Note: Descriptions are shown in the official language in which they were submitted.
c I ` 2 1 84075
wo 95/23597
SYSTEMIC DRUG DELIVERY SYSTEM THROUGH APPLICATION ON NAILS
This invention relates to a novel delivery system for achieving systemic
delivery of drugs and other ag~nts with plldl 11 i~COI~ or physiological action and
more s~,eLiri "y to a novel method of adl";";.le,i"g a therapeutically active
substance to a subject. The term "therapeutically active substance" is intended
also to include substances having a phy~iol~icAI, phd""~col~J:- ~1 or prophylactic
effect.
In many areas of pharmacology it is desirable to devise new routes of
a.l~,,;.,;~.ldliùn for therAreut "y active substances. Thus, for example, in many
instances normal routes of ad",;";~l,dLioll such as ad",i";~L,dLion by mouth or
pd.e,lLeldl a~", I;aLldLiOn are inconvenient or illd~J,UlU~JlidL~, such as, for example,
where a prolonged sustained release effect is required or if a therapeutically active
substance is likely to be degraded rapidly if ad",;.,;OLe,ed via customary routes.
Also, in cases where a therapeutically active substance needs to be ddlllill;~Leled
continuously at a low, but sustained dosage rate Ifor example to provide a
constantplasmaco,)ce~LldLiollwithoutpeaksandtroughs~availabledosageforms
often fail to achieve the desired effect, or the therapeutically active substance
needs to be adlll;.l;~Le,ed in a form which is inconvenient or dangerous to use, or
which is expensive to manufacture.
Thls, for example, although single shot depot COllLld~,é~uLi~eS and steroids
oftenfunctionsd~ ly~onceadepotcùllLla~e~uLiveorsteroidisadlllill;~Leled~
its action cannot be quickly and readily reversed. Similarly, it is often difficult to
prepare a sustained release dosage form for oral ad~,-i-,i:,L~Liu~ which can reliably
release a controlled amount of therapeutically active substance over a long period
of time. h.l 11 lel ",u, e, a given sustained release capsule or pill will re;ease its active
illylel,l;~ at a particular rate. Accordingly in order to provide the possibility of
varying the dosage rate, either a phd-lllaceutical supplier has to provide a number
of different dosage forms, each with a different release rate, or a physician will
W095/2359~ S 2184075 P
need to attempt to control the release rate by prescribing different numbers of
dosage units. Each of these proposals has attendant disadvantages.
It is thus generally accepted that improvements are needed in the modes and
methods of a~l"i";~,dLion of therapeutically active substances. This applies both
for the effect of drugs acting locally as well as the effect of drugs which are
absorbed into the blood, Iymphatic and tissue fluids, and ~lallarl:lled sy~",i,,~'!y
for an action at sites distant from the point of :1,, " 1, for which latter purposes
drugs are l,a~iLion_'!y given orally or pàl~:llLt~ y. The present invention is
a~.e~,iri-.~.lly co,)c~",~d with the drugs and l~,ol~y;~,. "y actiYe agents adl"i";~
for systemic action at sites distant from the point of .~ n
Improvements in this field may, for example, be necessary simply to provide
alternatives available for patient p,l:r~,~"ce or convenience, or to allow greater
c~,,,,ulia,~ce; thus there may be obj~_Lions to oral, rectal, sublingual or intravenous
routes of a-l",i";~,dlio~-. In some instances there may be a need to overcome first
pass metabolic dey,adaLio,) of drug in the liver, or variation in drug handling,consequent on conce"~,dlioll~ or dose-related kinetics. Again, to achieve an
optimal effect, there may be a need to keep the dosage constant, as well as a
necessity to avoid the peaks of blood conc~"~,aLion of drug, such as occur when
drugs are given orally or pal~ l 'ly in a dose necessary to achieve a particulareffect: abolition of peaks and ", ,L_ .,i,~g a constant plasma col)c~llLIdLioll would
reduce some wanted effects and increase patient c~",~Jlid".,e. A/ ILdill 19 a
constant effect by stable blood conc~,,L,aLioll, is difficult to sustain by oral or
~dlt~llk:lal ad",i";~L,dLio,l because peak conc~"L.dLio~s are followed by a decline;
with depo-injection a more constant level may be achiewd, but it is difficult toremove the drug, for example if unwanted effects are encountered in the course
of such d.llllilliallaliOn.
To overcome some of these problems, sustained dosage release patches
have been introduced, first for scupola,,,i,,e (hyoscine) and now for other
substances e.g. nitroglycerin, oestradiol, clonidine, fentanyl and nicotine, (see e.g.
.
