United States Patent [19]
`Etscorn (cid:9)
`
`[11] Patent Number: (cid:9)
`[45] Date of Patent: (cid:9)
`
`4,597,961
`Jul. 1, 1986
`
`[54] TRANSCUTANEOUS APPLICATION OF
`NICOTINE
`
`[76] Inventor: Frank T. Etscorn, 121 Stallion Cir.,
`Socorro, N. Mex. 87801
`
`[21] Appl. No.: 694,047
`
`[22] Filed: (cid:9)
`
`Jan, 23, 1985
`
`[51] Int. C1.4 (cid:9)
`[52] U.S. CI. (cid:9)
`
`[58] Field of Search (cid:9)
`
` A61K 9/70; A61K 31/465
` 424/28; 514/314;
`514/813
`424/14, 28; 514/343,
`514/813
`
`[56] (cid:9)
`
`References Cited
`U.S. PATENT DOCUMENTS
`1,775,998 9/1930 Greenberg (cid:9)
`3,598,122 8/1971 Zaffaroni (cid:9)
`3,598,123 8/1971 Zaffaroni (cid:9)
`3,731,683 5/1973 Zaffaroni (cid:9)
`3,742,951 7/1973 Zaffaroni (cid:9)
`3,948,254 4/1976 Zaffaroni (cid:9)
`4,292,299 9/1981 Suzuki et al. (cid:9)
`
` 604/304
` 604/304
` 604/304
` 424/28
`424/28
` 604/57
` 424/28
`
`OTHER PUBLICATIONS
`The Merck Index-Tenth Edition, 1983, Published by
`Merck & Co., Inc. Rahway, N.J., U.S.A., p. 935.
`Drug Alcohol Dependence, 13 (1984), pp. 209-213
`Elsevier Scientific Publishers Ireland Ltd.
`
`Primary Examiner—Ronald W. Griffin
`Attorney, Agent, or Firm—Browdy & Neimark
`[57] (cid:9)
`ABSTRACT
`Percutaneous administration of nicotine in a dose ap-
`proximating the dose delivered by a variety of nicotine-
`containing products, such as cigarettes, cigars, snuff and
`chewing tobacco, is carried out using an occlusive pad.
`The nicotine is delivered so as to mimic the pharmaco-
`logical effects of nicotine provided by the conventional
`use of tobacco, and a therapeutic function is achieved
`by reducing or eliminating the need for the tobacco
`product. A suitable transdermal application pad com-
`prises a reservoir for liquid nicotine base to be affixed to
`the skin in a variety of places. Due to the high lipid
`solubility and resultant high skin permeability of nico-
`tine, vehicles or solvents are not generally needed to
`enhance dermal absorption.
`
`19 Claims, 2 Drawing Figures
`
`10
`
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`20 (cid:9)
`
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`
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`
`U.S. Patent (cid:9)
`
`Jul. 1, 1986 (cid:9)
`
`4,597,961
`
`./.
`
`20 (cid:9)
`
`10
`
`14
`
`16 (cid:9)
`"Ave'i //AWL"
`
`12
`
`18
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`FIG.I
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`114
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`118' (cid:9)
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`
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`
`TRANSCUTANEOUS APPLICATION OF
`NICOTINE
`
`FIELD OF THE INVENTION (cid:9)
`The present invention relates to the cutaneous admin-
`istration of nicotine, and more especially to a new
`method of administering nicotine through the skin using
`a transdermal delivery system, especially for the pur-
`pose of satisfying a nicotine habit while minimizing or
`eliminating side effects caused by absorbing tobacco
`constituents through the lungs along with products of
`combustion of tobacco.
`
`5
`
`10
`
`15
`
`35
`
`BACKGROUND OF THE INVENTION (cid:9)
`The health hazards from tobacco smoking are well
`established. Of the approximately 4,000 by-products of
`combustion found in cigarette smoke, many of which
`are known carcinogens, the three substances studied
`most have been tars, carbon monoxide and nicotine. 20
`Tars and carbon monoxide hae been directly implicated
`in the production or exacerbation of numerous health
`disorders.
