Drug delivery to the nail

following topical application

Dr Sudaxshina Murdan
UCL School of Pharmacy

1
 Ungual drug delivery
• Why?

• Why is it so difficult ?

• What affects drug permeation into nail ?

• How can we enhance drug permeation into

nail ?

• Drug delivery vehicles for application to

nail
2
The nail unit

Grows on average
3 mm per month
(fingernails)
1 mm per month
(toenails)
Fingernails and toenails
grow out in 6 and 12-18
months respectively.

Size, shape, curvature

Colour (blood vessels)
Variability 3
The nail plate lies on the nail bed, is produced by the nail matrix
and is framed and ensheathed by the nail folds and the
hyponychium.

All these components, i.e. nail plate, nail bed, nail folds, matrix
and hyponychium make up the nail unit.

proximal nail fold Lateral nail fold

cuticle
hyponychium

Nail plate

Nail bed (underneath

Nail matrix (underneath lunula nail plate)
the skin) 4
 Nail plate

Distal groove

Finger pulp

5
 The nail unit
The nail unit starts to develop in the 10th week
of embryogenesis and is almost completely
formed by the 17th week, after which changes
in the nail unit are mainly associated with
growth;

The nail unit is well perfused by blood and

lymphatic vessels, has a rich nerve supply, and
is anchored in place by attachment to the
distal phalanx

6
Baby’s first nailplate

7
 The nail unit - functions

It allows one to manipulate objects,

enhances the sensation of fine touch,
protects the delicate tips of fingers
and toes against trauma, and is used for
scratching and grooming

Also, (nail biting) provides a sense of

relief as well as an activity to alleviate
boredom 8
Cosmetic organ

9
 Fingernail as a tool
Photograph (taken at the Museum of London, London) of a pottery bowl 3000 BC.
Decorative markings on the pottery were created by fingernails.

10
 Diseases of the nail
• range from relatively innocuous conditions such as
pigmentation in heavy smokers, to painful and
debilitating states where the nail unit can be
dystrophied, hypertrophied, inflammed, infected etc

• Not all the parts of the nail apparatus are affected,

for example, in some diseases, only the perionychial
tissues (the nail folds) are affected while the nail
plate is normal. In other diseases, the nail plate’s
shape, surface features, colour, mechanical
properties and attachment to underlying soft tissues
are altered

11
 Disorders of the nail (cont.)
The nail plate may be absent in newborns, excessively long or short,
large or small, thickened and hypertrophied.

Nail plate curvature can also be affected. Nail clubbing in

broncho-pulmonary and cardiovascular diseases.

Nail plate surface may be rough, excessively ridged with a dull or

shiny appearance or covered in pits

Nail plate colour, mechanical properties, attachment to

underlying tissues can be affected

Nail folds may be inflammed/infected

12
13
14
15
16
17
18
19
20
21
22
Hoof nail deformity

Hoof nail deformity: a

previously unknown
hereditary nail malformation.
Jung, G W; Salopek, T G
The British journal of
dermatology 169, 4, 946-8,
2013

23
Treatment of
congenital
onychodysplasia
of the index
finger with
specialized nail
device
Park, S. -W.;
Lee, D. -Y.
Clinical and
experimental
dermatology 38,
7, 791-792 oct
2013
24
 Onycholysis in
Playstation Thumb

Renato
Marchiori
Bakos,
Lucio Bakos,
Arch
Dermatol
2006, 142,
1664-65
25
 Nail health in the news

http://www.telegraph.co.uk/health/healthnews/11167455/Healthy-nails-
healthy-life-what-your-nails-are-telling-you.html

26
 Treatment of nail disorders
• Nail disorders can have numerous origins, e.g. chemicals,
infections, trauma, and congenital, hereditary, systemic and local
diseases.

• Treatment will depend on the originating cause.

• Some disorders, e.g. white spots grow out with the growing nail
plate (although new ones can reappear).

• Changes in the nail due to exposure to local/systemic chemicals

and trauma can be treated by removal of the insult.

• Other symptoms of nail diseases are resolved following the

treatment of the underlying condition, such as, drug treatment
of infections, surgical removal of tumours or of foreign bodies
and surgical treatment of abnormalities, such as ingrowing 27
toenails.
 Common diseases of the nail
• The two most common diseases are:

• Onychomycosis (fungal infections of the

nail plate and/or nail bed). Accounts for
50% of nail disorders.

