CA1273878A - Nicotine-containing preparation for transdermal administration - Google Patents
Nicotine-containing preparation for transdermal administrationInfo
- Publication number
- CA1273878A CA1273878A CA000556623A CA556623A CA1273878A CA 1273878 A CA1273878 A CA 1273878A CA 000556623 A CA000556623 A CA 000556623A CA 556623 A CA556623 A CA 556623A CA 1273878 A CA1273878 A CA 1273878A
- Authority
- CA
- Canada
- Prior art keywords
- oil
- nicotine
- preparation according
- preparation
- tobacco
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
A nicotine-containing preparation is disclosed for transdermal application as a substitute for the use of tobacco products. The formulation comprises an oil/alcohol emulsion of nicotine which provides a bimodal rate of release. The formulation comprises an alkaline pH (8-10} to optimize transdermal delivery of nicotine.
The formulation is stable at room temperature and easily stored and transported, for example in a plastic applicator bottle.
A nicotine-containing preparation is disclosed for transdermal application as a substitute for the use of tobacco products. The formulation comprises an oil/alcohol emulsion of nicotine which provides a bimodal rate of release. The formulation comprises an alkaline pH (8-10} to optimize transdermal delivery of nicotine.
The formulation is stable at room temperature and easily stored and transported, for example in a plastic applicator bottle.
Description
7 3 ~ 7 ~17 '~ICOTINE-COJr~ PPEP~R~TIO~ FO~ TR ~ SDER~L
~IINIS~ TIONU
FI~LD OF lllE IlnFEErrIO~
This invention relateg to a nicotine-containin~ prepara~ion for tran~der~al application a an alternatiYe to tobaooo product~ and to a method of administering nicotine through the skin.
The inYention proYides an effectiYe ~eans of nicotine intake that permits a te~porary substitute for the u~e of to~acco product~. The initial rate of nicotine release to the ~ubcutaneou~
blood QUpply i3 sufficiently rapid to proYide a ~olus nicotine supply to alleviate the i~ediate withdraual symptoms associated with snokinq ceg~ation. Sub3equent relea~e occur~ ~t a slo~er rate to proYide a sustained relief, hence decreasing the required frequency of u~e. The habituated use frequency serYes to permit an effectiYe mean~ of breaking the nicotine habit. Product safety i~
a~sured by the w e of lo~ nicotine concentration, controlled rate of release, pH buffering, antioxidants, ~nd an accurate dispensing applicator.
B~l~CGPOInlD OF llIE I~lorrIO~
Yarious *nokin3 substitutes for a~sistin~ ce~ation of the tobacco habit haYe been preYiously described. SeYeral patents exist for nicotine che~ing gu~s ~e.g. ~anadian Patent No. ~3~ 8 ~Lichkneckert et al.~ and U.S. Patent No. 3,845,217 ~Ferno et al.~.
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~3~ .'8 HoweYer, the u~e of ~uch gum i~ ~u~peGted of cau3in~ mouth ulcer3, the rate of nicotine release i~ poorly controlled and the ~u~ is difficult to u~e unobtru~iYely. The~e prior patent~ reYiew the health hazarda attributed to ~okin~ ~nd the benefit~ afforded by any c~oking su~titute that would a~ t ~oking ces~ation or curtail the use of tobacco products with potential carcinogenic actiYity.
More recently, U.S. Patent No. 4,57~,85~ ~Ferno et al.}
dsscribo* na~al ad~ini3tration of a s~okinq sub~ti~ute co~po~ition.
HoweYer, penetration through both the nasal and buccal ~embrane~ ia relatively rapid and resulta in an un~atiafactorily abrupt effect with a rapid decline.
Recently a tran~der~al applicator patch ha~ been patented for nicotine deliYery ~U.S. Patent No. 4,597,961~. Such a patch can al~o be u3ed for tran~der~al deliYery of ~eYeral pharmaceutical~
~e.g. nitro~lycerin, cortico~teroids, anti-~icrobial~, anti-diabetic~, etc.). The patch ha~ the di~adYantage~ of being relatiYely expen~iYe to produce, difficult to apply unobtru~iYely, and ~ay lead to ~kin irritation after prolonged u~e. The patch doe~
haYe the ~ajor adYantage of providing an occlu~iYe layer that ~erYes to pronote hydration of the ~tratu~ corneu~ with re~ultant enhanced per~eability.
7 3~3 4~17 S~nn~aR~ OF llE~ I~nYE ~ IO~
It is an o~ject of the inYention to oYerco~e proble~s in the prior art as described aboYe. It is another objeot to pro~ide a ~ethod of deliYering nicotine tran~dermally from a controlled rate of release formulation that aYoids the problems of the prior art as discu~sed aboYe. while ~ufficiently mimicking the s~oking experience so as to proYide a temporary su~stitute that assi~t~ in reduction or total ce~sation of the to~acco habit.
It is a further object to proYide an economical alternatiYe to ~oking that provides an effective aid to breaking the cigarette habit.
It is another object of the inYention to proYide a transdermal nicotine formulation with a bi~odal or trimodal rate of relea~e to en3ure deliYery of ~oth a rapid initial bolus as well as a sustained release to ~ini~ize frequency of u~e. It is a further object to proYide ~ te~porary ~ubstitute for tobacco use that is le~s hazardous than the tobacco habit.
Accordingly, one aspect of the inYention proYides a preparation for tran~dermal administration; which co~prises nicotine or other tobacco alkaloid, or lobeline, or a ~ixture thereof, a lo~er alcohol, and a der~ally co~patible oil, the preparation being buffered to an alkaline pH Yalue Another aspect of the in~ention proYides a ~ethod of ad~ini~tering nicotine as a ~ubstitute for s~oking, which c wpri~es .'~ 7~ 3 5~17 ~pplyin~ to an external body ~urface a preparation compri~ing niootine or other tobacco alkaloid, or lobeline, or a ~ixture thereof, a loYer aleohol, and a der~ally oo~patible oil, the preparation ~eing buffered to an ~lkaline pH Yalue, and per~itting the niootine-related product in ~id prep~ration to be absorbed transder~ally.