~ W0 9512359~ C 21 4 5 r~
EP-A-0 117 027). Whilst these have many of the advantages mentioned above,
their use has been limited to these and a few other drugs because the use of
patches does not overcome the problem of the i"".e" ' "ly of the stratum
corneum of the skin, and the need to use a patch of ~rc~lJ~ le size. Thus
a relatively small daily dose of drug can be a~",;";~L~ d - usually the order of 0.2-
~0 mg per day. Fullll~llllule, because of the pe"" ' ' y ~lldld~ Lius of the
stratum corneum of the skin, the nature of the drug which can be delivered by
patch is seriously restricted both by the size of molecule, which generally needs
to be less than 1000 daltons, and by the need for a critical lipid/water solubility.
Attempts to enhance the al~s~"~ioll through the skin have been made using
hydrating agents such as urea, various pen~L,dLiù,~ ~"hal~ci"g agents such as
dimethylsulphoxide and similar compounds, p~"" ' '~.~es, fatty acids, Azone,
surfactants, alcohols, glycols, essential oils, terpenes, terpenoids and their
derivatives and amines (see, e.g. "Skin Absorption Enl,a~c~,a", Williams, A.C. et
al.,CriticalReviewsinTherapeuticDrugCarrierSystems,9~3,4):305-352(1992))
and a range of proteolytic enzymes such as papain, but although these do enhancepe~,~L,dLiùn, they have not allowed the marketing of new systems for delivery ofdrugs other than oestradiol through the stratum corneum of the skin. In additionthere is a risk of irritation and contact 5~ iLi~dLio~l initiated through skin
La~ ,l,ans cells resulting in a c~"".a,c,Lively high incidence of unwanted localeffects, particularly with drugs such as nicotine. (Examples of percutaneous
formulations for a,i", ,;~Lt:lillg nicotine as part of a regime for aiding smokers to
reduce their dependence upon tobacco are given in EP~A-0 289 342 and CA-A-1
273 878). Also many object to the use of an obvious patch on the skin. Thus it
appears that further improvements to the existing systems are desirable.
The use of io~Lu?h~ jis and el~,L~upu,dliùn has been proposed for
augmenting drug delivery through the skin but there are many problems ~cc~
with safety, convenience and expense. For example, GB-A-2 206 493 describes
ani~,~Lopl~ isdeviceforpercutaneousorperungualadlllillk~Lldlionofadissolved
substance, for example a drug. In use, a pair of ele~,L,udes are attached to a
patient's skin or nail, separated by a pad of electrolyte and an e.m.f. of typically
WO 95/23S97 ~ 2 1 8 4 0 7 5 ~ r 159 ~
.
1.35 - 1.83 volts applied. There is no sl~gDestion of a~", ~ialldlioll of any
substance percutaneously or perungually in the absence of an applied e.m.f., i.e.
by passive abs~,,ulion, as in the present invention.
Attempts have been made to enhance p~ lalion of therapeutically active
substances through the stratum corneum by using pe"~l,aliol~ e~ anc~,a such as
dimethylsulphoxide, see e.g. GB-A-2 057 263, but the use of such pt..":l,dli
a,~l~a~c~,a are generally restricted to compositions in liquid form and provide
problems with respect to .Ly;_l,aliL,) with drug l~y;~llaliOIl bodies. Further,
dimethylc~ l, hu,.ide is irritant and toxic.
By contrast, the ~ io,l of therapeutically active substances to finger
and toe nails has been reported for the specific purpose of applying antifungal
agents or dllLiLiu~iLs adapted to treat infections of the nail. Thus, for example,
EP-A-0 515 312 discloses topical formulations CCllLd;ll- 19 It:,Li"ari~,e in the form
of nail varnishes designed to treat onychomycosis. W0-A-87102580 describes
further examples of co""~osilions for delivering drugs topically to human nails.However all such culllpoailions are restricted to uses wherein the cu",,uuailiL~-~ is
intended for iocal action without transport of the ther~re~ 'ly active substanceto the site remote from the finger or toe nail, in particular to a systemic tissue
C~lll,ualllllt:lll. Thus an article entitled "Topical and Systemic Absorption ofSodium Pyrithione following Topical ~ri ~ , to the Nails of the Rhesus
Monkey", Mayer, P.R. et al/., Skin Pl lal " làcol. 1992; 5 :154-159 describes the fate
of radio-labelled pyrithione applied to finger nails and toenails of rhesus monkeys
and states that "only slight drug cL~,,ct:,,l,alions were measurable in plasma".Further in a cl~a.,,iplion of a parallel human study, it was stated that "less than
10% of patients... had quantifiable conc~,,l,aliu.,s (greater than 10 nglml ) of 2-
methylsufonyl pyridine... a long-lived Ille:ldiJulilt: which is a marker of systemic
exposure to pyrithione derivativesU.