• Nail psoriasis

28
 Onychomycosis
• Affects 3-10% of the population in Europe (higher
figures eg 14% are sometimes quoted)

• Prevalence is higher in the elderly (20% of people aged

over 60 years, up to 50% of people aged over 70 years)
and

in diabetics (up to one-third of diabetics)

in immunosuppressed

• Prevalence seems to be on the increase

29
increased urbanization, community showers, sports, and the use of occlusive footwear
Fungal infection

30
 Subungual dermatophytoma complicating dermatophyte onychomycosis

British Journal of Dermatology

Volume 138, Issue 1, pages 189-190, 4 JAN 2002 DOI: 10.1046/j.1365-2133.1998.02050.x
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2133.1998.02050.x/full#f1
 Onychomycosis treatment
• Moderate to severe disease - oral
antifungals e.g. terbinafine, itraconazole

• Disadvantages - non-responders,
relapse, systemic side effects, hepatic
function tests, blood counts are
recommended

32
 Nail psoriasis
• 1-3% of most populations are affected
by skin psoriasis

• 80% of people suffering from skin

psoriasis also show nail psoriasis

• long term condition, difficult to cure,

relapse is common, treatment long-
lasting 33
Nail psoriasis

34
 Nail psoriasis treatment
• Preparations that are used for skin psoriasis

• Injection of corticosteroids into the nail folds;

injections are extremely painful and are repeated
monthly, for 4-6 months

Cortisone injection into nail Subungual haemorrhage

35
folds after intralesional injection
 Topical therapy of nail diseases

• Both drug and formulation contribute to medicine

efficacy

• Many advantages - specificity, reduced side effects,

low cost, etc

• But efficacy is low e.g 18% complete cure rate

• Currently, topical therapy is only recommended for

early, mild, superficial disease

• Nail plate is a good barrier, permeability is very low

36
A few nail preparations

37
 Routes of drug delivery into
the nail

38
Gupta and Simpson, Journal of Dermatological Treatment, 2016, 27, 1, 2-4
 Complete cure rate (%) at
week 48 following once daily
application*

Formulation Trial 1 Trial 2

Kerydin* 7 9

Jublia* 18 15

Penlac* 6 9

Onytec** 6
Loceryl 13-54% once or twice
 Currently, there are few
effective topical formulations

permeability of the nail plate is very

low

only a small % of drug that is applied

onto the nail plate penetrates into the
nail plate – structure of plate
40
Dorsal nail surface - cells overlap

41
Cells of the dorsal nail plate

42
Ventral nail surface

43
Nail cross-section

44
 The nail plate
• 80-90 layers of dead, keratinised, flattened
cells that are tightly bound to one another

• consists mainly of keratins

80% hair-type, 20% ‘soft’ skin-type

• contains 10-30% water but only 0.1-1 % lipid

(different to skin, which contains 10-20% lipid)

Fingernails approx. 0.5mm; toenails about 1mm

thick 45
In vitro drug permeation tests

Drug formulation
Franz diffusion cell
Nail plate

Wet cotton wool

Nail plate

Agar gel
46
 to assess ungual drug delivery

what membrane?

• ideally, whole nail plate

• nail clippings

• healthy nail / diseased nail

• bovine hoof membrane (model)

47
 Nail clippings
Small area of drug permeation

48
Hoof membranes

49
In vivo anti-fungal efficacy
test

Nail plate

Agar gel

50
Agar gel often used when fungal
inhibition is tested

51
 Drug permeation into the nail may be
influenced by:

• properties of the drug (e.g. size, shape, charge,

hydrophobicity),

• formulation characteristics (e.g. nature, pH),

• nail properties (e.g. hydration, disease state),

• interactions between the permeating molecule

and the keratin network of the nail plate

• use of any penetration enhancers

(chemical/physical)
52
Factors which influence
ungual drug permeation

• Molecule size – most important

factor

53
 Kobayashi et
al, 2004

P represents Permeability
coefficient

MW of
drugs
Nail
clippings
54
 P represents Permeability coefficient
Mertin & Hoof membrane often used as a model
Lippold, 1997 55
Charge
• Kobayashi et al 2004 - Non-ionised permeated
more (10x) than ionised, irrespective of the
charge – due to small increase in the apparent MW
due to ion hydration

• Soong et al, 1991 – Uncharged molecules

permeated to a greater extent.