As well a3 reduGing exposure to caroinogens pre~ent in conYentional to~acoo produot~ ~or their combu~tion product~, the tran~der~al for~ulation of the inYention i ~uffered at an alkaline pH and for~ulated to preYent for~ation of oarcinogenie by-products during storage andfor u~e. The for~ulation is sta~le at roo~
te~perature offering an estended ~helf-life and is also stable oYer the te~perature regi~en encountered in the Canadian enYiron~ent ~-37 to ~4~C) en~bling outdoor use of the product. The for~ulation is easily stored and transported and readily usable in an unobtrusive fashion.
m e proparation of the inYention can be used safely during air flight, labour near fla~aable solYents, la~our requiring full ~nNal desterity ~e.g. driYing), as a substitute prior to, during, and after hospitalization (e.g. for surgerY~, as a substitute in croYded in~oor habitats ~e.g. at vork, shopping centres an~
eonYention , and in publio places su~jeot to non-s~oking regulations~ to redu e risk of exposure to a~econdhand s~okea for bystanders.
~: As ~ell as reducing the craYing for niootine, the innention : ', ''' "' :~, .' ,~ ' ~ ` ' ~ , ' ' ~ ' ~ ' , ' ' ' : .
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~3~78 ~/~?
offers advantages over the prior art in that it fulfills many of the rituals associated with the smoking habit, thereby alleviating psyahologlcal ractors assoaiated wlth addlct1on. The rltuals lnclude the transport or a small package on the person le.g. ln a pocket or purse) that is readily accessible for use as well as the conditioned response associated with the memory of tne tobacco odour present on the skin of the hands. Furthermore, since in many cases the smoker attempting to quit the habit may not wish ~o bring attention to the faat that he requires a temporary "crutch". the preparation of the invention should be as unobtruslve to apply as possible In general the use of a liquid formulatlon of nicotine as constltuted by an oil/alcohol emulsion, buffered at an alkaline pH
of a-10, with a suitable emulsifier ~e.g. surfactant, soap, detergent) antioxidant (e.g. vitamin El and tobacco fragrance (e.g.
isoprenoid aompound, menthol) would achieve the desiderata detailed above. The oil~alcohol emulsion provides the preferred bimodal rate of release with a nicotine bolus resulting from the rapid dermal absorption of niaotine from the alcohol, and the oil film prov1ding an oaclusive hydrating layer to enhance absorption. The oil also provides a slower, more sustained rate of release of nicotine resulting from the slow transfer rate from oil to skin. Ethanol and methanol are examples of suitable alcohols, while isopropanol is preferred. Mineral oil is an example of a suitable oil, although vegetable oils (e.g. sunflower, peanut, ~., , , 7~17 corn, oliYe, rape-~eed or coeoa oil) are preferred since they do not contain a3 ~uch potentially carcinogenic polyaromatic hydroc~r~ons ~PAH~ as mineral oil. Yeget~ble oil~ ~re also considered to be more suitable for for dermal medicament~ than mineral oil ~H~dgraft and 50mer~, Percutaneou~ ab~orption, J.
Pharm. Pharmacol. 8:625-634, lg56}.
The outer ~kin surface, namely the Str~u~ ~o~e~, proYideg a relatively ~trong rate limiting barrier in compari~on with the buccal and na~al muco~a. Thug, the dermal absorption rate and total degree of ab~orption for many compoundg are ugually much lower than those for other routeg. For thig reagon, tran~der~al accelerants are de~irable to increa~e the rate of transfer of nicotine between the 5~r~tM~ cor~e~ and the blood gupply of the subcutaneou~
capillarie~. The~e accelerant~ ~ay take the for~ of s~ulsifiers, golYent~ and other che~ical adjuvant~ ~additiYeg} pregent in the formulation. Their efficacy ha~ been well documented in the phar~aceutical literature concerning tran~dermal drug delivery ~Ryatt et al., Pharmacodyna~ic heagurement of Percutaneous Penetration Enhancement. J. Pharmaceut. Sci. 75~4}: 374-7, lg8~.
A wide Yariety of emulgifier~ can be employed, guch ag gorbitol, xylitol, godium lauryl gulfate, Tveenl~, Triton~' or other ~uitable gurfact~ntg ~oap~ or detergentg.
Ag Yell a~ a rapid initial rate of deliYery, the formulation proYideg a slo~er, ~ore gugtained relea~e of nicotine for long lagting efficacy. The initial rapid deliYery proYide~ a bolug .
.
7.'~7~3 ~ 17 supply of nicotine into the blood that re~ults in rapid ~atiation of the cra~in~ asaociated with ~o~ing cessation. A slo~er secondary, ~ore ~u~tained rate of relea~e proYide~ a ~aintenance blood nicotine leYel and a decrease in the frequenoy of use that tend to be a~sociated ~ith non-der~ally persistent for~ulation~. A
decrea~e in the required frequency of use would h~bitu~te the p~ychological addiction a~sociated Yith the ~mokin~ habit.
Nicotine ~S}-3-~ ethyl-2-pyridinyl) pyridine) i~ extractable fro~ tobacco leaYe~ ~V2~0~f~* ~*~E and ~. ~U~2~) of ~hich it con4titutes fro~ 2 to ~X of the dry wei~ht ~Merck, lg7~). It is a colourless, ~olatile, water and alcohol soluble su~stance ~ith a pKa of 7.9. Hence at blood pH of 7.4, nicotine exist~ predomin~ntly in the charged state a3 the nicotinium ion, thi~ bein~ its pharmacologically acti~e ~tate ~naangan and Boldin~, lg~4). m e pH
of the formulation i3 important for controlling the dermal absorption ~ate of nicotine. It is Yell documented that the nicotinium ion penetrate3 biome~branes much ~ore 310~1y th~n the frse base ~uniondzed) form pre~ent at alkaline pH. For this reason, prior formulation~ relatinq to nicotine gum and na~al sprays haYe enployed an acid pH to decrea~e the rate of penetration through buccal and na al muco~al me~branes. Fortunstely, in using the present inYention, the der~l barrier is sufficiently res~riGtiYe to per~dt the use of an alkaline buffered formulation. As Yell as proYiding rapid penetration, the alkaline pH decreases the rate of formation of potentially carcinogenic nitrosation product~ of .
