1. DRUG DELIVERY TO NAILS
FORMULATIONS AND
EVALUATIONS
By:
Ch. Pradeep kumar
170209881021
UNDER THE GUIDANCE OF
Asst.Prof. Monika Nijhawan
M. Pharm
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2. Contents:
Introduction
Anatomy of nail
Diseases of nail
Challenges of nail drug delivery
Per ungual drug absorption
Factors effecting penetration of drug through nail
plate
Enhancement of nail penetration
Formulations
Evaluations of nail lacquers
Advance techniques
Conclusion
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3. INTRODUCTION
Drug delivery to nail (ungual drug delivery),major
challenge, with the lack of understanding of both the
barrier properties of nail and formulation to achieve
enhanced ungual delivery restricting the efficiency of
topical treatment for nail disorders .
Nail disorders mainly due to fungal infection ,when
give the drug through oral/systemic route ,potency of
drug is decrease at the site of action .
To avoid this lose of drug potency topical route of
administration is used.
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4. Topical therapy can be optimized by the use of
Potent drugs to ensure that effective drug concentration are
acheived at the site of action
Drugs with the correct physico-chemical properties for
permeation into nail plate
Penetration enhancers are facilitate ungual drug permeation
Appropriate formulations which aid ungual drug uptake, are
easy to use and which stay in contact with nail plate,releasing
drugs continuously over long periods of time.
This drug delivery used for the treatment of nail disorders
(onychomycosis,Nailpsoriasis).Naillacquers,Bioadhesive patch
are used in this drug delivery system.
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5. ANATOMY OF NAIL
The fingernail has a three-layer structure (outer
to
inner)- the dorsal , intermediate and ventral
layers, with a thickness ratio of approximately
3:5:2,respectively.
Dorsal layer is dense and hard , consisting of cornified
keratin only a few cells thick (approximately 200µ).
The intermediate layer highly fibrous structure oriented
in a perpendicular direction to the nail growth,
The ventral layer isvery thin and it
consist of a few layer of cell which
connect the nail plate to the nail bed. below.
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7. DISEASES EFFECTING THE NAIL
Onchomycosis
Psoriasis
Yellow nail syndrome
Pitting of nail
Hyper keratosis
Paronychia
ONCHOMYCOSIS:
a)Distal and lateral subungual onchomycosis
b)Superficial onchomycosis
c)Total dystrophic onchomycosis.
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8. It is a fungal infection, caused by three main classes of organisms :
Dermatophytes (fungi that infact hair,skin, nails and feed on nail tissue)
Yeasts
Non dermatophyte molds
The pathogen responsible for infection is most often the fungus Trichophyton
rubrum.
Dermatophytes include mainly Epidermatophyton, Microsprum and
Trichophyton. Yeasts include candida species.
Treatment :
Oral antifungal drugs: Terbinafine (lamisil tablets) and
itraconazole (spornox),
Topical applications:
Amorolfine (loceryl®) and ciclopirox (penlac®, loprox® in
Canada) nail lacquers
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9. PSORIASIS:
Nail psoriasis is an inflammatory disease and occurs in up to
80% of patients with skin psoriasis and is frequently left
untreated .The nail matrix, nail bed and nail
folds may all be affected resulting in nail pitting,
discoloration, fragility, crumbling or loss. It affects between 1 and
3% of most population, but its most common in Europe and North
America.
Treatment :
Topical applications: Injection of corticosteroids into the nail folds
is the main stay of therapy and 5-fluorouracil.
Oral applications: methotrexate, etretinate,cyclosporine
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10. PARONYCHIA:
Paronychia is an inflammation involvingthe lateral and posterior
fingernail folds. Paronychia infections 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. People who have their hands in water
for extended periods may develop this condition, and
it is highly contagious. Paronychia is two types acute
paronychia, chronic paronychia.
Treatment:
Orally amoxicillin with clavulanic acid. Topically ketoconazole
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cream and hydrocortisone.
11. MAJOR CHALLENGES OF NAIL DRUG DELIVERY
The nail plate is much thicker creating amuch longer diffusional
pathway for drug delivery. Additionally, stable disulphide bonds,
responsible for the hardness of the nail, are believed to restrict drug
penetration. Unlike theskin, the nail plate behaves as a hydrophilic gel
membrane and not a lypophilic barrier .
The chemical and physical differences between the nail plate and the
Stratum corneum of skin reason the long term use of topical formulation.
Currently marketed topical therapies for
onchomycosis Amorolfine (Loceryl®,
Galderma) and Ciclopirox (Penlac®, Dermik). Penlac®
is applied once daily for up to 48 weeks. However, the formulation is
removed every 7 days with alcohol before reapplication.
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12. PERUNGUAL DRUG ABSORPTION
FOLLOWING TOPICAL APPLICATION
The highly keratinized, compact nail plate appears pretty
impermeable.
Evidence for the nail permeation when nail plate absorbs the
water ,its subsequently plate softening.
Diffusion of topically applied urea into nails, resulting in the
separation of the nail plate from the nail bed .