A further article entitled "F~ ' ' ly LllaldLLt:liaLiLs of the human nail
plate", Walters K.A. et al., I.~l~,..aliondl Journal of Cosmetic Science 5, 231-246
~ W095123597 ~ ij 2 i 84075 r~ 159
(1983) discusses the ~irre~cl~ces between the pélll - '- " of skin and nails to
various substances, especially i"yl eu~a., ~a of c~s" lèLiL s . The article concludes that
"it may soon be possible for the pharmaceutical manufacturer to chemically tailor
drugs which wiil prove more effective in the topical Illal ,ag~",e"l of nail infections.
Further it also appears that cosmetic scientists will soon be able to more prudently
select the raw materials for nail products to minimize the troubling consequences
of perungual a~su"uLiUll". (.3ee also ~'PhySi~Oul~ellliL~al cl~dlaL~ dlion of the
human nail: pe""edLio~ pattern for water and the homologous alcohols and
dirre,e.~..es with respect to the stratum corneum", Walters, K.A. et al, J. Pharm.
Plla""acol. 1983, 35: 28-33 and 'lpeneLlaLioll of chemicals into, and through, the
nail plate", Walters, K.A., Pharmacy lllLt:lllaLi~ndl~ April 1985, pp 86-89). Such
pl ~ ;c ns teach away from the use of n3ils for systemic a i" ~ LI a Lion of drugs.
The present invention which has all the advantages of the patch system, but
without the disadvantages, is based upon a surprising discovery that finger nails
and toe nails provide an effective route of systemic a i,,,;,.i,L~aLiùn for a wide range
of ther~rP~I "y active substances by simple local l, r 1 ' ' ~. Nails also have the
advantage that drug delivery through them is not c~", ' -' by the presence of
hair follicles and sweat glands, as in skin, nor the very wide variation in
pell., ' ":y of the stratum corneum at different body sites and in different
individuals.
Thus according to the present invention there is provided a method of
aLi",;";~Le,i"g a therapeutically active substance to a subject, which c~",,uri~s
applying the substance to the surface of one or more finger or toe nails wherebythe substance is absorbed and lldll~,UUI Led Sy:lL~II.' 'Iy to a site of action remote
from the finger or toe nail.
The invention further provides the use of a pl~d""a.,eutically acce,uLdL`~,
carrierin the manufacture of a pl,a",)dceutical co",~,~siLion adapted for ,, ' ~n
to finger naiis and/ortoe naiis, I,lldlal,Le,ised in that the co"" o,iLiùll contains at
ieast one therapeutically active substance whereby in use the substance is
W095123597 ,I-~..f~ ; 2184~)75 1~
absorbed and Lldlla,uOILed systemically to a site of action remote from the finger
or toe nail.
The use of a phdlllldcc~utically acct:~JLd~'~ carrier in the manufacture of a
ph~- " ,actnJtical co""uù~ilion adapted for lF F ' ~ to finger nails and/or toe nails,
i l~dlcl~ d in that the CCIII~.~aiLidn contains at least one therapeutically active
substance which is capable of passing from the applied cù~ uai~iOn, through the
naii to which it is applied, and into a systemic tissue Culll~Jdl Llllt:l~L aiso forms an
aspect of the inYention.
In carrying out the invention the therapeutically active substance may be
applied in the form of a composition colll,uliaillg one or more Colll~Jù"e"L~ for
~ u~u~ g retention of the c~",,uo~ilioll within or on the nail surface. Thus, for
example, the composition may comprise a film-forming cu~yùllelll or it may be inthe form of a varnish, lacquer, gel or solution. Alternatively the substance may be
applied to the nail in a patch. Film-forming components may be chosen so as to
modulate the rate of p~ lldliUn of the therapeutically active substance. I.e. itmay enhance or restrict the rate of pe,~t:l, dlion or it may allow the nail itself to act
as a reservoir. Alternatively or adLiili~" "y, the LUlll~JO,iliù~l may include an
additionai c~l"~.ùl,~"L which has the capacity to modulate the rate of pe~l,dlio,~
of the therapeutically active substance in this way. Again the cOlll,uOailiùll may
itself enter the nail and modulate the inward dbso"ution of the drug. Agents mayalso be added to decrease local effects such as irritancy arising from the
therajle~ "y active agent or co"" on~"la of the formulation.
It is to be understood that the method of the invention does not require the
,, ' Liull of ul~ udes to the finger or toe nails in order to provide an e.m.f.whichpromotestransportbye!~cl,u~.ho,~aisorio,)LoiJhole~ia~ Onthecontrarythe
therapeutically active substance is Ll d"a~.u, Led passively through the finger or the
toe nail in acc~, ia,)ce with the invention. The term ~passively" ~and derived
terms) as used herein is intended merely to refer to the absence of an applied
e.m.f. to r~.,L,udes. Passive transport in accordance with the invention can
_ _ _ _ _ . . . ..