`Thus, tars are the causitive agents in cigarette smoke
`most implicated in the induction of such cancers as 25
`lung, larynx, oral cavity, esophageal, bladder, kidney,
`pancreatic stomach, and uterine and cervix cancers.
`Tars are also considered responsible for the induction of
`the hepatic microsomal ensyme systems which result in
`more rapid deactivation of a variety of drugs such as 30
`benzodiazepines as well as anti-depressants and analge-
`sics. Tars are also responsible for the production of
`bronco pulmonary diseases, including pulmonary em-
`physema, chronic bronchitis and smokers respiratory
`syndrome. (cid:9)
`Carbon monoxide, a deadly gas, is an important
`health hazard even in minute quantities because it com-
`bines with the hemoglobin in the blood so that the he-
`moglobin can no longer carry sufficient oxygen. More-
`over, the stimulant effect of the nicotine in the smoke 40
`causes an increase in cardiac workload and oxygen
`demand, whereas the carbon monoxide effectly blocks
`the ability of the heart muscle to capture the needed
`oxygen. In other words, carbon monoxide and nicotine
`work together in a synergistically negative manner in a 45
`way which often results in anoxia and ultimately in
`cardiac damage. In addition, carbon monoxide has also
`been implicated as a causative agent in the development
`of such disorders as coronary artery disease and athero-
`sclerosis. (cid:9)
`Nicotine appears to be the most pharmacologically
`active substance in tobacco smoke, yet it appears to be
`not as significant from a health standpoint as the tars
`and carbon monoxide. However, nicotine is very im-
`portant from another standpoint, i.e. it is the reinforcing 55
`substance in tobacco which maintains the addiction. In
`this respect, a theme commonly heard among workers
`in the field of smoking research is, "People would be
`disinclined to smoke cigarettes if an alternate route of
`nicotine delivery could be devised." (cid:9)
`Several such attempts have been made to administer
`nicotine in alternate ways, but with varying and gener-
`ally ineffective results. For example, nicotine-contain-
`ing pills have been studied; however, effective blood
`levels of nicotine are not achieved because drugs ab- 65
`sorbed in the stomach pass through the liver first where,
`in this case, 80-90 percent of nicotine deactivation oc-
`curs. Similar findings have been demonstrated with
`
`50
`
`60
`
`1
`
`4,597,961
`
`2
`nicotine chewing gum although it has been sufficiently
`successful to warrant its marketing.
`There are other long established and traditional ways
`of absorbing nicotine through the mouth, including
`chewing tobacco, snuff and the newly introduced prod-
`ucts such as "Bandits" which constitute diffusion bags
`of tobacco, all of such means relying on oral (or nasal)
`absorption of nicotine through the mucous membrane.
`However, because of the taste and other sensory effects
`of tobacco, such a manner of satisfying the nicotine
`habit is acceptable to only a very limited number of
`persons. Moreover, these habits still require the utiliza
`tion of tobacco, and such use remains a problem espe-
`cially for people with gum, mouth or throat problems as
`a result of long-term tobacco chewing or snuff "dip-
`ping" and who are unable to quit.
`With regard to the nicotine gum referred to above, it
`has produced mouth ulcers in a number of individuals
`resulting in its rejection. In addition, the nicotine gum
`produces some gastric absorption with the resultant first
`pass through the liver and consequent rapid loss of
`activity. Moreover, first hand reports indicate that some
`people using the gum rejected it on the basis of taste.
`Moreover, denture wearers have difficulty with gum in
`general; this is important as many people who experi-
`ence the medical problems associated with years of
`smoking may also be denture wearers.
