Drug Delivery Through Nail - A Review

Pravin D.Chaudhari*, Shilpa P. Chaudhari ¹, Pramod K. Kolsure², C.Bothiraja³

ABSTRACT:

The purpose of this review is to explore the difficulties in penetration of drug across nail plate & enhancement of bioavailability of antifungal drug. The existing clinical evidence suggests that a key to successful treatment of fungal diseases by topical antifungal product lies in ineffectively overcoming the nail barrier.

Current topical treatments have limited therapeutic effectiveness possibly because they can not 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 .Here in the present article a method to analyse the drug permeated across nail barrier is suggested.

INTRODUCTION:

The nail is horny structure. Nail plate is responsible for penetration of drug across it. As it is hard enough the penetration becomes difficult, only a fraction of topical drug penetrates across it. Hence the effective therapeutic concentration is not achieved. The nail plate may appear abnormal as a result of decreased glow.It`s involvement of nail bed, reduction of blood supply, physical or chemical features of nail bed. As a result variety of diseases occurs. These diseases can be cured by achieving desired therapeutic concentration of drug by nail drug delivery system.

STRUCTURE OF THE NAIL

The nails are composed of flat,horny scales which form protective covering for the distal of the finger & toes.^1,2,3Each   nail consist of  following parts -

1) A body, the attached uncovering of the nail

2) A free edge, the anterior unattached extension of the body

3) The nail root, the posterior or proximal part of the nail, which lies beneath a fold of the skin. 

Most of the body of the nail is pink because it is sufficiently translucent to transmit the colour from the underline vascular tissue. The proximal part of the nail is whitish & called the lunula because of it has pale moon shape due to the air mixing with the keratin matrix. It has no physiological function.

The fold of skin, which extends around the proximal & lateral borders of the nail, constitutes the nail fold, & the skin, which lies beneath the nail, forms the nail bed. The furrow between the nail bed & nail fold is the nail groove. The nail itself is a hard horny & consists of several layers of clear, flat cells that contain shrunken & degenerated nuclei. The striated appearance observed in section cut perpendicular to the surface is produced by the arrangement of the cell in layer.

The bed consist of epithelium and dermis continuous with the epidermis & dermis if the skin of the nail folds. The epidermis of the nail folds usually has zones characteristic of palmar skin, although the stratum lucidum may thin or absent in some cases. The stratum corneum of the proximal nail fold turns into the nail groove, spreads over the upper surface of the root, and is continuous for a short distance on to the surface of the body of the nail as the eponychium.

The epithelium of the nail bed corresponds to Malpighian layer of the of skin & like the later, consists of polygonal prickle cell & stratum cylindricum resting upon a basement membrane. The epithelium of the posterior part the nail bed, the part that lies beneath the root & the proximal portion of the body corresponding to the lunula, is thicker than elsewhere & is called as the matrix because it functions for nail growth. Growth of nail takes place by a transformation of the more superficial cells of the matrix in to true nail cells. In the process the outer, harder layer is pushed forward over the malpighian layer. The nails generally increase in length by about 0.5 mm / week. Fingernails grow more quickly than toenails & growth is quickly when the environmental temperature is high. Nail plate is almost completely formed by the 20^th  week of the fetal life .Under the distal free edges of nail, the epithelium of the nail bed become continuous with the malpighian layer of skin & the other layers characteristic of the skin thickened and is known as the hyponychium .

The dermis of the nail bed differs some what from that of ordinary skin. Its connective tissue fibers are arranged partly longitudinal to the long axis of the nail & partly in a vertical plane extending from the posterior to the nail. Dermal papillae are found beneath the proximal part of the nail root but disappear beneath the distal part of the root, to be replaced by longitudinal dermal ridges which, increase in height as they pass forward, continued to the distal end of the nail bed. Because of the dermal ridges longitudinally, the boundary between the epithelium and connective tissue appears smooth in longitudinal section and irregular and papilla like in cross section.

The human nail plate consists of three layers; the dorsal & intermediate layer derived from the matrix, & the ventral layer from nail bed. The intermediate layer is three - quarter of the whole nail thickness & consists of the soft keratin. The upper layer, dorsal, is only a few cell layer thick but consist of hard keratin, with a relatively high sulphur content, mainly in the form of amino acids cysteine, which constitutes 94 % by weight of nail.⁴ The upper layer of the nail mainly diffuses into & through the nail plate. The ventral layer consists of soft hyponychial in which many pathological changes occurs.Thus, in the treatment of these nail diseases, an effective drug concentration in the ventral nail plate would be of great importance.

