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303 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 3(5): September-October 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093***

ICV 5.13*** Pharmaceutical Sciences REVIEW ARTICLE……!!!

NAIL DRUG DELIVERY SYSTEM: A REVIEW

GOPAL RATHORE*1

, Dr. ABHA DOSHI1

1Mumbai Education Trust‘s Institute of Pharmacy, Bandra (W), Mumbai, India.

2Gayatri herbals Pvt .Ltd, Kalika towers, Kolbad road, Thane (W), Mumbai, India.

KEYWORDS:

Nail Plate,

Bioavailability,

Antifungal, Penetrate,

Nail barrier.

For Correspondence:

GOPAL RATHORE*

Address:

Mumbai Education

Trust‘s Institute of

Pharmacy, MET

Complex, Bandra

Reclamation, Bandra

(W), Mumbai 4000-50,

India.

E-mail:

[email protected]

ABSTRACT

The purpose of this review is to focus the difficulties in penetration

of drug across nail plate and enhancement of bioavailability of

antifungal drug. The existing clinical system suggests that a key to

successful treatment of fungal diseases by topical application of

antifungal product in ineffectively overcoming the nail barrier.

Current topical treatments have limited therapeutic effectiveness

possibly because they cannot sufficiently penetrate in the nail plate to

transport a therapeutically sufficient quantity of antifungal drug to

the target sites to eradicate the protection. Also the analysis of the

drug's penetration is a difficult task. This review covers the anatomy

of a human nail, diseases related to nail plate, physiocochemical

properties of nail and techniques used to enhance the topical

bioavailability of the drugs across the nail, latest trends in drug

delivery across the nail.

mailto:[email protected]



INTRODUCTION :

Nail Anatomy & Physiology: A human nail is made up of three parts: the matrix, the plate, and

the nail bed. The matrix acts as a base for the rest of the nail, containing nerves as well as lymph

and blood vessels. The matrix creates the rest of the cells that make up the nail. The only part of the

matrix that is visible to the naked eye is the white, crescent portion of the nail known as the lunula.

On top of the matrix is the nail bed, which is made up of the dermis and epidermis. The visible

portion of the nail or the nail plate is made up of keratin and amino acids. It is formed by the

flattened, dead cells pushed up by the matrix and the bone of the finger determines its shape. Nails

are meant to protect the fingertips and toes as well as the tissues around them from injury. It also

helps the fingers themselves function in a more accurate manner. The nails place slightly more

weight on the finger tips allowing for more precise movements. It also increase sensitivity in the

fingertip. Despite the fact that the exposed part of the nail is comprised of dead cells it is attached to

a very sensitive portion of skin full of nerves. Any contact with the nail sends signals directly to

these nerves increasing sensitivity [8]

.

Fig. 1: Structure of human finger nail

COMMON DISEASES OF NAIL:

The nail plate may appear abnormal as result of acongenital defect, disease of skin with

involvement of the nail bed, systematic disease, reduction of blood supply, local trauma, tumors of

the nail fold or nail bed, infection of the nail fold and infection of the nail plate.

Leuconychia:

Leuconychia is the white spots or one or more lines appears on nails & grow out spontaneously.

The disorder may be caused by trauma, illness, malnutrition or any major metabolic condition,

chemotherapy or other damaging event and is the result of any interruption in the protein formation

of the nail plate.

Treatment: - To relief from the symptoms by including lot of nutrition in your daily diet. Proteins,

vitamins and zinc are essential elements that are to be added in daily food.



Fig. 2. Leuconychia

Onychomycosis:

Onychomycosis is yellow-brown patches near the lateral border of the nail. Beneath the masses of

soft horny debris accumulate and the nail plate gradually becomes thickened, broken and

irregularly distorted. One or many nails may be affected and there may be associated infection of

the skin. Most of the infections are caused by Trichophyton rubrum, T. inerdigitale, TineaUnguis,

or ringworm of the nails, is characterized by nail thickening, deformity and eventually results in

nail plate loss [4,5]

.

Fig 3. Onychomycosis

Treatment: orally antifungal terbinafine, itraconazole.