`Nicotine itself has been subjected to considerable
`study. Nicotine is a liquid alkaloid which is colorless,
`volatile and strongly alkaline. On exposure to air it turns
`brown. It is known to be very lipid soluble. The Merck
`Index, 9th Edition, 1976, page 847, indicates that nico-
`tine base is readily absorbed through mucous membrane
`and intact skin, but the salts are not. On the other hand,
`nicotine has no known therapeutic application (The
`Pharmacological Basis of Therapeutics, fifth edition,
`Goodman and Gilman, 1970, page 467) and has been
`primarily used in research as an experimental tool for
`investigating neural function.
`It is known to administer a wide variety of pharma-
`ceuticals transdermally through the skin, and two pa-
`tents which disclose bandages for administering drugs
`are the Zaffaroni U.S. Pat. Nos. 3,598,122 and
`3,948,254. Drugs indicated to be administerable include
`anti-microbials sedatives, hypnotics, psychic energizers,
`tranquilizers, hormones; anti-pyrectics, anti-diabetics,
`cardovascular agents, anti-spasmatics, anti-malarials,
`decongestants, nutritional agents, anti-bacterials, anti-
`neoplastics, anti-inflammatory agents, desensitizing
`agents, vaccines, anti-allergies, anti-fungals, anti-per-
`spirants, deodorants, astringents and irritants. Thus,
`while the field of drugs and pharmaceuticals mentioned
`in these patents is very wide, there is no disclosure of
`administration of nicotine; and nicotine appears to have
`few properties in common with the categories of drugs
`mentioned in these patents. In view of the fact that
`nicotine has no therapeutic use, its relationship to any
`agents mentioned in these patents appears even more
`remote.
`It is further known that the absorption of many topi-
`cally applied drugs may be enhanced by occlusion,
`which consists of covering the treated skin with an
`impermable plastic sheet or film which prevents water
`evaporation or drug decomposition. Under such cir-
`cumstances the keratin layer then becomes softer and
`less effective as a bearer, so that absorption of the drug
`is facilitated (Annual Review of Medicine, Volume 33,
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`4,597,961
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`3
`Chapter 18, 1982, "The Principles of Drug Therapy in
`Skin Disorders", R.C. Heading, pages 475,476).
`Insofar as is known, it has not previously been pro
`posed to transdermally administer a drug for the pur
`pose of reducing or eliminating a dependence, or for
`administering a drug of addiction in a manner that is
`safer and less damaging than the route by which such
`drug is normally administered. Insofar as is known, no
`ganglionic stimulating agent has been previously deliv-
`ered transdermally, and it is believed that it has not been
`previously proposed to administer nicotine transder-
`mally.
`
`4
`factors become reduced in importance, it then upon
`becomes easier to treat the nicotine addiction.
`2. Patients with disorders such as emphysema, car-
`diac problems or lung cancer and who are unable to quit
`5 smoking thus exascerbating their medical problems are
`able to satisfy their nicotine habit while sparing them-
`selves further damage from the tars and carbon monox-
`ide in tobacco smoke.
`3. Nicotine absorbed transdermally is not transported
`10 first pass through the liver where 80-90 percent of
`nicotine deactivation occurs, but goes directly and rap
`idly into systemic circulation with rapid rises in nicotine
`blood level. Thus, the nicotine habit can be satisfied
`SUMMARY OF INVENTION
`while subjecting the body to far lesser quantitites of
`It is, accordingly, an object of the invention to over- 15 nicotine.
`4. Using the present system, blood levels of nicotine
`come problems in the prior art, such as indicated above. (cid:9)
`can be easily adjusted to acceptable and effective dos-
`It is another object to administer nicotine through the (cid:9)
`ages for the suppression of craving by varying the
`skin using a transdermal delivery system, especially for (cid:9)
`amount and duration of nicotine delivery. This is diffi-
`the purpose of satisfying a nicotine habit while minimiz-
`ing or eliminating side effects caused by absorbing nico- 20 cult if not impossible to accomplish with nicotine gum,
`because the person's rate of chewing is a major factor
`tine through the lungs along with products of combus-
`which manipulates dosage.