• Mertin and Lippold, 1997 – greater permeation of

uncharged drugs.

• Myoung & Choi, 2003, salt form of ciclopirox

permeated to a slightly greater extent than the
free acid.

• Walters et al, 1985 – no effect of pH on ungual

flux of miconazole – charge did not have an effect
on permeation 56
 Hydrophilicity/ lipophilicity of diffusing
molecule

Walters et al, 1985 –

suggested a lipidic
pathway for the more
lipophilic alcohols

57
 Hydrophilicity/ lipophilicity of
diffusing molecule (cont.)
Top curve: hoof
membrane,
Bottom curve: nail
plate

Mertin &
Lippold, 1997

Also, Kobayashi et al, 2004 – no relationship found

between permeability coefficient and octanol-water 58
partition coefficient.
Nature of vehicle

Cosolvents
Top curve –
DMSO
Bottom curve -
isopropanol

Presence of water Plotted from Walters

favours permeation et al, 1985 59
 Nature of vehicle (cont.)

• Ciclopirox
marketed gel (0.77%) vs lacquer (8%)

• More drug in the deeper nail layers

and through the nail when gel was
used

Hui et al, 2004

60
 Nail properties
• Thickness ?
• Disease state. Detachment of nail plate
from nail bed? More crumbly plate?

• Hydration – increased hydration leads

to increased drug diffusivity in healthy
nails

61
 62
SEM dorsal images of a healthy toenail (left column) and a diseased nail (right column).
SEM cross-sectional images of a healthy toenail (left column) and a diseased toenail (right column).
63
 Characteristic Healthy nail Diseased nail

Pore size 0.78 ± 0.29 1.52 ± 0.59

Nail thickness (mm) 0.49 ± 0.15 1.20 ± 0.67

Nail density (g/cm3) 1.34 ± 0.01 1.29 ± 0.00

Diseased nail – mechanical properties – nailplate breaks easier

64
To enhance ungual permeation,
we need to disrupt the nail
plate

65
Physical disruption of nail plate

66
 Enhancing ungual drug permeation

by filing dorsal nail

surface

Dorsal and ventral filed

Dorsal filed
Ventral filed
Not filed
Kobayashi et al, 1999 67
 Filing (cont.)
• In clinical trials, filing was found to increase
permeation.

• In Patient Information Leaflets of topical

anti-fungal lacquers, patients are asked to
file nail. File is provided in pack.

• More aggressive abrasion of the nail plate

surface, using using dental drills have been
used. E.g. in one study drilling was performed
to reduce nail thickness to 1-2 mm

68
 Etching the nail plate
Nail pieces were etched by applying
phosphoric acid gel (10%) for 60s.

• Repka et al. 2004

69
Increases surface roughness and area of nail
plate,

Decreases effective membrane thickness,

increases adhesion of film to nail

increases permeation of drug into the nail 70

Ablation of the nail plate using
pulsed lasers

Different lasers produced different holes

Ho:YSGG laser, Er: YAG, XeCl laser, and

ultrashort laser systems.
Neev et al. Lasers Surg Med. 1997;21:186-92. 71
Microporation of the nail plate

the drilling of individual holes in the nail plate by the PathFormer.

http://www.pathscientific.com/technology.ps.html.

72
Application of low frequency ultrasound (US)
via a coupling medium

US1 (230 um)

US2 (200 um)

25
C u m u la tiv e a m o u n t p e r u n it a re a

US3 (150 um)

US4 (150 um)

20
US5 (150 um)
( m g /m m 2 )

15 US6 (150 um)

M2 (180 um)
10
M3 (190 um)

M4 (180 um)
5
M5 (190 um)

0
0 5 10 15 20 25 30 35
Time (h)

Top 6 curves (with US); bottom curves control.