Nail Growth is greatest in childhood and decrease slowly with aging. Due to pressure from posterior nail fold the grows forward instead of upward. Nail growth is also affected by local disturbances in the nail fold or by abnormal keratinization of the nail plate. General or local factor may result in the development in the nail of thicken, ridging, pitting, discoloration, brittleness, splitting, and even separation of nail from its bed (onycholysis). A transverse groove may result from severe illness. The changes in colour for a variety of reasons for instance white spots in the nail plate, which is seen 62% of normal people, is due to imperfect keratinization with retention of nuclear material.

{mospagebreak title=Physiochemical characterization of the human nail}

PHYSIOCHEMICAL CHARACTERIZATION OF THE HUMAN NAIL

The plate consists of laminated sheets of keratinized cells. In section, thin lipid seams are seen to separate the layer. This lipids form the original cell membrane coating granules during the plate formation⁵. Apparently no evidence exists concerning fundamental permeation mechanisms & possible influence of chemical structure on transport across the nail plate. Previous result shown that it is possible to determine nail plate permeability coefficients using standard diffusion cell techniques. Result obtained for water agreed well with the literature data on water transportation through the nail plate. In pursuant studies the techniques have been extended to the permeation of some n-alkanols. These are useful prototype compound with systematically varying oil/water (o/w) distribution coefficients & diffusion coefficient. Such structural influence on physiochemical properties, when considered together with relative permeability’s, have helped decipher the barrier mechanism of several membranes.

Permeation by water & the n-alcohol through dodecanol has been investigated in specially constructed diffusion chamber. The permeability coefficient of water is 16.5 x 10^-3 Cm h^-1 & that for methanol is 5.6 x 10^-3Cm h^-1.Ethanol’s permeability coefficient measured 5.8 x 10^-3. Permeability coefficients decreased systematically thereafter to a low value of 0.27 x 10^-3 Cm h^-1 at n-octanol.

 The middle chain length alcohol, n-pentanol through n-octanol, have similar permeability coefficient but n-decanol & n-dodecanol show higher rates of permeation. The data suggest that, as a membrane, the hydrated human nail plates behave like a hydrogel of high ionic strength to the polar & semi polar alcohols. Declining permeability rates appear linked to decreased partitioning into the complex matrix of the plate as the compounds becomes hydrophobic. The result for n-decanol & n-dodecanol introduce the possibility that a parallel lipid pathway exists which favors the permeation of these exceedingly hydrophobic species. So the nail become less permeable to the n-alcohols as their hydrophobicity is increased.

{mospagebreak title=Diseases of the nail}

DISEASES OF THE NAIL^{7, 8, 9}

The nail plate may appear abnormal as result of, a congenital 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, infection of the nail plate.

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

Onychomycosis Yellow-brown patches near the lateral border of the nail. Beneath the masses of soft horny debris accumulate & the nail plate gradually becomes thickened, broken & irregularly distorted. One or many nails may be affected & there may be associated infection of the skin. Most of the infections are caused by Trichophyton rubrum , T. inerdigitale .

Tinea Unguis,or ringworm of the nails, is characterized by nail thickening,deformity,and eventually results in nail plate loss.

Onychatrophia 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.

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.

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 or the home, 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.

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

Leuconychia is evident as white lines or spot in the nail plate and may be caused by tiny bubbles of air that are trapped in the nail plate layers due to trauma. This condition may be hereditary and treatment is required as the spots will grow out with the nail plate.

Beaus lines are nails that are characterized by horizontal lines of darkened cells and linear depressions. The disorder may be caused by trauma, illness, malnutrition or any major metabolic condition, chemotheraphy or other damaging event, and is the result of any interruption in the protein formation of the nail plate.

Koilonychia is usually caused through iron deficiency anemia. These nails show raised ridges and are thin and concave.

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 may be a normal occurrence in dark-skinned individuals, and are fairly common.

Psoriasis of the nails is characterized by raw, scaly skin and is 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 a clients with nail psoriasis.

{mospagebreak title=Treatment of nail disorders }

TREATMENT OF NAIL DISORDERS -^{10, 11, 12}

The main challenge associated with developing topical treatments for nail disorders is to deliver the active (antifungal) in therapeutically effective concentrations to the site of infection, which is often under the nail. Some research efforts have focused on improving penetration by chemically modifying the nail matrix.