Topically application amorolfine, ciclopirox.

Onychatrop:

Onychatrop is an atrophy or wasting away of the nail plate which causes it to lose its luster,

become smaller and sometimes shed entirely. Injury or disease may account for this irregularity.

Treatment: orally use drug triamcinolone.

Fig.4. Onychatrop

Onychogryposis:

Onychogryposis are claw-type nails are characterized by a thickened nail plate and are often the

result of trauma. This type of nail plate will curve inward, pinching the nail bed and sometimes

requires surgical intervention to relieve the pain.

Treatment: use topical antifungal drug.

Marketed formulation: funginix, dermisil, terrasil, zetaclear.

Fig.5. Onychogryposis



Onychorrhexis:

Onychorrhexis are brittle nails which often split vertically, peel and \ or have vertical ridges. This

irregularity can be the result of heredity, the use of strong solvents in the workplace, including

household cleaning solutions. Although oil or paraffin treatments will rehydrate the nail plate, one

may wish to confer with a physician to rule out disease.

Treatment: Cream or lotion consisting of natural plant oil will keep the hand moist and help cure

the disease.

Fig.6. Onychorrhexis

Onychauxis:

Onychauxis is evidenced by over thickening of the nail plate and may be the result of internal

disorders.

Treatment: use of marijuana cream.

Prevention by: proper nail trimming and wear light shoes.

Fig.7. Onychauxis

Yellow Nail Syndrom:

Yellow Nail Syndrome (YNS) is a rare condition characterized by yellow nails with lack cuticle,

grows slowly and is loose or detached associated with onycholysis in one or more nails.

Treatment: topical – zinc application, clarithromycin.

Oral – tocopherol.

Fig.8.Yellow Nail Syndrom

Koilonychia:

Koilonychia is usually caused through iron deficiency anemia. These nails show raised ridges

and are thin and concave.

Treatment: iron supplements.

Fig.9. Koilonychia



Melanonychia:

Melanonychia are vertical pigmented bands, often described as nail ‗moles‘, which usually form

in the nail matrix. It could signify a malignant melanoma or lesion. Dark streaks maybe a normal

occurrence in dark-skinned individuals and are fairly common.

Treatment: cure by use of natural – hoodia gordonii plus. Revitol cellulite solutions.

Fig.10. Melanonychia

Psoriasis:

The nails are characterized by raw, scaly skin and are sometimes confused with eczema. When it

attacks the nail plate, it will leave it pitted, dry and it will often crumble. The plate may separate

from the nail bed and may also appear red, orange or brown, with red spots in the lunula. Do not

attempt salon treatments on clients with nail psoriasis.

Treatment: injection of corticosteroids, 5-fluorouracil.

Fig.11. Psoriasis

Paronychia:

Paronychia is a inflammation involving the lateral and posterior fingernail folds. Paronychia

infection of the nail fold can be caused by bacteria, fungi and some viruses. This type of infection

is characterized by pain, redness and swelling of the nail folds.

Treatment: Orally amoxicillin with clavulanic acid. Topically ketoconazole cream and

Hydrocortisone.

Fig.12. Paronychia

REQUIREMENTS FOR LOCAL THERAPY

• Potential active (antifungal) agent.

• High concentration of the drug in the formulation.

• Diffusion at levels exceeding MIC.

• Adequate method of delivery.

• Ease and convenience of application.



The diffusion of drug through nail depends on:

1. The Physicochemical properties of the nail

2. The Properties of chemical

3. The Physicochemical characteristics of the vehicle containing the active agent.

1. PHYSICOCHEMICAL PROPERTIES OF NAIL

The entire nail structure is hard keratin. The hardness of the nail plate not only depends on the

junctions between the cells and the transverse orientation of the keratin filaments with respect to

the axis of the nail growth. Moreover, the multiplicity of the lateral bonds between keratin fibers

(disulfide bridges, hydrogenbonds, acid- base bonds, electrostaticbonds) also account for high

resistance. The keratin of nails has been classified as ―hardtrichocyte keratins‖. It contains

significant amount of phospholipids, mainly in the dorsal and intermediate layers, which contribute

to its flexibility [2]

.