`tion of tobacco. (cid:9)
`5. People with gum, mouth and throat problems, as a
`It is a further object of the invention to provide a new
`result of long-term tobacco chewing or snuff "dipping"
`method of assisting persons break the habit of smoking
`25 and who are unable to quit, are aided in giving up their
`tobacco or the use of any tobacco product.
`habits with the use of transdermally applied nicotine.
`It is still another object of the invention to provide a
`6. Other advantages compared to nicotine containing
`nicotine transdermal delivery system.
`gum include obviating the problems of mouth ulcers in
`These and other objects of the invention are broadly (cid:9)
`some individuals; elimination of nicotine taste as a sec-
`achieved by providing nicotine in a form, such as on a 30 ondary reinforcer; provision of a less conspicuous form
`bandage or the like, whereby it is applied to the skin and (cid:9)
`of nicotine consumption (a cutaneous patch is much less
`permitted to enter the body transdermally. Under such (cid:9)
`conspicuous than gum chewing; for example, in stress-
`conditions the nicotine, being highly lipid soluble, is (cid:9)
`ful situations which typically serve as cues for smoking,
`absorbed directly and rapidly through the skin thereby (cid:9)
`such as business meetings, etc., gum chewing is less
`satisfying the nicotine habit while minimizing or elimi- 35 acceptable than the use of a transdermal patch); usabil-
`nating side effects which would otherwise be caused (cid:9)
`ity by those who reject gum on the basis of taste and
`when absorbing nicotine through the lungs along with (cid:9)
`some denture wearers who cannot chew gum; and pro-
`products of combustion. Such a delivery system can (cid:9)
`vision of an alternate mode of nicotine administration.
`also assist a person to quit smoking. (cid:9)
`In this latter respect, even if the transdermal administra-
`A transdermal bandage containing a reservoir of 40 tion is only equal in effectiveness to nicotine gum for
`nicotine may be applied to a variety of inconspicuous (cid:9)
`many persons, this will provide a further method of
`places on the human body, e.g. the postauricular area. (cid:9)
`reducing smoking dependence, it being known in the
`By supplying the smoker with an alternate source of (cid:9)
`field that different techniques work better for different
`nicotine in the dose range of from 15 to 25 nanograms (cid:9)
`individuals.
`per liter of blood, the need for cigarettes is reduced or 45 (cid:9)
`7. In the event that the subject of the instant invention
`eliminated. Using such a mode of administration pro- (cid:9)
`becomes available over-the-counter (as are cigarettes,
`vides a number of beneficial results as follows: (cid:9)
`snuff, chewing tobacco, etc.), the instant invention will
`1. An improved system becomes available to aid mo- (cid:9)
`provide a means for those, unable or unwilling to quit
`tivated smokers in eliminating their cigarette addiction. (cid:9)
`smoking, to ingest nicotine without subjecting them-
`Numerous potent non-pharmacological factors which 50 selves and their environment to smoking with its atten-
`help maintain the cigarette addiction are the rituals (cid:9)
`dant dangers of carbon monoxide and tars. It would also
`involved with the act of smoking, including the sight of (cid:9)
`allow ingestion of nicotine in places where smoking is
`a pack of cigarettes, the smell, the taste, etc. These (cid:9)
`prohibited, to avoid the consequences of performance
`previously neutral cues acquire powerful reinforcing (cid:9)
`decrements resulting from acute withdrawals. More-
`properties as a result of prolonged associations with 55 over, for women unable to quit smoking during preg-
`nicotine. Practice of the present system, however, as- (cid:9)
`nancy, transdermal nicotine would at least eliminate
`sists in extinguishing these addiction-maintaining cues (cid:9)
`carbon monoxide, thereby avoiding the deliterious ef-
`by supplying nicotine in the absence of such cues. (cid:9)
`fects of smoking on the fetus due to the blocking effects
`Indeed, a plurality of extinguishing techniques can be (cid:9)
`of carbon monoxide on oxygen absorption.