However possible means to enhance nail penetration must be explored in greater depth before effective local treatments for fungal nail infections are developed.

SELECTION OF POTENTIAL NAIL PENETRATION ENHANCERS-

The utility of compounds possessing sulfhydryl (-SH) groups (mercaptan compounds) to enchance nail penetration has been reported. The primary mechanism for enhancement of nail penetration as thought to be by reduction of disulphide linkages in the nail keratin matrix.Keratolytic agents such as salicylic acid, urea and papain have been investigated as potential nail penetration enhancers.

Mercaptan Compounds-

Amino acid derivatives:  The molecule chosen for these studies was N-(2_mercaptopropionyl) glycine. Mercaptan compounds have been established to reduce keratin in human hair via a sequence of two reversible, nucleophilic displacement. High concentration of the mercaptan and alkaline pH favor the forward reaction due to the increased formation of the mercaptide anion required for reduction.

Pyrithione and its derivative: Pyrithion (2-mercaptopyridine-1-oxide)is a fungicidal and bactericidal agent. Compounds containing a -SH group are themselves oxidized while reducing disulphide linkages in nail keratin.

Sulfites and Bisulphites-

Sulphites and bisulphites are known to be reducers of disulphide linkages in keratin, and thus are popularly used for permeation waving of hair.

Keratolytic Agents-^{13, 14}

Salicylic acid, urea and guanidine hydrochloride were investigated. These substances were thought to tertiary structure and possibly secondary linkages (such as hydrogen bonds) in keratin. Thus promoting penetration through the nail. Compounds such as urea and guanidine hydrochloride are known to be denaturating agents, resulting in disruption of the water structure around proteins, decreasing the hydrophobic effect, and thereby promoting unfolding and dissociation of the protein molecules.

{mospagebreak title=Assay of nail`s inner drug content}

ASSAY OF NAIL`S INNER DRUG CONTENT BY   UNIQUE METHOD ^15,16

The existing clinical evidence suggests that a key to successful treatment of Onchomycosis by a topical antifungal product lies in it effectively overcoming the nail barrier. Current topical treatments have limited effectiveness; possibly because they cannot sufficiently penetrate the nail plate to transport a therapeutically sufficient quantity of antifungal drug to target site to eradicate the infection.

1) Human Finger Nail plates: Nail plates are collect from adult human cadavers & stored in a closed container at 0C. Before each experiment nail samples are gently washed with normal saline to remove any contamination, then rehydrate by placing them for 3 hrs on a cloth wetted with normal saline.

2) Preparation of Formulation: The test carrier formulation contains absorption enhancer (DMSO) & other excipients. Normal saline is the control. Concentration of sample in test carrier formulation & in normal saline control is measured. Also pH, pKa values for test, control formulations were measured. A µL(5) aliquot is removed from each vial & radioactivity is measured in a Packard Liquid  Scintillation counter (Model 1500).  

3) Dosing & surface Washing Procedures: A µL (5) dosing aliquot of the test solution is applied to surface of a nail plate with a micro syringe twice daily. Approximately 8 hrs apart for 7 days, Starting the second the day,  each morning before dosing, the surface  of the nail is washed with cotton tips.

4) System: Nail Incubation : A Teflon one-chamber diffusion cell is used to hold each nail. A small cotton ball wetted with 0.1ml normal saline is placed in the chamber to serve as a nail bed & provides moisture for the nail plate. The ventral (inner) surface of the nail is placed face down on the wet cotton ball. Hydration of the nail plate & the supporting cotton bed is measured with a relative humidity temperature meter.  The cells are placed on a platform in a large glass holding tank filled with saturated sodium phosphate solution. A digital relative humidity/temperature meters is used for monitoring room temperature, the chamber temperature, & humidity. The holding is then covered, thereby monitoring the cells at a constant humidity of 40%.

5) Sampling & procedure:    After completion of incubation phase the nail plate is removed from the diffusion cell. The nail plate is transferred to a clean Teflon diffusion cell for processing. The nail plate is inverted so that the ventral (nail bed) surface faced up & the dorsal (outer) dosed surface faced down. The nail samples are removed as a powder by drilling. The powdered nail sample are transferred into glass scintillation vial & weighed. An aliquot of 5.0 ml Packard toluene -350 is added to the scintillation vial to dissolve the powder. All samples are incubated at 40C for 48 hours followed by the addition of 10 ml scintillation cocktail. The radioactivity of each sample is counted by a liquid scintillation counter.