2. PROPERTIES OF THE CHEMICAL:

Among the other physicochemical properties of chemicals, these are the important set of

properties which affect the most, the drug absorption through nail.

a) SOLUTE MOLECULAR SIZE:

As the nail plate is produced mainly by differentiation of cells in the nail matrix and it comprises

three horizontal layers: a thin dorsal lamina the thicker intermediate lamina and a ventral layer

from the nail bed. Because the nail plate is composed of many strands of keratin held together

through disulfide bonds, the space between the strands must have a finite size causing the nail

plate to act like a molecular sieve. Small molecules can weave through these spaces while larger

molecules are unable to pass. The molecular weight of most antifungal agents is >300 Da.

accordingly, these drugs will have difficulty penetrating the nail plate, a likely reason for low

clinical efficacy observed. So, the optimum small particle size of the drug is the fore most

prerequisite for formulation point of view.

b) HYDROPHILICITY / HYDROPHOBICITY

There is a marked difference between the permeability characteristics of the nail plate and the

epidermis. These observed differences have been largely attributed to the relative amounts of lipid

and protein regulation within the structures and the possible differences in the physicochemical

nature of the respective phases. The lipid levels in the nail plate are nearly 1%, which combined

with lower water levels of about only 10% affords the nail plate. Studies using DMSO,

homologous alcohols of different molecular weights have shown that, the nail plate was

permeable to dilute aqueous solutions of low molecular weight homologous alcohols. As well as



the significant decrease in the permeation of the hydrophobic entity n-octanol following

delipidization of nail plate by chloroform / methanol also suggested that the nail plate possessed a

highly ―polar‖ penetration route and become rate controlling for hydrophobic solutes. The

chemical composition of nail and experimental evidence indicate that the aqueous pathway plays

a dominant role in drug penetration into nail. Water is the principal plasticizer for the nail. Upon

being hydrated, hard nail plates become softer and more flexible. Nail hydration is influenced by

many factors, such as solution pH and certain chemicals [12]

.

3. PROPERTIES OF VEHICLE:

pH of vehicle and solute charge

Antifungal agents have a range of pKa values and so studies have been reported that compare the

penetration of the ionic and non-ionic forms of the parent. These studies investigated the

penetration of miconazole (pKa=6.7), benzoic acid (pKa= 4.2), pyridine (pKa=5.3) and 5-

fluorouracil (pKa=7.9) in vehicles over pH range from 2 to 8.5. In the case of miconazole, it was

reported that penetration was in dependent of the pH of the vehicle. However, in all the other

cases, the ionic forms of the parent did not penetrate as well, as the non-ionic forms. A recent

study investigating the penetration of ionic and non-ionic compounds and the relationship with

molecular weight also found non-ionic compounds penetrate better[11]

.

ENHANCEMENT OF NAIL PERMEATION

Targeting drug treatment to diseases that reside within or below the nail plate is problematic due

to the highly restrictive barrier of the human nail. To optimize topical formulations for nail drug

delivery, inclusion of an effective penetration enhancer (PE) is imperative. Research is currently

being undertaken to design novel in vitro methods to assess the ability of compounds to penetrate

the nail plate. In addition, methods of chemical and physical analysis of the nail are being

developed.

(A) PHYSICAL MEANS

The composition of the nail plate suggests that, the use agents that effect by delipidization or

fluidization of the intracellular lipids can help in drug permeation. Many approaches have been

used to resolve these barriers to drug delivery [2]

.

These include:

a. Transdermal diffusion

b. Iontophoresis

c. Electroporation

d. Microneedles & thermal poration Iontophoresis



Electroporation: is a method in which, with the application of an electric pulse of about 100–

1,000 V/cm creates transient aqueous pores in the lipid bilayers making the solute particles

permeable through it [11]

.

Microneedle enhanced delivery systems: a method using arrays of microscopic needles to open

pores in the SC directly to the skin capillaries; also has the advantage of being too short to

stimulate the pain fibers, thus facilitating drug permeation.