`utilized in association with the present invention. Thus, 60
`BRIEF DESCRIPTION OF DRAWING
`instead of completely substituting the technique of the
`instant invention for smoking, an interspercing regimen (cid:9)
`For a better understanding of the invention, as well as
`can be adopted wherein nicotine-containing transderms (cid:9)
`the above and other objects and the nature and advan-
`according to the invention may be alternated with ciga- (cid:9)
`tages of the instant invention, possible embodiments
`rettes to slowly extinguish the reinforcing properties of 65 thereof will now be described with reference to the
`the non-pharmacological factors, and also reduce the (cid:9)
`attached drawings, it being understood that these em-
`severity of the initial termination of smoking as well as (cid:9)
`bodiments are intended as merely exemplary and in no
`the incidence of relapse. As the non-pharmacological (cid:9)
`way limitative.
`
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`
`5
`FIG. 1 is a schematic cross-sectional view of a first
`embodiment of the invention; and
`FIG. 2 is a schematic cross-section view of a second
`embodiment according to the present invention.
`
`DETAILED DESCRIPTION OF EMBODIMENTS 5
`FIG. 1 is a schematic cross-sectional view of a nico-
`tine-containing transdermal bandage 10 having a width
`or diameter of about 1.5 centimeters and a thickness of
`about 2.0 centimeters. It comprises a nicotine imperme- 10
`able backing 12 formed of a suitable, preferably flexible
`and impervious plastic or rubber material, such as poly-
`vinylidene chloride, polyethylene, polypropylene, ny-
`lon, silicone rubber, etc., having a cavity 14 along one
`surface thereof. Within the cavity 14 is provided liquid 15
`nicotine 16 in an amount of 1-4 microliters. Sealing the
`nicotine film 18, again formed of a suitable microporous
`and flexible plastic or rubber which is inert to the nico-
`tine. Lastly, suitable adhesive 20 is provided on either
`side of, or completely around the nicotine permeable 20
`membrane.
`The precise nature of the materials from which the
`bandage 10 are formed may be easily determined from
`common knowledge, such as disclosed in the aforemen-
`tioned Zaffaroni patents, coupled if necessary with rou- 25
`tine testing for inertness relative to nicotine, The ban-
`dage 10 may be kept sealed in an air-tight pouch prior to
`use to prevent reaction of the nicotine with air.
`FIG. 2 shows a second embodiment of a nicotine
`bandage 110 having a nicotine impermeable backing 112 30
`with a relatively large cavity 114, and which may or
`may not be covered with a nicotine permeable mem-
`brane or microporous film 118. The reservoir 114 is
`surrounded with adhesive 120. Located within the cav-
`ity is a suitable absorbant material 122, such as a sponge 35
`or cotton, on which is absorbed the desired quantity of
`liquid nicotine, preferably in the range of 1-4 microli-
`ters to provide a dosage desirably in the range of about
`15-25 nanograms per liter of blood per administration.
`Dosage and duration of nicotine administration trans- 40
`dermally according to the present invention can be
`controlled in several ways separately and in combina-
`tion. In general, a carrier can be mixed with the nicotine
`which will either speed or slow its passage through the
`microporous membrane and/or into the skin. The thick- 45
`ness, number of pores and/or size of pores can be varied
`to either increase or decrease the speed of passage of
`nicotine through the microporous membrane. The
`quantity of nicotine in the reservoir can be either de-
`creased or increased to reduce or increase the duration 50
`or amount of dosing. All other factors being equal, use
`of the embodiment 10 of FIG. 1 will give a smaller dose
`over a longer term compared with use of the embodi-
`ment 110 of FIG. 2, merely because of the presence of
`the microporous membrane 18 which slows the deliv- 55
`ery of the nicotine to the skin.