. ~ . .
~ , :. ,, :
~: ' ' . ' ' 7 ~ 7 ~/17 nicotine that are known to form durinq the ~torage of tobacco product~.
The lipophilicity ~fat ~olubility~ of a che~ical ~pecie~ i~
thought to be an i~portant phy~ico-che~ical factor for controlling the rate of tran~derm~l per~eation. The logarith~ of the octanolfwater partition coefficient ~Kow~ for nicotine i~ equal to 1.17 at pH 11. A log Kow of 1.17 implie~ that at equili~rium, the nicotine concentration in the oil phase of an oilf~ater biph siG
~ystem will be ca. 15 ti~e~ that of the aqueou~ pha~e. Hence once the initial alcohol of the oilfalcohol for~ulation has eYaporated fron the ~kin ~urface, the partition will fa~our the oil film adhering to the superficial aqueous layer ~Yeat~ covering the skin. m e rate of departition from the oil to the ~eat will be relati~ely ~low, hence the oil filn Yill proYide a form of controlled relea~e to the der~i3. To opti~ize the log Ko~, and ; hence the partition in faYour of the oil, it i~ de~irable to ~aintain an alkaline dermal pH. ~Der~al pH i~ nornally ca. 5.5}.
A~ ~ell as biophy~ical and chemical factor~, p~ychological factor~ are al~o i~portant for determining the efficacy of the in~ention. On espo~ure to air or light, nicotine turn~ broYn and exhibits a pyridine odour ~herck Index, 1976~. The pre~ence of a ; tobaGco odour ~e.g. pyridine) on the skin, e~peGially the h~nds, ~ould aerYe to further ~imulate the ~okinq esperience and aid ~ithdrawal h~bituation. Recent ~tudie~ ~oody et al. 1986~ haYe de~on~trated that dermal ab~orption throu~h the Yentral pal~ar ,'~
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;' ~ " : : . ' ' ' .- - . . . - ~ .
10~17 ~urf~ce is much gr~Rter than throu~h the foreheRd or forear~ in rhesus ~onkey~ for diethyl-m-tolu~mide ~EET~. Hence the pal~ar surface provide~ a suitable, easily accessible ~ite for der~al application of nicotine for~ulation in ~an, ag ~ell as a site of tobacco odour fa~iliar to the s~oker.
The for~ulation can further include one or ~ore antioxid nts ~e.q. vita~in E} and ultraYiolet liqht ~ W ) blockers ~e.~. PABA} to reduce for~ation of potentially carcinogenic ni~ro~ation products and to pronote both storage and derual stability. The nicotine for~ulation o~n be stabilized in liquid, ~el or Yalve ~oint~ent}
for~, preferably to be applied to the Yentral or dorsal pal~ar 3urfaces for a~sisting ~okinq ces3ation.
The fornulation ~ay be packaged in a s~all ~10-35 ~l} plastic or gla~3 applicator bottle. This applicator is only for exe~plary purposes and should not be considered as restriGtive. The fornulation could also be enclosed in unit-dose plastic pillow-type dispensors or in drop di~pensing bottles. The for~ulation could be thickened to proYide a paste. salYe ~ointnent} or ~tick le.q.
lip~tick or lipbal~ type applicator~. Different concentrations of nicotine can be enployed Yith the lo~er concentrations to be used by less hardened s~okers or for tho~e no longer requiring hiqh concentrations to alleYiate ~ithdraY~l.
hicro-encapsulation or nicro-i~pregnation of nicotine into controlled release plastics of other suitable matrices and present as ~icroparticles ~e.g. nicrospheres~ suspended in the formulation :
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can ~l~o be used to pro~ide ~ore effective ~u3tained relea~e, if required. This process i3 well described in the phar~eucutical literature but has not been propose~ for nicotine ~eli~ery. The Wurster method or other suitable procedure~ can be u~ed for ~icro-for~ulation.
Suitable ~Qterials for for~in~ the microparticles include biocompati~le plastics, such a~ polyYinyl chloride, polyYinyl aloohol, polyethylene, polymethyl ~eth~cryla~.e, polytetrafluoroethylene, ethylene Yinyl alcohol and Nylon, a~ well a~ rubber, sodium taurocholate, ~tarch-xanthate, lignin, bentonite, methyl- hyroxy~ethyl- or carboxy~ethyl-cellulose, wax or ~lay.
The ~icro-formulant proYides a tertiary for~ of release hence constituting a tri~odal rate of release oYerall. Sun screening agents ~UY ~lockers~ e.g. PABA, can also be included to prote~t the for~ulation fro~ photodegradation. The applicator bottle should preferably be opaque.
DET~ILED QEscRIpTIo~ OF lllE I m lRrIOX
In the following exa~ples nicotine is obtained fro~ tobacco leaf following standard extraction and purification procedures ~e.~.
Merck, 1~76}, or che~ically ~ynthesized ~e.g. Crai~ or Spath'~
synthesis~. This is not restricti~e and other to~acco alkaloid~ as well as lobeline can be substituted or u~ed in conjunction ~ith the nicotine. The Exa~ples are intended to be exe~plary only and are , - ~ .
' 1~17 not to be construed a2 bindin~.
E~a~Ple 1 A ~olution was prepared haYin~ the following co~po~ition:
Nicotine 15 mg Isopropanol 7.5 ml Mineral Oil 7.5 ~l Sodiu~ bicarbonate 0.5 g The nicotine is dis~olved in the isopropanol at room temperature and the ~olution added to a 25 ~l opaque plastic dispensing bo~tle.
m e oil i~ then added followed by the sodiu~ bicarbonate which ; serYes as a buffer. Other CQ~On buffering a~ents ~ay ~e used ~e.g.