Other physical techniques include manual and electrical nail abrasion, acid etching, ablation by

lasers, microporation, application of low-frequency ultrasound and electric currents.

(B) CHEMICAL MEANS

The high disulfide bond content of nail has been found to be responsible for the hardness of the

nail. In recent years, the ability of compounds that possess –SH groups to increase nail

permeation has been documented. Promising enhancers in sulfhydryl containing endopepetidase

enzyme, 2-mercaptoethanol, 1,4-Dithiothreitol which contains 2-SH groups and various

reducing sulfites and bisulfites. These increase the ability of the nail to hydrate. As well as nail

softening agents (keratolytic agents) like urea and salicylic acid can be used in the formulation

for enhancing the drug permeation through chemical-mean [2]

.

Approaches of nail drug delivery

a) Topical application

Oral administration of antifungal therapy is inherently associated with GI and systemic side

effects. Obviously, topical delivery is the most desired therapy due to relatively less severe side

effects and better patient compliance particularly in case of pediatric patients. Unfortunately,

there are at least two factors that could limit the accumulation and activity of drugs in the nail on

topical application. First, the physicochemical properties of the drug need to be favorable for

absorption through nail matrix. The nail matrix reported to be relatively more permeable to polar

compounds than nonpolar compounds. Second, binding of the drug to keratin reduces the

availability of the free drug. Antifungal drugs are reported to possess high binding affinity to

keratin.

b) Chemical penetration enhancement

The common approach for enhancing nail drug delivery has been to use keratolytic and

thiolytic agents. These agents are known to increase the permeability of nail matrix by chemical

modification of keratin. However, their permeability enhancement potential is limited by the

factors like penetrability of enhancer and the duration of its presence in the nail matrix might



significantly influence the chemical modification of keratin. Topical monotherapy is considered

less efficient in treating nail disorders such as onychomycosis due to poor trans‐nail

bioavailability of drugs.

c) Physical penetration enhancement

James and coworkers carried out iontophoresis of prednisolone sodium phosphate across

thumb nail and determined the time course of prednisolone in plasma However, there is need for

systematic preliminary studies to assess the efficacy and resolve the mechanistic aspects of

iontophoresis across nail (James M. P.,et al., 1986). Recently the iontophoretic trans‐nail

delivery method showed good results in treating nail fungal syndromes. S.Narsimha Murthy and

co‐workers have studied the effect of Iontophoresis on the permeability of salicylic acid across

human nail plate. They conducted diffusion study using Franz diffusion cell incorporated with

electrode with it (Murthy S.N., et al., 2005). The results showed drastic increase in the

permeability of a test penetrant across nail plate as compared with the conventional method of

penetration [11]

.

Recent advances in nail delivery

Apart from the traditional formulation like nail lacquers, nail varnish, and nail patches recent

technologies are introduced in the development of more efficient drug delivery. Here some of the

recent technologies are listed which open the new horizons for drug delivery to the human

nail[12]

.

a) Electrochemotherapy for Nail disorders :

The goal of this therapy is to develop an active method of drug delivery across the nail plate

which in turn is believed to increase the success rate of topical monotherapy and decrease the

duration of treatment of nail disorders. Currently, the electrically mediated techniques for drug

delivery across the nail plate are investigated. Recently the iontophoretic trans‐nail delivery

method studied. Iontophoresis was found to enhance the transport of drugs across the nail plate

significantly. Similar to transdermal iontophoresis, the predominant mechanisms contributing to

enhanced transport of drugs in the case of transnail iontophoresis are electrophoresis

electroosmosis. Iontophoretic permselectivity of the human nail plate and its applicability on

the trans‐nail delivery of drugs are also under investigation.

b) Mesoscissioning technology:

Mesoscissioning technology creates a micro‐conduit through the skin or nail within a specified

depth range. Fully open pathways can be painlessly scized (cut) through the stratum corneum of

the skin or through the nail. Microconduits, 300‐500 microns in diameter, are produced within



seconds and without sensation. These pathways can be used to deliver drugs across the skin