`In general, no additive is necessary to assist in the
`transdermal administration of nicotine, because nicotine
`base is very highly lipid soluble and is quickly and com-
`pletely absorbed into the systemic circulation. How- 60
`ever, should it be desirable to increase or decrease the
`rate of penetration, then the nicotine base can be carried
`by a suitable solvent such as propylene glycol, glycerin,
`mineral oil, polyethylene glycol, DMSO or alcohol. It
`may also be mixed with water in which the alkaloid is 65
`readily soluble, thereby forming a water soluble salt;
`such a salt, however, is less lipid soluble and penetrates
`the skin much more slowly than the alkaloid base.
`
`4,597,961
`
`6
`It may be desirable to add a carrier which will slow
`absorption in view of the fact that nicotine is highly
`toxic. In this way, the nicotine may be diluted to reduce
`dangers of misuse; for example, the nicotine may be
`mixed with an oil such as indicated above, or preferably
`an oil having an unpleasant taste, such as castor oil.
`Other types of fillers may be utilized as well; for exam-
`ple, the nicotine may be retained in a gelatinous base.
`Other additives may be incorporated to reduce the
`possibility of accidential oral ingestion, such as a mer-
`captan.
`Using transdermal delivery while varying the poros-
`ity of the membrane separating the nicotine from the
`person's skin and/or the quantity of nicotine and man-
`ner in which it is retained, the dose and duration of
`nicotine administration are precisely controllable. Also,
`the total dosage and delivery rate can easily be adjusted
`to suit the needs of the particular patient, i.e. a different
`dose of nicotine will be desirable to reduce the craving
`of a one pack-a-day smoker versus a three pack-a-day
`smoker. According to the present invention, it is possi-
`ble to mimic smoking in terms of the amount of nicotine
`delivered, thereby reducing or eliminating dependence
`on any form of tobacco.
`It is preferred that the nicotine be administered trans-
`dermally using an occlusive technique, i.e. the use of a
`pad in which the backings (e.g. backing 12 or 112 in the
`illustrated embodiments) are impermeable and opaque
`to provide protection from light and air so as to insure
`transport across the skin before the nicotine has a
`chance to become deactivated. Aternatively, a less im-
`pervious backing 12 or 112 can be used, and the entire
`pad can be covered with an impervious plastic cover-
`ing.
`It is preferred that the pad 10 or 110 or the like be
`placed inconspicuously on an area of the skin such as
`behind the ear. This postauricular area insures rapid
`transport to the brain with little blood dilution. Alterna-
`tively, the pad can be placed elsewhere such as on the
`underside of the wrist, in which case there is delayed
`transport of the nicotine to the brain with enhanced
`blood dilution. The particular areas selected is deter-
`mined on the basis of the severity of the addiction. The
`onset of nicotine activity is in the range of 1-2 minutes
`with a duration of action up from 30-45 minutes, these
`values varying as a function of the dose administered,
`the permeability of the porous membrane, the surface
`area covered by the nicotine, and the site of application.
`The following examples will further illustrate ways in
`which the present invention can be practiced, it being
`understood that the specific conditions set forth are not
`to be considered limiting of the invention.
`
`COMPARATIVE EXAMPLE ONE
`A series of tests were conducted on rats for the pur-
`pose of flavor aversion learning. Thus, if a rat is made to
`sample a novel flavor such as saccharin and several
`hours later subjected to gastrointestinal malaise from
`X-irritation, drug injection or rotational stimulation, the
`rat will reject the once-palatable flavor if it is subse-
`quently offered. In essense, the rat behaves as though
`the saccharin were responsible for the illness. In this
`test, it was attempted to provide the gastro-intestinal
`malaise by administration of 2 mg/kg of IP nicotine
`base. A thirty-minute delay was interposed between the
`end of drinking the saccharin (15 minutes were allowed
`for drinking) and the nicotine injection. Four groups of
`rats were used, one being injected with physiological
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`A microporous nicotine permeable membrane 18,
`having a thickness of 20-50 microns, covers the reser-
`voir 14. On application of the pad 10, the membrane 18
`contacts the skin. The nicotine impermeable backing
`5 layer 12 essentially encloses or covers the nicotine 16
`and forms the actual reservoir 14 to protect the drug
`from breakdown as a result of exposure to light or air,
`and permits prolonged storage.