~arbonate, phosphate). m e pH is adju~ted to a~out 9 ~ith O.l~
NaOH The for~ulation is ~haken Yigorously each time jus~ prior to US8. Ratio~ of oil~alcohol other than 1~1 giYen here can also be u~ed.
E~a~D1e 2 Exaaple 1 ~s repeated except th~S ethanol or ~ethanol or a ~isture thereof was substituted for the isopropanol.
Al ,. ~ ` ` ` . :~ . ................... . `
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13~17 E~an~le ~
Exa~ple~ 1 and 2 were repea~ed, except that Yegeta~le oil ~e. g sunflower, sesa~e, peanut, cocoa, corn, olive or rape-seed} was substituted for the ~ineral oil.
E~u~le 4 Exa~ples 1 and 3 were repeated, except that the formulation~
included 0.1 g ~ita~in E, ~ethylhydroxybenzoate, sodiu~ ~enzoate, ascor~ate ~Yita~in C}, butylated hydroxytoluene ~BRT~ or other suit~ble antioxidant.
E~Dle 5 Exa~ples 1 and 4 Yers repeated, except that the for~ulations Yere aug~ented by the addition of PABA or Beta-carotene as a UY
blockinq agent, a transder~al accelerant selected fro~ Azone, ~EET, DnSO, and DnFA and an enulsifier ~e.g surfactant, soap, or detergent) ~elected fro~ 30rbitol, xylitol, Tween~, TritonlM and sodiu~ lauryl ~ulfate.
:~ ~sa~lDle 6 ~ Further preparations Yere for~ulated a~ in the prior Exa~ples, n , ,a.~ ,,,, , ~, , . ' ' ' - ~ .
~ ~ ': ' ' ' ' ' ' ' - . ' . ' .
,, , ' ' ' ' . -' . ' ~ ' ' ~ ' . , ~ ~ , , , ' ' ' ' .
~.X7;~
1~/17 but with nicotine concentration~ of 0.1, 0.5, 0.~5, 1.0, 2.0, 5.0, 7.5 and 10 ~fml for~ulation E~P1e 7 Formulation~ were prepared a~ in the prior Exa~ple~ ~ut with ~icro-encap~ul~ted or ~icro-i~pregnated nicotine. The ~icro-for~ulation m~trix i~ a plastic ~elected fro~ polyYinyl chloride, poly~inyl alcohol, polyethylene, polytetrafluoroethylene, polymethyl methacrylate, ethylene Yinyl alcohol, and Nylon, rubber or other ~uitable ~terial ~uch a~ sodiu~ taurocholate, ~tarch-xanthate, liynin, bentonite, methyl- hyroxy~ethyl- or carbosy~ethyl-cellulo~e~ Yax or clay.
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$ ~7 EY~fPLE 8 If de~ired, tobacco fragrance~ ~either actual e.g. i~oprenoids or ai~ulated, e.g. licorice, tarragon, ani~e oil~ can be ineluded in any of the exs~plary for~ulation~.
Y~ pLE g Menthol and/or cap~aicin ~ay be inoluded in any of the exe~plary for~ulation~ to pro~ide cold and heat ~ensation~, re~pectiYely.
E~IeLE 10 Antifreeze agent~ ~e.g. ethylene glycol, propylene glycol, glycerol~ ~ay ~e included in any of the exemplary for~ulation~.
1~' .
~ , . .
.''',-'" '' ' " .
~IINIS~ TIONU
FI~LD OF lllE IlnFEErrIO~
This invention relateg to a nicotine-containin~ prepara~ion for tran~der~al application a an alternatiYe to tobaooo product~ and to a method of administering nicotine through the skin.
The inYention proYides an effectiYe ~eans of nicotine intake that permits a te~porary substitute for the u~e of to~acco product~. The initial rate of nicotine release to the ~ubcutaneou~
blood QUpply i3 sufficiently rapid to proYide a ~olus nicotine supply to alleviate the i~ediate withdraual symptoms associated with snokinq ceg~ation. Sub3equent relea~e occur~ ~t a slo~er rate to proYide a sustained relief, hence decreasing the required frequency of u~e. The habituated use frequency serYes to permit an effectiYe mean~ of breaking the nicotine habit. Product safety i~
a~sured by the w e of lo~ nicotine concentration, controlled rate of release, pH buffering, antioxidants, ~nd an accurate dispensing applicator.
B~l~CGPOInlD OF llIE I~lorrIO~
Yarious *nokin3 substitutes for a~sistin~ ce~ation of the tobacco habit haYe been preYiously described. SeYeral patents exist for nicotine che~ing gu~s ~e.g. ~anadian Patent No. ~3~ 8 ~Lichkneckert et al.~ and U.S. Patent No. 3,845,217 ~Ferno et al.~.
A
. ` ~ . .- ~ .. . . .
. . . . . .
.. . -:
.
~3~ .'8 HoweYer, the u~e of ~uch gum i~ ~u~peGted of cau3in~ mouth ulcer3, the rate of nicotine release i~ poorly controlled and the ~u~ is difficult to u~e unobtru~iYely. The~e prior patent~ reYiew the health hazarda attributed to ~okin~ ~nd the benefit~ afforded by any c~oking su~titute that would a~ t ~oking ces~ation or curtail the use of tobacco products with potential carcinogenic actiYity.
More recently, U.S. Patent No. 4,57~,85~ ~Ferno et al.}
dsscribo* na~al ad~ini3tration of a s~okinq sub~ti~ute co~po~ition.
HoweYer, penetration through both the nasal and buccal ~embrane~ ia relatively rapid and resulta in an un~atiafactorily abrupt effect with a rapid decline.
