on studies in human volunteers. This con- material defining the skin-contacting surface of trasts with the use of animal models commonly the preparation and which layer is freely employed by other investigators in the area of 10 permeable to the nicotine contained in the solid, transdermal drug delivery, particularly in the light of semi-solid or mucilaginous medium, or b) in a the marked differences in dermal and transdermal peripheral layer of adhesive material defining absorption and pharmacokinetic characteristics bet- part of the skin-contacting surface of the ween human and animal models. preparation. 15 10. A process for the manufacture of a preparation according to any one of Claims 1 to 8, characterised in that it comprises adding a Claims given amount of nicotine to a solution of a solidifying or gel-forming agent or mixture 20 thereof in a suitable solvent or mixture of 1 . A preparation for the once-daily, percuta- solvents and mixing or heating the mixture neous administration of nicotine which com- thereby obtained so as to form said solid, prises nicotine uniformly distributed in a solid, semi-solid or mucilaginous medium. semi-solid or mucilaginous medium which can 11. Use of nicotine for the manufacture of a be placed in intimate contact with the skin, said 25 medicament for use in the once-daily, percuta- solid, semi-solid or mucilaginous medium being neous administration of nicotine in a method for formed by adding a given amount of nicotine to the treatment of withdrawal symptoms associ- a solution of a solidifying or gel-forming agent ated with smoking cessation and in whiGh the or mixture thereof in a suitable solvent or nicotine is administered in an amount sufficient mixture of solvents and mixing or heating the 30 to maintain plasma levels of nicotine substan- mixture thereby obtained so as to form said tially equivalent to trough plasma levels result- solid, semi-solid or mucilaginous medium. ing from intermittent smoking. 2. A preparation according to Claim 1, 12. A method of treating withdrawal symptoms characterised in that the solvent used is associated with smoking cessation, which selected from water, an alcohol such as ethanol 35 method comprises administering once-daily, or stearyl alcohol, glycerol, ethylene glycol, percutaneously to a person an amount of propylene glycol, silicone, or a mixture thereof. nicotine sufficient to maintain in said person 3. A preparation according to Claim 1 or 2, plasma levels of nicotine substantially equival- characterised in that it is in the form of a solid or ent to trough plasma levels resulting from semi-solid and has a surface area in the range 2 40 intermittent smoking. to 15 cm2, more especially 5 to 10 cm2 and a 13. Use of nicotine for the manufacture of a thickness in the range 0.5 to 3 mm, more medicament for use in the once-daily, percuta- especially 1 to 2 mm. . neous administration of nicotine in a method for 4. A preparation according to Claim 1 or 2, combating the psychological dependence that characterised in that it is in the form of a cream, 45 occurs through frequent smoking and in which gel, jelly, mucilage, ointment or paste. the nicotine is administered in an amount 5. A preparation according to any preceding sufficient to maintain plasma levels of nicotine claim, characterised in that the solidifying or substantially equivalent to trough plasma levels gel-forming agent is selected from plant ex- resulting from intermittant smoking. tracts, vegetable oils, gums, synthetic or natural 50 14. A method for combating the psychological polysaccharides, polypeptides, alginates, hy- dependence that occurs through frequent drocarbons, synthetic polymers, minerals and smoking, which method comprises administer- silicon compounds or a mixture thereof. ing once-daily, percutaneously to a person an 6. A preparation according to Claim 5, amount of nicotine sufficient to maintain in said characterised in that the solidifying or gel-for- 55 person plasma levels of nicotine substantially ming agent is agar or carrageenan, or a mixture equivalent to trough plasma levels resulting thereof. from intermittent smoking. 7. A preparation according to any preceding claim, characterised in that it contains from 5 to 100 mg, more especially from 10 to 50 mg of 60 nicotine. 8. A preparation according to any preceding claim, characterised in that it additionally con- tains one or more components selected from an anti-microbial agent or a preservative, an 65