The amount of Nail sample removed is also measured by the difference in weight of the nail plate before and after drilling and collecting the core of power.

Drug penetration into the combined dorsal and intermediate layers of the center of the nail plate with the test carrier formulation and saline formulation. Both descriptive and statistical analysis (Student's t-test) shows a greater penetration of drug into the ventral (inner) layer of the nail plate with the test carrier than saline control.

{mospagebreak title=Conclusion and References}

CONCLUSION-

 The nail is having complex structure and also the treatment of various nail disorders is difficult task because of their unknown mechanism. Also the analysis of their inner drug content is difficult therefore unique method can be concluded as an alternative for nail fungal diseases.

REFERENCES-

1)Lewin, K. The normal finger nail. British J. Dermatology, 77,1961 pp.485-87.

2)Dykyj, J .D. Anatomy of the nail clin padiatr.med. surgery,6(2) 1989,pp.521-28.

3)Forslind,B. On the structure of the normal nail. A scanning electrion microscopy study. Archives for dermatologishe for schung 251,1975,pp.199.

4)Kobayashi Y, Miyamoto M,Sugibayashi k, Morimoto Y. Drug permeation through the three layer of the of the human nail plate. J. Pharma Pharmacol.51, 1999, pp.271-78.

5)Hashimoto K, Bernard G.G, Nelson R, Lever W. F. J Invest. Derm.47, 1966, pp.205-217.

6) Kenneth A, Walters, Gordon L, Flynn, &John R. Marvel. Physiochemical characterization of the human nail. J. Pharm. Pharmacol,35,1983, pp.28-33

7)Runne,U. The human nail; structure, growth & pathological changes. Current problem in dermatology.9, 1981, pp.102.

8)Baran R, Dawber RPR, eds. Diseases of the nail & their management, Oxford: Blackwell scientific publication, 1984.

9)Sau P et al; Brwens disease of the nail bed & periungnal area arch dermatol, 130, 1994, pp.204.

10)Gauri malhotra,Joel L.Zatz Investigation of nail permeation enhancement by chemical modification, Journal of Pharm.Sci. 91(2) 2002:312-323.

11)Sun Y,Liu JC,Kimbleton ES,Wang JCT 1997,Antifungal treatment of nails, United states patent US 0056164A.

12)Soong MH.1991.Transport properties of drugs & model compounds across the human nail.Phd dissertation.University of Minnesota.

13)Robbins CR.Chemical & Physical behavior of human nail,3^rd edition, New York:Springer-verlag 1997 pp-93-130

14)Heel RC,Brogden RN,Speight TM,Econazole; A review of its antifungal activity and therapeutics efficacy Drug 16,1978,pp-177-201.

15)Gupchup CV,Zatz JL, structural characteristics and permeability properties of human nail, A review J.Cosmet.Sci,1999,pp.363-385.

16)Ju-Hyun kim,chi H.Lee.A method to measure the amount of drug penetrated across the nail plate,Pharma.Research.vol.18,(10).2001:1468-1471.

{mospagebreak title=About Authors}

About Authors

Pravin D.Chaudhari*, Shilpa P. Chaudhari ¹, Pramod K. Kolsure², C.Bothiraja³.

Pravin D.Chaudhari*
Assistant Professor,
Department of Pharmaceutics,
Pad.Dr.D.Y.Patil Institute of Pharmaceutical Sciences and Research,
Pimpri,
Pune- 18
Maharashtra,
India.

Ph. - +91-20-27420261
+ 91-20-27271436
Fax - +91-20-27420026
Mobile- 09850179873
Email - pdchaudhari_@yahoo.com

Shilpa P. Chaudhari ¹
Lecturer,
Pad.Dr.D.Y.Patil College of pharmacy,
Pimpri,
Pune- 18
Maharashtra,
India.

Pramod K.Kolsure ²
M.Pharm. student
Department of Pharmaceutics,
Pad.Dr.D.Y.Patil Institute of Pharmaceutical Sciences and Research,
Pimpri,
Pune- 18
Maharashtra,
India.
Mobile- 09822626794
E-mail- Pramod_kolsure@yahoo.co.in

C.Bothiraja ³
Lecturer,
S.P.College of pharmacy, otur
Tal. - Junnar
Dist-Pune
Maharashtra,
India.