Recently a tran~der~al applicator patch ha~ been patented for nicotine deliYery ~U.S. Patent No. 4,597,961~. Such a patch can al~o be u3ed for tran~der~al deliYery of ~eYeral pharmaceutical~
~e.g. nitro~lycerin, cortico~teroids, anti-~icrobial~, anti-diabetic~, etc.). The patch ha~ the di~adYantage~ of being relatiYely expen~iYe to produce, difficult to apply unobtru~iYely, and ~ay lead to ~kin irritation after prolonged u~e. The patch doe~
haYe the ~ajor adYantage of providing an occlu~iYe layer that ~erYes to pronote hydration of the ~tratu~ corneu~ with re~ultant enhanced per~eability.
7 3~3 4~17 S~nn~aR~ OF llE~ I~nYE ~ IO~
It is an o~ject of the inYention to oYerco~e proble~s in the prior art as described aboYe. It is another objeot to pro~ide a ~ethod of deliYering nicotine tran~dermally from a controlled rate of release formulation that aYoids the problems of the prior art as discu~sed aboYe. while ~ufficiently mimicking the s~oking experience so as to proYide a temporary su~stitute that assi~t~ in reduction or total ce~sation of the to~acco habit.
It is a further object to proYide an economical alternatiYe to ~oking that provides an effective aid to breaking the cigarette habit.
It is another object of the inYention to proYide a transdermal nicotine formulation with a bi~odal or trimodal rate of relea~e to en3ure deliYery of ~oth a rapid initial bolus as well as a sustained release to ~ini~ize frequency of u~e. It is a further object to proYide ~ te~porary ~ubstitute for tobacco use that is le~s hazardous than the tobacco habit.
Accordingly, one aspect of the inYention proYides a preparation for tran~dermal administration; which co~prises nicotine or other tobacco alkaloid, or lobeline, or a ~ixture thereof, a lo~er alcohol, and a der~ally co~patible oil, the preparation being buffered to an alkaline pH Yalue Another aspect of the in~ention proYides a ~ethod of ad~ini~tering nicotine as a ~ubstitute for s~oking, which c wpri~es .'~ 7~ 3 5~17 ~pplyin~ to an external body ~urface a preparation compri~ing niootine or other tobacco alkaloid, or lobeline, or a ~ixture thereof, a loYer aleohol, and a der~ally oo~patible oil, the preparation ~eing buffered to an ~lkaline pH Yalue, and per~itting the niootine-related product in ~id prep~ration to be absorbed transder~ally.
As well a3 reduGing exposure to caroinogens pre~ent in conYentional to~acoo produot~ ~or their combu~tion product~, the tran~der~al for~ulation of the inYention i ~uffered at an alkaline pH and for~ulated to preYent for~ation of oarcinogenie by-products during storage andfor u~e. The for~ulation is sta~le at roo~
te~perature offering an estended ~helf-life and is also stable oYer the te~perature regi~en encountered in the Canadian enYiron~ent ~-37 to ~4~C) en~bling outdoor use of the product. The for~ulation is easily stored and transported and readily usable in an unobtrusive fashion.
m e proparation of the inYention can be used safely during air flight, labour near fla~aable solYents, la~our requiring full ~nNal desterity ~e.g. driYing), as a substitute prior to, during, and after hospitalization (e.g. for surgerY~, as a substitute in croYded in~oor habitats ~e.g. at vork, shopping centres an~
eonYention , and in publio places su~jeot to non-s~oking regulations~ to redu e risk of exposure to a~econdhand s~okea for bystanders.
~: As ~ell as reducing the craYing for niootine, the innention : ', ''' "' :~, .' ,~ ' ~ ` ' ~ , ' ' ~ ' ~ ' , ' ' ' : .
.~ ~ . . : ' .
~3~78 ~/~?
offers advantages over the prior art in that it fulfills many of the rituals associated with the smoking habit, thereby alleviating psyahologlcal ractors assoaiated wlth addlct1on. The rltuals lnclude the transport or a small package on the person le.g. ln a pocket or purse) that is readily accessible for use as well as the conditioned response associated with the memory of tne tobacco odour present on the skin of the hands. Furthermore, since in many cases the smoker attempting to quit the habit may not wish ~o bring attention to the faat that he requires a temporary "crutch". the preparation of the invention should be as unobtruslve to apply as possible In general the use of a liquid formulatlon of nicotine as constltuted by an oil/alcohol emulsion, buffered at an alkaline pH
of a-10, with a suitable emulsifier ~e.g. surfactant, soap, detergent) antioxidant (e.g. vitamin El and tobacco fragrance (e.g.
isoprenoid aompound, menthol) would achieve the desiderata detailed above. The oil~alcohol emulsion provides the preferred bimodal rate of release with a nicotine bolus resulting from the rapid dermal absorption of niaotine from the alcohol, and the oil film prov1ding an oaclusive hydrating layer to enhance absorption. The oil also provides a slower, more sustained rate of release of nicotine resulting from the slow transfer rate from oil to skin. Ethanol and methanol are examples of suitable alcohols, while isopropanol is preferred. Mineral oil is an example of a suitable oil, although vegetable oils (e.g. sunflower, peanut, ~., , , 7~17 corn, oliYe, rape-~eed or coeoa oil) are preferred since they do not contain a3 ~uch potentially carcinogenic polyaromatic hydroc~r~ons ~PAH~ as mineral oil. Yeget~ble oil~ ~re also considered to be more suitable for for dermal medicament~ than mineral oil ~H~dgraft and 50mer~, Percutaneou~ ab~orption, J.
Pharm. Pharmacol. 8:625-634, lg56}.
The outer ~kin surface, namely the Str~u~ ~o~e~, proYideg a relatively ~trong rate limiting barrier in compari~on with the buccal and na~al muco~a. Thug, the dermal absorption rate and total degree of ab~orption for many compoundg are ugually much lower than those for other routeg. For thig reagon, tran~der~al accelerants are de~irable to increa~e the rate of transfer of nicotine between the 5~r~tM~ cor~e~ and the blood gupply of the subcutaneou~
capillarie~. The~e accelerant~ ~ay take the for~ of s~ulsifiers, golYent~ and other che~ical adjuvant~ ~additiYeg} pregent in the formulation. Their efficacy ha~ been well documented in the phar~aceutical literature concerning tran~dermal drug delivery ~Ryatt et al., Pharmacodyna~ic heagurement of Percutaneous Penetration Enhancement. J. Pharmaceut. Sci. 75~4}: 374-7, lg8~.