~ WO 951U597 ' ~ 2 1 8 4 0 7 5 1 ~,~,. 15~1
include transport by diffusion as well as ttansport that is mediated by physiological
-,~ases or by the ,, ' 1 of p~ llaLiOIl ellilà-~c~ia.
All formulation types which have generaliy been appiied to the skin and hair
may, with suitabie ~J-I ~, Li- ~, be applied to nails.
As indicated, the method of the invention is Arrl;'`Ahl~ to a illlillallatiOI) of
a wide variety of therArP~ t "y active substances including, for example, ones
having a therapeutic effect on the centrai nervous system, cardiovascuiar system,
endocrinesystemorl~, ;.dluiysystemaswellastherapeuticallyactivesubstances
having an analgesic or anti-ailergic effect. Similariy, the method of the invention
may be applied to the ad"~ ,I,aliùn of therAr~lt - "y active substances which
have a therapeutic effect on the yd~l, ui"I~ i, Idl tract or the genito-urinary system
oroneswhichhavea~,~r,l,due:~.liveactivity. ThetherAre~ 'lyactivesubstances
can include not ûnly ~ "~ "y Sy~,li,~ai~ i drugs, but also hi~lor "y derived
mûlecules, forexample phy^;~losirAI substances such as growth factors, hormones
and their release factors, enzymes and Iylllplloi~illds. The substances to be
delivered may act as vaccines or immunomodulators.
Other examples include anti-infective agents, for example dllliiJiUli~.s
(including dlllillli-.lUiJidi and antivirai drugs), drugs which affect metabolic,~"oces~es sL~ch as calcium transport, iron Ill~LaiJul~_.ll and metaboiic ~.,ucess~s
involving folic acid, cytostatic and anti-neùpld~Li-, drugs, haemAtnpr~ietic drugs and
drugs that act on the mUsCUldl/~ ,.dl, neurai and neuromuscular system. Other
therapeutically active substances include ones which affect gene structure and
function. The therAreut ~ "y active substance can have d~l".~ lo~J;~~I activity
although it is to be L~ ,. aLùOd that such activity should be at a site distal from the
site of,, ' ~ to the nails. Drugs that act on oral tissues, e.g. drugs for
treating dental or gingival ,vaLI10l0l are also included.
The substances to be delivered by the method of the invention may have an
effect on "aLl~ùl~yi~.dl disorders which involve singie or many body systems
WO 95/~3597 1 . ~ 2 1 8 4 ~ 7 5 ~ 5 ~
including those whose ",e"l,d"i~", is still uncertain. It may also be used
prophylactically or for physiological or social purposes. The method can be usedfor the delivery of substances acting on any bodily system organ or tissue in
health ~r disease.
It is to be ullddl:~Iuod that the term "therapeutically active substance" as
used herein in intended to extend not only to substances which have a therapeutic
action per se, but also to substances which comprise so called "pro-drugs" i.e.
substances which convert to a therapeutically active form on ad",;.,i:,L,d~iol1.Similarly, the term "therapeutically active substance" extends not only to
substances which are ~,ue~ ir ~ "y adapted to cure or dlll~liuldIb the symptoms of
a disease, but also to substances which have a palliative effect as well as
substances which are used as so-called ~ dliUl~al'l drugs. One example in this
co~ e"Lion is the use of the method of the invention for ad",i";~ ,i"g nicotine as
part of a therapy designed to wean a tobacco smoker from his or her addiction.
The invention wiil now be described in more detail with particular reference
to the acco,,,ud,,ying drawings of which
Figure 1 depicts the results of an e,~ ,i",dnL measuring trans ungual
water loss.
Figure 2 depicts the results of an e,~,u~,i,,,~,,I measuring water losswith increasing stripping las a normal curve).
Figure 3 depicts the results of an e,~pb,i",e,~L measuring cumulative
pent:l,dLion of (3H)-Nicotine through human nail following a single
dppl;~.dLiol1 of a 50% (v/v) solution in 0.1 M HEPES buffer, pH 7.4.
Figure 4 depicts the results of an experiment measuring cumulative
p~l1c:LrdIiOll of (3H)-Clonidine through human nail following a single
ion of a 52.8 mg/mL solution in 0.1 M HEPES buffer pH 7.4.
SUBSTITUTE SHEET (RULE 26)
~ WO95lU597 ?;~ 2184~75 r~ IS7
Figure 5 depicts the results of an ~,ue,i"~e"~ measuring cumulative
penel.dlion of (3H)-DAGo through human nail following a single
n of an 8 mg/mL solution in 0.1 M HEPES buffer, pH 7.4.