73
 Cavitation

Suggested mechanisms by which low-frequency ultrasound

enhances membrane permeability.
Collapse of cavitation bubbles in the bulk medium result in
shockwaves which impact on the membrane (a), while bubble
collapse near the membrane results in the formation of liquid
microjets which impact on (b) and can even penetrate into the
membrane (c). 74
Application of electric currents

• Charged drug is repelled by same charge

electrode into the nail plate

• Uncharged drug permeates nail by

electro-osmosis

75
 Application of electric currents (cont.)

Charged drug

J Pharm Sci 2007; 96:305-311.

76
Chemical enhancement of nail plate
permeability

77
• Transdermal enhancing agents do not
enhance nail permeability

• Use agents which can destabilise nail

keratin

78
Sun et al, 1999 79
 Enhancers have been investigated

Keratinolytic agents compounds to cleave the

Urea and salicylic acid - disulfide (-S-S-) bonds in
soften the nail plate – nail proteins
not successful on their
own

Sulfhydryl compounds –
Sulfites and bisulfites which
contain SH groups which
can reduce the disulfide
reduce -S-S- bonds of nail
bonds in nail proteins 80
keratin
 Most promising enhancers

Compounds containing sulfhydryl (-SH)

groups e.g. acetylcysteine,
mercaptoethanol, mercaptan derivative
of an amino acid

Keratin-S-S-Keratin + 2 R-SH → 2 Keratin-SH + R-S-S-R

enhancer action was found to be fairly durable and poorly reversible 81

A – control
B- 10% urea
C- 5% AC Nail swelling

D- AC + urea

Sun et al, 1999 82

Drug in nail
Examples of –SH containing
compounds that have been
tested

83
 O
pyrithione
N SH

CH3 8-mercaptomenthone
Ineffective
HS CH2 CH2 OH
Disorders lipid in
mercaptoethanol O skin
H3C C CH3
SH
O
CH3 CH C NH CH2 COOH
SH HOOC CH CH COOH
Acetyl cysteine SH SH
meso-2,3-dimercapto succinic acid
84
Thioglycolic acid Ineffective (pH of gel = 9)
 Sulfites
R-S-S-R + Na2SO3 → R-S-H + R-S-SO3H
influence of ss

25

20
Intensity

15 after ss
before ss
10
cf and ss in donor
5

0
0 2000 4000 6000 8000 10000
time (min) 85
In our lab
 Sulfites (cont.)

Also tested:
Na2S2O5 + H2O → NaHSO3 -

not effective at 10% on nail (Malhotra &

Zatz 2002)

86
 oxidising agent hydrogen
peroxide

• On its own
• In combination with urea

Increased drug permeation and fungal kill

87
 Enzymes

keratinase enzyme – will hydrolyse nail

keratin and disrupt nail plate

Alone and
in combination with reducing agents

88
89
90
91
92
 Enzymes (cont.)
12

control
permeant/area (mcg/mm2)
Cumulative mass of

0
0 5 10 15 20 25 30
time (h)

42

permeant/area (mcg/mm2)
35
Cumulative mass of
28

21

14

0
With enzyme 0 5 10 15 20 25 30
time (h) 93
Delivery vehicles for drug
application to nail plate

94
 Delivery vehicles
• Solutions e.g. Kerydin, Jublia, tioconazole nail
solution, an undecenoate solution and salicylic acid
paint–
not resistant to water – apply daily

• Nail lacquers (Loceryl®, Penlac®, EcoNail)

More resistant to water

• Pressure sensitive adhesives (patches)

• paints, gels, ointments, pastes, extruded films

• Excilor pen 95
 Nail lacquers

consists of
• solvents
• film forming polymer
• resins
• Plasticisers

• Drug
• Enhancer?

96
 Nail lacquers
– have the correct viscosity for ease of application;

– the lacquer must dry quickly (in 3-5 minutes) and

– form an even film which

• adheres well to nail plates
• does not come off during daily activities,
• But can be removed cleanly with enamel remover and
• is well-tolerated locally
• colourless and non-glossy to be acceptable to male
patients.