A wide Yariety of emulgifier~ can be employed, guch ag gorbitol, xylitol, godium lauryl gulfate, Tveenl~, Triton~' or other ~uitable gurfact~ntg ~oap~ or detergentg.
Ag Yell a~ a rapid initial rate of deliYery, the formulation proYideg a slo~er, ~ore gugtained relea~e of nicotine for long lagting efficacy. The initial rapid deliYery proYide~ a bolug .
.
7.'~7~3 ~ 17 supply of nicotine into the blood that re~ults in rapid ~atiation of the cra~in~ asaociated with ~o~ing cessation. A slo~er secondary, ~ore ~u~tained rate of relea~e proYide~ a ~aintenance blood nicotine leYel and a decrease in the frequenoy of use that tend to be a~sociated ~ith non-der~ally persistent for~ulation~. A
decrea~e in the required frequency of use would h~bitu~te the p~ychological addiction a~sociated Yith the ~mokin~ habit.
Nicotine ~S}-3-~ ethyl-2-pyridinyl) pyridine) i~ extractable fro~ tobacco leaYe~ ~V2~0~f~* ~*~E and ~. ~U~2~) of ~hich it con4titutes fro~ 2 to ~X of the dry wei~ht ~Merck, lg7~). It is a colourless, ~olatile, water and alcohol soluble su~stance ~ith a pKa of 7.9. Hence at blood pH of 7.4, nicotine exist~ predomin~ntly in the charged state a3 the nicotinium ion, thi~ bein~ its pharmacologically acti~e ~tate ~naangan and Boldin~, lg~4). m e pH
of the formulation i3 important for controlling the dermal absorption ~ate of nicotine. It is Yell documented that the nicotinium ion penetrate3 biome~branes much ~ore 310~1y th~n the frse base ~uniondzed) form pre~ent at alkaline pH. For this reason, prior formulation~ relatinq to nicotine gum and na~al sprays haYe enployed an acid pH to decrea~e the rate of penetration through buccal and na al muco~al me~branes. Fortunstely, in using the present inYention, the der~l barrier is sufficiently res~riGtiYe to per~dt the use of an alkaline buffered formulation. As Yell as proYiding rapid penetration, the alkaline pH decreases the rate of formation of potentially carcinogenic nitrosation product~ of .
. ~ . .
~ , :. ,, :
~: ' ' . ' ' 7 ~ 7 ~/17 nicotine that are known to form durinq the ~torage of tobacco product~.
The lipophilicity ~fat ~olubility~ of a che~ical ~pecie~ i~
thought to be an i~portant phy~ico-che~ical factor for controlling the rate of tran~derm~l per~eation. The logarith~ of the octanolfwater partition coefficient ~Kow~ for nicotine i~ equal to 1.17 at pH 11. A log Kow of 1.17 implie~ that at equili~rium, the nicotine concentration in the oil phase of an oilf~ater biph siG
~ystem will be ca. 15 ti~e~ that of the aqueou~ pha~e. Hence once the initial alcohol of the oilfalcohol for~ulation has eYaporated fron the ~kin ~urface, the partition will fa~our the oil film adhering to the superficial aqueous layer ~Yeat~ covering the skin. m e rate of departition from the oil to the ~eat will be relati~ely ~low, hence the oil filn Yill proYide a form of controlled relea~e to the der~i3. To opti~ize the log Ko~, and ; hence the partition in faYour of the oil, it i~ de~irable to ~aintain an alkaline dermal pH. ~Der~al pH i~ nornally ca. 5.5}.
A~ ~ell as biophy~ical and chemical factor~, p~ychological factor~ are al~o i~portant for determining the efficacy of the in~ention. On espo~ure to air or light, nicotine turn~ broYn and exhibits a pyridine odour ~herck Index, 1976~. The pre~ence of a ; tobaGco odour ~e.g. pyridine) on the skin, e~peGially the h~nds, ~ould aerYe to further ~imulate the ~okinq esperience and aid ~ithdrawal h~bituation. Recent ~tudie~ ~oody et al. 1986~ haYe de~on~trated that dermal ab~orption throu~h the Yentral pal~ar ,'~
J
. . , ' . . . .
;' ~ " : : . ' ' ' .- - . . . - ~ .
10~17 ~urf~ce is much gr~Rter than throu~h the foreheRd or forear~ in rhesus ~onkey~ for diethyl-m-tolu~mide ~EET~. Hence the pal~ar surface provide~ a suitable, easily accessible ~ite for der~al application of nicotine for~ulation in ~an, ag ~ell as a site of tobacco odour fa~iliar to the s~oker.
The for~ulation can further include one or ~ore antioxid nts ~e.q. vita~in E} and ultraYiolet liqht ~ W ) blockers ~e.~. PABA} to reduce for~ation of potentially carcinogenic ni~ro~ation products and to pronote both storage and derual stability. The nicotine for~ulation o~n be stabilized in liquid, ~el or Yalve ~oint~ent}
for~, preferably to be applied to the Yentral or dorsal pal~ar 3urfaces for a~sisting ~okinq ces3ation.
The fornulation ~ay be packaged in a s~all ~10-35 ~l} plastic or gla~3 applicator bottle. This applicator is only for exe~plary purposes and should not be considered as restriGtive. The fornulation could also be enclosed in unit-dose plastic pillow-type dispensors or in drop di~pensing bottles. The for~ulation could be thickened to proYide a paste. salYe ~ointnent} or ~tick le.q.
lip~tick or lipbal~ type applicator~. Different concentrations of nicotine can be enployed Yith the lo~er concentrations to be used by less hardened s~okers or for tho~e no longer requiring hiqh concentrations to alleYiate ~ithdraY~l.
hicro-encapsulation or nicro-i~pregnation of nicotine into controlled release plastics of other suitable matrices and present as ~icroparticles ~e.g. nicrospheres~ suspended in the formulation :
~, ,,, ., 1, .~
.... .