Figure 6 depicts the results of an experiment measuring cumulative
pe"~l,d~ion of (3HI-Plo~.,d,~olol throu~h human nail following a single
L;on of a saturated solution in 0.1 M HEPES buffer, pH 7.4.
Fic~ure 7 depicts the results of an experiment measuring cumulative
pt5,)el,dLion of (3H) 1\~' ,i,) through human nail following a single
n of a saturated solution in 0.1 M HEPES buffer, pH 7.4.
The precise ",e.il,a,)i~", by which therapeutically active substances are
transported to their site of action in accolJdl,ce with the invention has not been
fully dt:L~""i"ed, nor is it known what factors limit the passage of therapeutically
active substances through the nail. However it is believed that the major factorwhich contributes to the efficacy of the invention is the high water p~", ' :y of
the nail plate. Thus e,c~ ,i."~ a have shown that the rate of water transport
throuQh the nail plate can be up to 10 times the c~"~s,~,ol1d;,~g rate through the
stratum corneum of the normal epidermis (see Waters K.A. et al., J. Pharm.
Pi,a~",acol. 1983, 35, 28-33 and Figs. 1 and 2). An early paper (Johnson and
Shuster 1974) rliqcuqqPrl the pe", - ' :y of the stratum corneum to water and
more recently e,~ ,i",e-,l:, have been described which have used water flux to
der"~l1a~,d~t: and quantify the pc" ~ ' Iy 1,11dldCIt9li~Li~,s of the stratum corneum
~Puttick & Shuster 1985, Brit. J. Dermatol., 113, 775). Similar methods were then
applied to the nail in vivo and in vitro (Johnson & Shuster - unpublished). Thus it
was found that the rate of water lldl~SIllissio,l through nail and stratum corneum
is dependent on their thickness. This is illustrated yld~ y in Figs. 1 and .
SUBSTITUTE SHEET (RULE 26)
W0 95123!i97 ' ~ ~=' T` ~3 r S 2 1 8 4 0 7 5 ~1 . 1 r l ~ ~
respectively. When these earlier findings on the water pt:" "eai iliLy of the stratum
corneum of the skin were compared with those of the nail it was observed that
surprisingly the nail was 5 to 10 times more p~l "~eai le to water than skin despite
the 1 00-fold greater thickness of the nail plate than the stratum corneum. Thuswhen ~ ,sed per unit of thickness the nail is 1000 times more p~:""eai~le than
skin. More illl~JulLal-LIy in the present context it was realised that this greater
p~""dal,il;ly could be applied to the inward carriage of substances such as drugs
and prodrugs. F~ n)~ e~ by usin9 all 2o nails it was realised that the nail could
be made to absorb drug at a rate of 100 times more rapidly than the skin and even
more rapidly if the nails were treated as discussed below. Fullll~:,l.,o,t: fromknowledge of the nature of the nail it was concluded that lipid solubility would be
less critical than in the stratum corneum of skin, and more importantly, the limiting
molecular size of certain drugs capabie of being absorbed s~L~" '~ after
n~ ~' n to the nail would be au~.r~,_iauly greater than for stratum corneurn.
Finally because of the 100 fold greater thickness of nails, it was realised that the
nails could serve as a large and effective reservoir of drugs an effect most notably
established in the stratum corneum for topical co, LiCOak:l u; i~. From these findings
it is apparent that because of the much greater thickness of nails and the much
larger total surface area of all the nails than that which can be provided for certain
drugs by a conventional patch delivery system, the reservoir or storage effect
would be several hundred fold greater in the nail than in the stratum corneum
under a conventional patch delivery system. Also a larger reservoir would be
provided than in a conventional patch delivery system.
It has thus now become apparent that the nail can be used for the controlled
delivery of a very large range of drugs. The carrier to be used can vary with the
diff~rent drugs; thus it could be for example in the form of a conventional naillacquer a peel-off ~ ' a water soluble drying gel a stab~e emulsion, an
aerosol or liposomal or lipid or cream base; likewise a simple alcoholic or aqueous
solution could be used the choice depending on the characteristics of the drug to
be delivered and the dosage required. Likewise the drug Liol1 could be made
in one particular carrier in which the drug or prodrug could be dissolved or
SUBSTITUTE SHi~i`t (i'iULE 26)
W0 95123597 r r~ 2 1 8 4 0 7 5 ~ sq
.