(proof‐of‐concept in vivo human experiments have shown full anaesthesia occurs within 3

minutes through microconduits compared with 1+hour through intact stratumcorneum). Such

microconduits also permit access for subdermal analyte. extraction (including blood for

glucosetesting). In addition, they reduce the skin electrical impedance to less than 1000 ohms

for biopotential measurements. In nails, microconduits quickly reduce the painful pressure of

subungual hematoma (black toe) and could serve as a prophylactic to prevent such pressure

build‐up in runner's nails.

c) NanoPatch Nail Fungus:

NanoPatch Fungus uses AC/DC electrochemistry and targeted drug delivery to actively push

antifungal drugs right through the nail cuticle to the actual location of the fungus growth. This

would be the first treatment option to directly target nail fungus at its source of growth[10]

.

Table 1: Marketed formulations for nail disorders

Sr.No.

Name of product

Name of drug

Uses/Indications

Name of

company

1 Eco‐Nail

nail lacquer

5%

econazole+18%

SEPA

nail lacquer

Promotes the release of

econazole from dried lacquer

film, creating a large chemical

gradient at the lacquernail

interface, to drive econazole in

the deep nail plate SEPA acts as

a percutaneous penetration

enhancer which itself has no

effect on nail and do not

penetrate nail.

MacroChem

Corporation

2 Loceryl

nail film

antifungal

drug,

amorolfine

A non‐water‐soluble film of

amorolfine formed on the nail

plate, and this film remains in

place for 1 week. The film

contains a high concentration of

amorolfine and forms a depot

from which the drug is

delivered and which allows the

drug to permeate the nail plate.

Galderma

Australia Pty

Ltd

3 Umecta nail

film

Urea 40%

Psoriatic nails, brittle and thick

nails, and calluses

JSJ

Pharmaceuticals

4 Tazorac 0.1%

Gel

Tazarotene

Used in the Treatment of

Fingernail

Psoriasis

Allergan Inc



5 Zalain nail patch

Sertaconazol

nitrate

Once‐a‐week nail patch for

treatment of onychomycosis &

onychodystrophy

Labtec

6 Penlac nail

lacquer

Ciclopirox topical

solution

a broad‐spectrum antifungal

medication that also has

antibacterial and

antiinflammatory

properties

Dermik

Laboratories

Inc.

CONCLUSION:

Drug delivery to the nail (ungula drug delivery) constitutes a major challenge, with the lack of

understanding of both the barrier properties of the nail and formulations to achieve enhanced ungula

delivery restricting the efficiency of topical treatment for nail disorders. Nail diseases like

onycomycisis, nail psoriasis, yellow nail syndrome, paronychia and many more, being cured

successfully using medicated lacquers. This avoids the oral toxicity of antifungal drug and provides

longer contact time at the site of action. This systemic review covers the anatomy of a human nail,

diseases related to nail plate, the formulation designed for nail application and some techniques

used to enhance the topical bioavailability of the drug across the nail, latest trends in drug delivery

across the nail.

REFERENCES:

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and skin retention of three model penetrants. Eur. J. Pharm. 2004; 21: 337‐345.

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5. Chaudhari P. D., Chaudhari S. P., KolsureP. K., Bothiraja C. Drug Delivery Through Nail ‐

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8. Dykyj J. D. Anatomy of the nail clin padiatr.med. surgery. 1989; 6(2): 521‐28.

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Archives fodermatologishe for schung. 1975; 251:199.

10. James M. P., Graham R. M. English J.Percutaneous iontophoresis prednisolone—A

pharmacokinetic study. Clinical and experimental studyII. 1986; 54–61.

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keratinized tissues. Biochim Biophys Acta. 1973; 322: 269–278.

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13. NanoPatchAC, Inc, www.nanopatchac.co. Accessed May 29, 2009.Path Scientific, LLC,

111 www.pathscientific.com.Accessed May 29, 2009.

14. The University of Mississippi,www.pharmacy.olemiss.edu. Accessed May 28, 2009.

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on the permeation of miconazole. J Pharm Pharmacol. 1985;37: 498-499.

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http://www.nanopatchac.co/

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