., . :
-~
~ . .- .
.
-' . ~ , ' : :
~- .
, . :
,' ' ~
can ~l~o be used to pro~ide ~ore effective ~u3tained relea~e, if required. This process i3 well described in the phar~eucutical literature but has not been propose~ for nicotine ~eli~ery. The Wurster method or other suitable procedure~ can be u~ed for ~icro-for~ulation.
Suitable ~Qterials for for~in~ the microparticles include biocompati~le plastics, such a~ polyYinyl chloride, polyYinyl aloohol, polyethylene, polymethyl ~eth~cryla~.e, polytetrafluoroethylene, ethylene Yinyl alcohol and Nylon, a~ well a~ rubber, sodium taurocholate, ~tarch-xanthate, lignin, bentonite, methyl- hyroxy~ethyl- or carboxy~ethyl-cellulose, wax or ~lay.
The ~icro-formulant proYides a tertiary for~ of release hence constituting a tri~odal rate of release oYerall. Sun screening agents ~UY ~lockers~ e.g. PABA, can also be included to prote~t the for~ulation fro~ photodegradation. The applicator bottle should preferably be opaque.
DET~ILED QEscRIpTIo~ OF lllE I m lRrIOX
In the following exa~ples nicotine is obtained fro~ tobacco leaf following standard extraction and purification procedures ~e.~.
Merck, 1~76}, or che~ically ~ynthesized ~e.g. Crai~ or Spath'~
synthesis~. This is not restricti~e and other to~acco alkaloid~ as well as lobeline can be substituted or u~ed in conjunction ~ith the nicotine. The Exa~ples are intended to be exe~plary only and are , - ~ .
' 1~17 not to be construed a2 bindin~.
E~a~Ple 1 A ~olution was prepared haYin~ the following co~po~ition:
Nicotine 15 mg Isopropanol 7.5 ml Mineral Oil 7.5 ~l Sodiu~ bicarbonate 0.5 g The nicotine is dis~olved in the isopropanol at room temperature and the ~olution added to a 25 ~l opaque plastic dispensing bo~tle.
m e oil i~ then added followed by the sodiu~ bicarbonate which ; serYes as a buffer. Other CQ~On buffering a~ents ~ay ~e used ~e.g.
~arbonate, phosphate). m e pH is adju~ted to a~out 9 ~ith O.l~
NaOH The for~ulation is ~haken Yigorously each time jus~ prior to US8. Ratio~ of oil~alcohol other than 1~1 giYen here can also be u~ed.
E~a~D1e 2 Exaaple 1 ~s repeated except th~S ethanol or ~ethanol or a ~isture thereof was substituted for the isopropanol.
Al ,. ~ ` ` ` . :~ . ................... . `
.
.
~,~ 7..~
13~17 E~an~le ~
Exa~ple~ 1 and 2 were repea~ed, except that Yegeta~le oil ~e. g sunflower, sesa~e, peanut, cocoa, corn, olive or rape-seed} was substituted for the ~ineral oil.
E~u~le 4 Exa~ples 1 and 3 were repeated, except that the formulation~
included 0.1 g ~ita~in E, ~ethylhydroxybenzoate, sodiu~ ~enzoate, ascor~ate ~Yita~in C}, butylated hydroxytoluene ~BRT~ or other suit~ble antioxidant.
E~Dle 5 Exa~ples 1 and 4 Yers repeated, except that the for~ulations Yere aug~ented by the addition of PABA or Beta-carotene as a UY
blockinq agent, a transder~al accelerant selected fro~ Azone, ~EET, DnSO, and DnFA and an enulsifier ~e.g surfactant, soap, or detergent) ~elected fro~ 30rbitol, xylitol, Tween~, TritonlM and sodiu~ lauryl ~ulfate.
:~ ~sa~lDle 6 ~ Further preparations Yere for~ulated a~ in the prior Exa~ples, n , ,a.~ ,,,, , ~, , . ' ' ' - ~ .
~ ~ ': ' ' ' ' ' ' ' - . ' . ' .
,, , ' ' ' ' . -' . ' ~ ' ' ~ ' . , ~ ~ , , , ' ' ' ' .
~.X7;~
1~/17 but with nicotine concentration~ of 0.1, 0.5, 0.~5, 1.0, 2.0, 5.0, 7.5 and 10 ~fml for~ulation E~P1e 7 Formulation~ were prepared a~ in the prior Exa~ple~ ~ut with ~icro-encap~ul~ted or ~icro-i~pregnated nicotine. The ~icro-for~ulation m~trix i~ a plastic ~elected fro~ polyYinyl chloride, poly~inyl alcohol, polyethylene, polytetrafluoroethylene, polymethyl methacrylate, ethylene Yinyl alcohol, and Nylon, rubber or other ~uitable ~terial ~uch a~ sodiu~ taurocholate, ~tarch-xanthate, liynin, bentonite, methyl- hyroxy~ethyl- or carbosy~ethyl-cellulo~e~ Yax or clay.
. ~
' ''~ `' .:
. ~ . ~ . ' ' ' ` ~ , ' `
$ ~7 EY~fPLE 8 If de~ired, tobacco fragrance~ ~either actual e.g. i~oprenoids or ai~ulated, e.g. licorice, tarragon, ani~e oil~ can be ineluded in any of the exs~plary for~ulation~.
Y~ pLE g Menthol and/or cap~aicin ~ay be inoluded in any of the exe~plary for~ulation~ to pro~ide cold and heat ~ensation~, re~pectiYely.
E~IeLE 10 Antifreeze agent~ ~e.g. ethylene glycol, propylene glycol, glycerol~ ~ay ~e included in any of the exemplary for~ulation~.