11
suspended, and then the whole covered by further material, e.g. a conventional
lacquer, a water-soluble peel-off base or in some circ~",aLd"ces an occlusive
dressing or patch cor ,;"3 an additional reservoir of drug, with or without its
own Illen,b,d,~e. Thus, an advantage of the invention is that a large range of
carrier bases can be used and selected so that the effect of the nail itself could be
optimised to act both as a reservoir and rate limiting delivery system for the applied
drug, by using partiti~ning between the vehicle and nail and s~hsequPnt systemicabso".~ion from the naii. In addition to this method of controlling systemic
abs~"~ n from the nail, the absorptive cl~alacl~ lics of the nail could ll ~e,~ lv~s
be modified: thus nail thickness could be dec,~a~d e.g. by abrasion and other
physical methods, and modifiers of p~", ~at " y could be used e.g. using
pe~ dLion enl~a"c~:,b as previously mentioned or en~ymes to enhance delivery.
In other instances systemic aL,su,,~,lio,, of drug from the nail could be limited by
ll~ail ~9 nail dehydration e.g. by using a hypertonic solution. The use of thenail as a reservoir for the absorbed drug can be modulated in several ways. By
prior .~,, " .rn of saturated or even supersaturated solutions of drug the nail
reservoir can be rapidly filled after which continued constant absorption can beachieved by further surface .~ ' l as described. In addition, by ~ on of
a suitable source of fluid to the nail surface (e.g. in a pad), drug can be rapidly
extracted from the nail and its effect thereby ~IIll.ldLt:d. Variations in such
~pp' : :-~n would also permit ~peciri "y designed pulsed absor~uLio~ of drugs.
Fu, ~ ""o,~, since the rate of deliver,v is related to the surface area of the
nail, and since each nail has a different surface area ând thickness, enabling a~on:.isl~"Lly different water flux (varying from for exampie ~ to 13 g/m21hr in one
study going from the first to the fifth digit on the hand and similarly for the feet),
it will be possible to use nails singly or in Collli il~àliOI~ to control the dose of drug
absorbed by a range of some 50-fold. Thus the method provides a unique control
of dosage delivery.
As indicated, in making the present invention available data on water
transport through the stratum corneum of the skin was initially reviewed and
Sui3sTlTuTE SHEET (RULE 26)
W0 95/23597 ' ~ 2 1 8 4 0 7 5 ~ ' 1!;9 0
12
compared with data relating to water transport through the nail. Although it wasalready known that antifunga~ drugs could be applied to a diseased nail and a local
therapeutic effect may so",~ es be induced nobody had proposed the use of the
nail itself and its reservoir properties for other than the local delivery of drugs to
the nail e.g. for the treatment of local fungal disease. The concept of the present
invention of systemic ddlll;~ dLiol1 of drugs by this route is thus totally novel and
e-:Ldd. Furthermore, whereas the stratum corneum of the normal epidermis
acts as an effective barrier preventing the transport of most substances throughthe skin into the system circulation the finger and toe nails by way of contrasthaveaverymuchhigherp~""ea~ililyforsuitabledrugs. hlll~l~""u,t"whereasthe
stratum corneum is best able to absorb substances which exhibit an d,UI~l U~Cil I Id Ldly
50:50 distribution between aqueous and lipid phases or are more lipophilic finger
2nd toe nails have been found to be able to absorb therapeutically active
substances which are more hyd,u,.,l,'''ic
It is, acco"" ,~ly, a particular advantage of the invention that the range of
therapeutically active substances which can be a.l",i~ d is not limited in the
same way as the stratum corneum to particularly critical lipid/water solubility
partition Clldldl Ltlli~LiCs. Also, the c~"",osiLi"l1s which are applied to the finger
and toe nails do not need to be in the form of oil/water emulsions and effectiveCOIIIuuailiullS can be prepared which are essentially lipid-free. F--lllltnlllold
whereas it has been found that substances having molecular weights in excess of
1000 daltons usually fail to pass through the stratum corneum in sd~i~rd..lory
quantities higher molecular weights substances could be a-l",i"i~ d in
acc~".lal,ce with the invention via finger and toe nails.
of a therapeutically active substance in acc~,da"ce with the
invention has a further advantage that the active substances can be a~",i"is~ d
in a wide range of dosage amounts. Thus for example, if a given c~",po~ilion is
designed to provide a dosage amount of 10, ""~ d~lla of therapeutically active
substance which is released over a 12 hour period the dosage amount can be
increased in multiples by applying the col,,,uoai~ion to 1, 2 3... 20 finger and toe
SUBSTITUTE SHEET (RULE 26)
~ W095123597 ~ S 2 1 8~75 1~1. .s.~
13
nails. In other words, the dosage range may be varied by up to 20 times simply
by seiecting the number of naiis to which the con~posiIiùl1 is applied. Also,
because different nails have different surface areas (c.f. the thumb and first toe
nails with the fifth finger and fifth toe nails) an even wider range of possibledosage rates can be achieved by applying the c~"lposi~ion of the invention to
~ifferent finger and toe nails. The rate of ad~ Lld~i~n may be further adjusted
by i,lcul~uola~ g penetration el1llal~ccl:,.