Most importantly, the drug must be released from

the film so that it can penetrate into the nail and
achieve fungicidal concentrations. 97
 Nail lacquers
Loceryl  - amorolfine (5%) → 25% in film

Penlac  - ciclopirox (8%) → 35% in film

drug
Lacquer film

Nail plate

Nail bed 98
 Nail lacquers
• Are effective at treating mild-to-moderate fungal
infections

• They are well tolerated

• Are cost effective for mild to moderate

onychomycosis

• For severe disease, they may be used

• in combination with oral therapy (reduces
oral drug intake and cost of treatment and
higher cure rate achieved)

• on their own, in children, in pregnant and in

breastfeeding women, in patients with
hepatic and/or renal impairment
99
 Increased drug flux into nail
plate/ increased cure rate

• When drug concentration in lacquer

was higher (5 vs 2%)

• Duration of contact / treatment

• Increased frequency of application

(not stat sig)
100
Formulation of drug-containing
lacquers is very important

• Choice and proportions of polymer,

solvents, resin, plasticiser

• Formulation studies are empirical,

knowledge is lacking, not much help
from cosmetic lacquers

101
Lacquer films containing precipitated drug crystals 102
 Econail lacquer
• Presence of 2-n-nonyl-1,3-dioxolane
increased penetration of econazole into
nail

• Softens the film

• Adhesion promoter

103
 Future of lacquers
• Rational development of nail lacquers

• Lacquers containing combinations of

drugs,

• Lacquers containing ungual enhancers

• Hydrophilic lacquers, water-washed

• Bilayered lacquers? 104
Nail Patch

105
 Nail patch

4 July 2013

106
 Nail Patch
adhesive polymer + solvent + drug

cast solution onto the backing membrane

dry for 72 hrs at room temperature

place release liner

107
 Nail Patch
• Must adhere on the nail for a long time

• Drug must leave patch and enter the

nail in sufficient amounts

108
109
 New drugs
• With improved properties, e.g. low
keratin binding of efinaconazole

• Tavaborole – low MW

110
 Homework for revision
• Formulations and drugs

111
 References
• An atlas of diseases of the nail, Rich & Scher, London, Parthenon, 2002
• Topical Nail Products and Ungual Drug Delivery. Eds. S. Narasimha Murthy and H Maibach,
CRC Press: Boca Raton.
• Focal Controlled Drug Delivery, 2014, chapter on Nail

• J Del Rosso, 2014, The role of topical antifungal therapy for onychomycosis and the
emergence of newer agents, The Journal of clinical and aesthetic dermatology, 7, 7, 10-18
• Gupta, Aditya K.; Simpson, Fiona C. 2014. Investigational drugs for onychomycosis , Expert
Opinion on Investigational Drugs, 23, 1, 97-106 .
• Elsayed 2015. Journal of Controlled release, 2015, 199, 132-144

• S Murdan, 2002. Drug delivery to the nail following topical application, Int. J. Pharm., 236, 1-
26.
• S Murdan. 2008. Enhancing nail permeability of topically applied drugs,, Exp. Opin. Drug
Deliv. 5 (11) 1267-1282.
• Gupchup GV, Zatz JL. Structural characteristics and permeability properties of the human
nail: a review. J. Cosmet Sci 1999;50:363-385.
• Sun Y, Liu JC, Wang JCT, De Doncker P. Nail Penetration. Focus on topical delivery of
antifungal drugs for onychomycosis treatment. In: Bronaugh,R.L. and Maibach, H.I.
(Eds).`Percutaneous Absorption. Drugs-Cosmetics-Mechanisms-Methodology. New York:
Marcel Dekker Inc., 1999, 759-787.
• Shivakumar HN, Juluri A, Desai BG, Murthy SN. Ungual and Transungual drug delivery. Drug
Dev Ind Pharm. 2012;38:901-11.

• S Murdan, D Hinsu, M Guimier. 2008. A few aspects of transonychial water loss (TOWL):
inter-individual, and intra-individual inter-finger, inter-hand and inter-day variabilities, and
the influence of nail plate hydration, filing and varnish. Eur. J. Phar. Biopharm. 70, 684-689.
http://dx.doi.org/10.1016/j.ejpb.2008.05.018
• M Mohorčič, A Torkar, J Friedrich, J Kristl, S Murdan, 2007. An investigation into
keratinolytic enzymes to enhance ungual drug delivery, Int. J. Pharm., 332, 196-201.
• S Murdan, 2004. Nail varnish as a drug delivery vehicle, The Drug Delivery Companies 112
Report, Spring/Summer, 40-42.