`The backing layer may be formed from such materi-
`10 als as silicone rubber or plastic. The nicotine permeable
`membrane as well as the high lipid solubility of nicotine
`insures rapid transport the via passive diffusion from the
`reservoir 14 through the skin to the underlying vascula-
`rized tissue. Around the outer margin of the pad is a
`15 layer of pressure-sensitive or contact adhesive 20 de-
`signed to attach the pad firmly to the skin as well as to
`provide a tight seal to prevent the drug from leaking
`from under the pad.
`
`7
`saline, one with 0.5 mg/kg of nicotine base, the third
`with 1.0 mg/kg of nicotine base and the fourth with 3.0
`mg/kg of nicotine base, all IP.
`No evidence of aversion was found in these animals.
`It appeared that the half-life of nicotine was two short
`for a version acquisition. In addition, the rats adminis-
`tered 3 mg/kg all convulsed possibly conducing a retro-
`grade amnesic effect.
`EXAMPLE 1
`Eight studies were conducted analogous to compara-
`tive example 1 above, except that the nicotine was ad-
`ministered transcutaneously to the rats.
`One of these studies involved giving unshaved rats
`either saline, or 10, 30 or 50 mg/kg of nicotine 30 min-
`utes after having sampled the saccharin solution. The
`nicotine was applied to an area approximately one inch
`behind each animal's head in order to eliminate the
`possibility of the animal ingesting the drug while
`grooming. There was a reliable dose-response effect and
`strong aversions developed to the saccharin solution.
`The more nicotine applied, the greater the unwilling-
`ness of the rats to drink saccharin solution. In addition,
`the duration of the illness was considerably longer than
`with the IP injected nicotine of comparative example 1.
`This study demonstrated that it was possible to absorb
`sufficient nicotine through the skin to produce enough
`nausea for conditioning flavor aversion.
`Other studies in this series involved various tech-
`niques for removing hair at the site, of transdermal appli-
`cation of the nicotine. In one study the depillatory,
`"Nair", was used. However, it adversely affected skin
`permeability for several days after its use and rendered
`previously tolerable dosages of nicotine quite toxic
`producing profound convulsions.
`In a later study in the series, the fur of the rats was
`shaved in the area of transdermal application. This per-
`mitted application of much smaller dosages and sug-
`gested that application of nicotine to the unshaved skin
`produced a "wicking" by the fur of a sizable portion of
`the nicotine away from the skin, with result that the
`nicotine became decomposed to some extent. Doses of
`3, 9 and 27 mg/kg in shaved rats produced virtually
`identical aversions as 10, 30 and 50 mg/kg, respectively,
`in unshaved rats.
`In a further study, mixing of the nicotine with DMSO
`in ratios of 1:1 and 1:4 of nicotine: DMSO for the pur-
`pose of producing more rapid absorption, caused a
`raised blister on the skin of shaved rats.
`EXAMPLE 2
`In order to test transcutaneous application, the pres-
`ent inventor applied to himself, in the postauricular area
`on several occasions, 3 mg and 5 mg respectively of
`nicotine base. Nausea was not induced at these dose
`levels although some effect was felt at the 5 mg level.
`EXAMPLE 3
`A bandage is made as shown in FIG. 1 consisting of
`an occulsive pad 10 including a backing 12 approxi-
`mately 1.5 cm in diameter containing a reservoir 14 filed
`with nicotine base. The reservoir contains from 1 to 4
`microliters of nicotine, roughly equivalent to 1-4 mg.
`To use the pad, a protective nicotine impermeable seal-
`ant film consisting of plastic or waxed coated paper,
`alumimun foil or a variety of other sealant materials is
`provided to cover the nicotine reservoir. This sealant
`film is stripped from the pad immediately prior to usage.