Ful Lllel '' 'u~ by applying a therapeutically active substance to finger or toenails in acc~,-la"ce with the invention, the therapeutically active substance can
enter the systemic circulation without initially entering the hepatic circulation.
In formulating compositions for use according to the invention customarv
binding agents and film forming materials may be used. Thus, for example, any
of the polymeric film forming substances normally used in nail varnishes may be
used, provided that they are cOlll,ua~ibl~ with the therapeutically active substance.
Examples include poiyvinylacetate, acrylate and methacrylate esters and
nitroc~ '~ ?
Similarly, for other dosage forms such as those used in d~l ~I.,.I.Jl~ l andcosmetic ,, ' ns, the same range of adjuvants may be used for ~ n to
the nail for example emulsifying agents, surfactants, thickening agents, 5t;
colorants, buffers, a~Iiu~ddd~lL~, etc.
The con-,~l,LldLion of therapeutically active substance can vary over a wide
range but normally would not exceed about 100 or 200 l~ àlllS per millilitre.
Nolmally a conc~"L~dLion in the range of 10 l~ ,lug~allla to 100 I" ~jl d",a permillilitre would be used, most preferably 0.1 to 50 ", "i~ dlllS per millilitre, and
especially 0.5 to 2011 '1i~, dlll::l per millilitre.
SUBSTITUTE SH~ET (RULE 26
wossn3ss7 ~ 2 1 84075 ~ S~ o
14
PHARMACOLOGICAL TESTING
1. In Vrtro E,."_~i
The transport of therapeutically active substances through nail tissue was
examined for eleven drugs. The drugs included those used in conventional patch
delivery systems and others which are not known to be delivered in this way. Thedrugs were chosen to include a range of molecular size, chemical elld~dcle~iaLi~s -
polar/non-polar, lipid/water solubility and a variety of phd"l,ac~lo~icdl effects.
~ h~
A modified Franz cell was used, and normal big toe nails ~mostly obtained
after surgical removal for ingrowing nails or injury) were stuck between two sheets
of Teflon with aligned holes, se~.d, d~il Ig a donor from receptor reservoir. The nails
were soaked in HEPES buffer pH7.4 for 24h, the donor reservoir was then served
with 1ml volume of a solution of the drug in buffer (see Table 1 for dose
col1ce~L~dlions) and the passage of the radio-isotope of the drug into the receptor
reservoir was measured at timed intervals up to 36h. When the e~pe,i",d,)L was
cc""~ ,Led residual isotope was measured in the nail after incineration. Replicates
were made for all the drugs studied.
The results are given in Table 1 and Figures 3 to 7.
Table 1 su"""arises evidence of transungular transport for all eleven drugs
studied and Figures 3 to 7 are examples of plots and show that the rate of
transun~ulartransportwasappro~illldl~,lylinearstagesofpell,,ed~ion. Noattempt
was made in these experiments to optimise the transport of the durgs and the
maximal rates are likely to be appreciably greater than has been de",onsl,dLed.
SUBSTITUTE SHEET (RULE 26)
~ wossl23ss7 218497~ ~ -
TABLE 1
Rates of r ~ ~t.<.~ through human nail
and size of drug reservoir ~ u ?~ in the nails
S : --e undet ~est Nail A : ~d Rste rlme for Dru~
Thickness Dose of Drug (~g/cm2/ calc of Content
(mg) in 1ml h) rate lh) of Nai~ as
HEPES % of Dose
A - . - d
L-Nicotine* 1.43 510 97.8 12 - 36 1.08
~free base)
13-Oestradiol 1.53 0.003 59.6x10- 8 - 36 2.61
Quinuclidinyl* 1.00 1.95x10-4 7.0x10- 2 - 24 7.31
benzilate 6
Verapamil HCI 0.75 30 3.3 12 - 36 16.3
Indo,,,c:~l,a.;,, 1.05 0.32 0.028 12-36 2.76
DL-~o~.,c,nol~l 0.95 50 1.36 4 - 36 4.81
HC1
1.20 30 1.23 2 - 36 1.73
Morphine-13-D- 1.6~ 0.~ 15.0x10- 12 - 36 3.83
glucuronide 3
Acetylsalicyiic 1.70 3.3 0.037 4 - 36 7.64
acid
Clonidine HCI* 1.82 143 10.7 4 - 36 1.64
DAGO* (enkephalin ~nalogue) 1.48 25 2.9 2-24 0.73
*not a saturated solution
SUE,STITUTE SHEET (RULE 26)
2 1 84075
WO95/23597 ~ 4a ~l~ r ~,. 9~( ~9
16
2. In Vivo E,."~ s
Different conce"lldlio"s of nicotine were applied to different nails in a
healthy individual, a non-smoker, not in contact with smokers, and nicotine and
cotinine output were me2sured in 24h urine samples. The results are shown in
Table 9. The samples were not light protected or l~rlig~,dL~d and are therefore
indicative of lower levels of nicotine and cotinine than were originally present in the
collected urine samples. Although they cannot be corrected for breakdown of
nicotine and its ",~Ldb~liLe after collection, nevertheless it can be seen that
sig"iri..d~t quantities of the nicotine and its ",~Ld~oliL~ were found in the urine.