1~' .
~ , . .
.''',-'" '' ' " .
Claims (10)
- I CLAIM:
l A preparation for transdermal administration not involving the use of transdermal applicator patches, which comprises:
(a) nicotine or other tobacco alkaloid, or lobeline, or a mixture thereof;
(b) a lower alcohol, and (c) a dermally compatible oil, the preparation being buffered to an alkaline pH value. - 2. A preparation according to claim l, containing from about 0.1 to about 10 mg of component (a) per ml of the total components (b) and (c) .
- 3, A preparation according to claim 2, wherein the ratio of alcohol (b) to oil (c) is from about 0.01 to 100.
- 4. A preparation according to claim 1, which is buffered to a pH
value of from about 8 to 10. - 5. A preparation according to claim 4, wherein the buffer is sodium bicarbonate, sodium carbonate or potassium hydrogen phosphate.
- 6. A preparation according to claim 1, wherein the lower alcohol (b) is methanol, ethanol or isopropanol and the oil (c) is mineral oil, corn oil, cocoa oil. cottonseed oil, peanut oil, sunflower oil, olive oil or rape-seed oil.
- 7. A preparation according to claim 1, which is in the form of an emulsion, solution, lotion, cream, paste, gel, salve or stick.
- 8. A preparation according to claim 1, which comprises an emulsion of from 0.1 to 10 mg/ml of nicotine in a mixture of equal volumes of mineral oil and isopropanol.
- 9. A preparation according to claim 1, and including one or more members selected from the group consisting of an antioxidant, a UV
blocking agent, a transdermal accelerant, an emulsifier, an antifreeze agent, and a tobacco fragrance additive. - 10. A preparation according to claim 1, in a microencapsulated or micro-impregnated form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US347187A | 1987-01-15 | 1987-01-15 | |
| US003,471 | 1987-01-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1273878A true CA1273878A (en) | 1990-09-11 |
Family
ID=21706026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000556623A Expired CA1273878A (en) | 1987-01-15 | 1988-01-15 | Nicotine-containing preparation for transdermal administration |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1273878A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992019241A1 (en) * | 1991-05-07 | 1992-11-12 | Dynagen, Inc. | A controlled, sustained release delivery system for smoking cessation |
| US5298257A (en) * | 1987-05-01 | 1994-03-29 | Elan Transdermal Limited | Method for the treatment of withdrawal symptoms associated with smoking cessation and preparations for use in said method |
| US5362496A (en) * | 1993-08-04 | 1994-11-08 | Pharmetrix Corporation | Method and therapeutic system for smoking cessation |
| US5403595A (en) * | 1991-05-07 | 1995-04-04 | Dynagen, Inc. | Controlled, sustained release delivery system for smoking cessation |
| WO1995023597A1 (en) * | 1994-03-04 | 1995-09-08 | Trans-Onycha Limited | Systemic drug delivery system through application on nails |
| US5549906A (en) * | 1993-07-26 | 1996-08-27 | Pharmacia Ab | Nicotine lozenge and therapeutic method for smoking cessation |
| US5780051A (en) * | 1992-04-02 | 1998-07-14 | Dynagen, Inc. | Methods and articles of manufacture for nicotine cessation and monitoring nicotine use |
| JP2005504094A (en) * | 2001-09-27 | 2005-02-10 | ファーマシア アクティエボラーグ | Novel formulations and their use |
| WO2007066150A2 (en) * | 2005-12-07 | 2007-06-14 | Pharmakodex Ltd | Transdermal administration of active agents for systemic effect |
-
1988
- 1988-01-15 CA CA000556623A patent/CA1273878A/en not_active Expired
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5298257A (en) * | 1987-05-01 | 1994-03-29 | Elan Transdermal Limited | Method for the treatment of withdrawal symptoms associated with smoking cessation and preparations for use in said method |
| US5403595A (en) * | 1991-05-07 | 1995-04-04 | Dynagen, Inc. | Controlled, sustained release delivery system for smoking cessation |
| WO1992019241A1 (en) * | 1991-05-07 | 1992-11-12 | Dynagen, Inc. | A controlled, sustained release delivery system for smoking cessation |
| AU657973B2 (en) * | 1991-05-07 | 1995-03-30 | Dynagen, Inc. | A controlled, sustained release delivery system for smoking cessation |
| US5780051A (en) * | 1992-04-02 | 1998-07-14 | Dynagen, Inc. | Methods and articles of manufacture for nicotine cessation and monitoring nicotine use |
| US5549906A (en) * | 1993-07-26 | 1996-08-27 | Pharmacia Ab | Nicotine lozenge and therapeutic method for smoking cessation |
| US5662920A (en) * | 1993-07-26 | 1997-09-02 | Pharmacia Ab | Nicotine lozenge and therapeutic method for smoking cessation |
| US6280761B1 (en) | 1993-07-26 | 2001-08-28 | Pharmacia Ab | Nicotine lozenge |
| US5593684A (en) * | 1993-08-04 | 1997-01-14 | Pharmacia Ab | Method and therapeutic system for smoking cessation |
| US5362496A (en) * | 1993-08-04 | 1994-11-08 | Pharmetrix Corporation | Method and therapeutic system for smoking cessation |
| WO1995023597A1 (en) * | 1994-03-04 | 1995-09-08 | Trans-Onycha Limited | Systemic drug delivery system through application on nails |
| JP2005504094A (en) * | 2001-09-27 | 2005-02-10 | ファーマシア アクティエボラーグ | Novel formulations and their use |
| JP2010006845A (en) * | 2001-09-27 | 2010-01-14 | Mcneil Ab | New formulation and use thereof |
| WO2007066150A2 (en) * | 2005-12-07 | 2007-06-14 | Pharmakodex Ltd | Transdermal administration of active agents for systemic effect |
| WO2007066150A3 (en) * | 2005-12-07 | 2007-11-15 | Pharmakodex Ltd | Transdermal administration of active agents for systemic effect |
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