`
`20 (cid:9)
`
`EXAMPLE 4
`A bandage is made as shown in FIG. 2 comprising an
`occlusive pad 110 with a backing 112 approximately 1.5
`cm in diameter and having an open reservoir 114 cov-
`25 ered by a nicotine impermeable sealant film to be re-
`moved before application of the pad 110 to the skin. The
`open reservoir 114 contains a dense matrix of inert fi-
`brous or porous material, such as cotton, to prevent
`spillage of the nicotine prior to application of the pad to
`30 the skin. In use, the nicotine wicks from the cotton
`matrix as the nicotine diffuses across the skin.
`The foregoing description of the specific embodi-
`ments will so fully reveal the general nature of the in-
`vention that others can, by applying current knowl-
`35 edge, readily modify and/or adapt such specific em-
`bodiments without departing from the generic concept,
`and, therefore, such adaptations and modifications
`should and are intended to be comprehended within the
`meaning and range of equivalents of the disclosed em
`40 bodiments. It is to be understood that the phrasiology or
`terminology employed herein is for purposes of descrip-
`tion and not of limitation.
`What is claimed is:
`1. A method of administering nicotine for the purpose
`45 of satisfying a nicotine habit while minimizing or elimi-
`nating side effects caused by absorbing nicotine through
`the lungs along with products of combustion of to-
`bacco, comprising transdermally administering nicotine
`via an occlusive pad adhered to the skin at a dosage rate
`50 sufficient to satisfy said nicotine habit, said occlusive
`pad comprising a nicotine-impermeable backing and
`nicotine-permeable, porous, inert membrane, said nico-
`tine impermeable backing and said nicotine-permeable
`membrane defining a cavity therebetween, said cavity
`55 containing liquid nicotine therein.
`2. A method according to claim 1 wherein said nico-
`tine is in the form of nicotine base without a solvent,
`vehicle or carrier.
`3. A method according to claim 1 wherein said nico-
`60 tine is in the form of nicotine base diluted with a phar-
`maceutically acceptable carrier, solvent or vehicle
`which reduces penetration of the nicotine base through
`the skin.
`4. A method according to claim 1 wherein said nico-
`65 tine is administered by application to the skin behind the
`ear.
`5. A method according to claim 1 wherein said pad
`comprises 1-4 microliters of nicotine base.
`
`NOVARTIS EXHIBIT 2024
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 6 of 8
`
`

`
`9
`6. A method according to claim 1 wherein said nico
`tine is transdermally administered at a dosage rate of
`15-25 nanograms per liter of blood.
`7. A method of administering nicotine for the purpose
`of satisfying a nicotine habit in accordance with claim 1, 5
`wherein said nicotine is transdermally administered to a
`patient physically addicted to nicotine.
`8. A method of assisting a person to quit smoking,
`comprising transdermally administering nicotine via an
`occlusive pad adhered to the skin at at a dosage rate 10
`approximately the same as provided when absorbing
`nicotine by smoking, said occlusive pad comprising a
`nicotine-impermeable backing and nicotine-permeable,
`porous, inert membrane, said nicotine-impermeable 15
`backing and said nicotine-permeable membrane defin-
`ing a cavity therebetween, said cavity containing liquid
`nicotine therein.
`9. A method according to claim 8 comprising carry-
`ing out a series of said transdermal administrations and 20
`interspercing said transdermal administrations with
`cigarettes to slowly extinguish the reinforcing proper-
`ties of non-pharmacological factors.
`10. A method according to claim 8 wherein said pad
`comprises 1-4 microliters of nicotine base. (cid:9)
`11. A method according to claim 10 wherein said
`nicotine is in the form of nicotine base without a sol-
`vent, vehicle or carrier.
`12. A method according to claim 10 wherein said
`nicotine is in the form of nicotine base diluted with a 30
`pharmaceutically acceptable carrier, solvent or vehicle
`which reduces penetration of the nicotine base through
`the skin.
`
`25
`
`4,597,961