Fu,Ll,e""."~ on the day corresponding to the highest urinary output the subject,a non-smoker, ~ ,ienced symptoms associated with nicotine a~",i"i~L,dLion.
The results appear in the following Table 2:
TABLF 2
sample nicotine~uq/1) cotinine(uq/1)
1% Nicotine "peel off" 1 ND ND
10% Nicotine "peel off" 2 ND ND
10% in "water base" 3 ND < 10
10% "water base" covered with
2% in nail lacquer 4 20 20
10% in water base 5 < 10 < 10
ND - non detected
The results from the in vivo study confirms the in vitr~ findings that
transungual absorption of drugs occurs and can provide quantities of drugs
sufficient for systemic therapeutic action. The in vi~ro studies used a range ofdrugs and absu,,utiol~ occurred with different levels of lipophilicity and watersolubiiity, polarity, molecular size, etc. These results indicated that with suitably
SUBSTITUTE SHEET ~RIJLE 26~
_ . .. _ _ _ _ _ .. . . .. ... . ..
~ W095123597 ;~l~rl~ 2184075 P~
adjusted vehicles, including enhancing agents if necessary, far more drug could be
made to pass through the nail because of selective pdl Lilionil,g. Thus, we can
predict that transungual absorption could be increased still further. Nevertheless
the quantities which were absorbed through the nail were in msny instances
adequate to provide systemic therapeutic effects. Some, like nicotine and clonidine
are well absorbed through the l,a,lsde""al patch system and nail l, ~' ~ lion would
provide an alternative system, but others e.g. melatonin and the 5 amino acid
peptide enk~f.ll ', which were absorbed in acceptable quantities, nail application
provides distinct advantage over the Lldnsdl:lllldl system. From the degree of
transport of an enkephalin molecule we believe that peptides, polypeptides and
probably small proteins could be absorbed by the system. This would provide a
great advantage for the a.l,l,;"i~l,dlion of a number of peptide drugs and biological
agents, including those capab~e of being produced by biol~cllnology techniques.
The results also d~ ollaL~dl~ that the nail provides a ~;y"iri-,a,-t large
reservoir from which systemic absorption of drugs can proceed. Such a reservoir
could supersede the use of an external reservoir as in a patch system, or indeedcould be used further to ampiify such a reservoir designed to co",, ' "enl the
specific ulldlclcLe,iaLi.,s of the nail. Thus, Table 1 shows the magnitude of the
reservoirin the nails ~ OIIaLldLt:d by combustion and Id~iGisULO~;c measurement
and .:,~u, essed as a percentage of the drug material applied to the donor reservoir) .
In milligram tsrms, the figures were 5.49 for nicotine, 4.8g for verapamil HCI, 2.39
for DL-propranolo HCI, 2.35 for clonidine HCI and 0.14 for DAGO (enkephalin
analogue, Tyr Ala Gly Phe Gly; obtainable under catalogue E7384 from Sigma
Chemical Company).
r
SUBSTITUTE SHEET (RULE 261
W0 95/23597 ' `` i ~ 2 ,1 8 4 n 7 5 1'.~ . I'9 0
18
The following examples illustrate the invention:
FY~rnnle 1
,
A nicotine corllai~ 9 nail varnish was prepared by dissolving 2 wt% nicotine
in a co" " "e, cia'ly available thixotropic nitrocellulose collodion sold by SNPE Chimie
underthe desiu,,aLioll Suspension Base 320
Exam~le 2
A second and third formulations were prepared as described in Example 1,
but conl.,;,, ,9 5 wt% and 10 wt% nicotine.
Examr ie 3
Formulations similar to those described in Examples 1 and 2 were prepared
using a resin based LllikoLrupic gel manufactured by SNPE Chimie and clesig"aLedThb~oL,upic GEL 373.
Examl~le 4
Formulations similar to those described in Examples 1-3 or alternatively in
aqueous buffer solutions may be made using the drugs listed in Table 1.
SUBSTITUTE SHEET (RULE 26)