Mertin& Lippold stated a relationship between human nail and bovine hoof
membrane permeability co-efficient.permeation studies of nail done by
using modified franz diffusion cell.
log PN= 3.723+1.751 log PH,
here PN = Permeability coefficient of drug through nail plate
PH = Permeability coefficient of drug through the hoof 12
14. Nail lacquer as perungual drug delivery:
Drug release from nail lacquer film governed by fick’s law of diffusion .
FICK’S LAW:
J = - D dc/dx;
here J is flux across per unit surface area of nail plate
D is diffusion co-efficient of drug in the film
dc/dx is conc.gradient across the diffusion path
Fig5.
Flux of amorolfine
(mg/cm2/h) through human nail
plate from a methylene chloride
and from an ethanol nail lacquer.
Lacquers were applied once, at
time 0. Vertical line indicates the
time when the surface of the nail
was washed with acetone..
Fig 1 14
15. FACTORS EFFECTING THE PENETRATION OF DRUG
THROUGH NAIL PLATE
Molecular size of diffusing molecule
Hydrophilicity/lipophilicity of diffusing molecule
Nature of vehicle
PH vehicle and solute charge
1)MOLECULAR SIZE OF DIFFUSING MOLECULE:
• Molecular size has an inverse relationship with penetration into
the nail plate. The larger the molecular size, the harder it is for
molecules to diffuse through the keratin network and lower the
drug permeation
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16. Movement of larger solutes through the
'pores' in the keratin fibre network is
obviously more difficult than the movement
of smaller molecules. Fig.2 shows
permeability of human nail less than the
hoof membrane. Human nail plate have a
Fig 2
denser network of keratin fibers , this result Relationship between log of
in greater chain-chain interactions, it leads permeability co-efficient (p) and the
molecular size
to smaller ‘pores’. Human nail permeability coefficient
(∆), hoof permeability coefficient (o)
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17. 2)Hydrophilicity/lipophilicity of diffusing molecule:
•Increasing lipophilicity of the molecule reduces the permeability coefficient
until a certain point , further increase in lipophilicity result in increased
permeation.
•The increase in permeation of the higher alcohols (C 10
and C12) with increasing lipophilicity was suggested to
occur through a lipidic pathway.
Fig 3
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18. 3)NATURE OF VEHICLE:
•Increasing concentration of the co-solvent results in decreasing
permeability coefficient,in other words ,as the amount of water
decreases permeability coefficient decreases.
•Water hydrates the nail plate which consequently swells.
Considering the nail plate to be a hyderogel, swelling results in
increased distance between the keratin fibers, larger pores through
which permeating molecules can diffuse and hence, increased
permeation of the molecules.
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19. 4)pH OF VEHICLE AND SOLUTE CHARGE
•The pH of aqueous formulations affect the ionisation of weakly
acidic/basic drugs, which in turn influences the drug's
hydrophilicity/hydrophobicity, solubility in the drug formulation,
solubility in the nail plate and its interactions with the keratin matrix.
Example:Permeation studies of weakly basic drug , miconazole
permeability coefficient is same at all pH ,i.e. there was no effect of P H
and charge of drug on its permeability coefficient.
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20. ENHANCEMENT OF NAIL PENETRATION
Methods used for enhancing of nail penetration are
1)Mechanical methods to enhancing nail penetration
a)Nail abrasion
b) Nail avulsion
2)Chemical methods to enhancing nail penetration
a)Keratolytic enhancers
b)Keratinolytic enzymes
c) 2-n-nonyl-1-3-dioxolane
d) Compounds containing sulfahydryl group.
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21. MECHANICAL METHODS TO ENHANCING NAIL
PENETRATION
• Mechanical methods including nail abrasion and nail avulsion
• These methods are invasive and potentially pain full
NAIL ABRASION:
• Nail abrasion involves sanding of the nail plate to reduce thickness or
destroy it completely. Sandpaper number 150 or 180 can be used,
depending on required intensity . sanding must be done on nail edges .
NAIL AVULSION:
In this method surgical remove of nail plate is done, it is two types total
or partial avulsion of nail plate, under local anesthesia.
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22. CHEMICAL METHODS TO ENHANCE NAIL
PENETRATION
Chemically, drug permeation into the nail plate can be
assisted by breaking the physical and chemical bonds
responsible for the stability of nail keratin. This is
destabilizes
the keratin it leads to the lose of integrity in nail plate.
Fig 4 22
23. a)Keratolytic enhancers:
Keratolytic agents which increase the penetration of drug molecule by hydrating
the nail plate and swelling of nail plate, it decrease the dense of the nail plate
and forms ‘pores’ for diffusion of drug molecules.
Examples: Urea, Salicylic acid, Thioglycolic acid.
b)Keratinolytic enzymes:
Keratinolytic enzymes like keratinase hydrolyses the keratin filaments, keratinic
tissues. Thereby weakening the nail barrier and enhancing the drug penetration.
c)Compounds containing sulfahydryl groups:
Compounds containing sulfahydryl group (-SH) cleave the disulphide bonds in nail
proteins,as shown in the reaction
Nail-S-S-Nail+R-SH = 2Nail-SH+R-S-S-R
R represents a sulfahydryl containing compound.
Examples : Acetylcysteine,cysteine,mercaptoethanol
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24. FORMULATIONS USED IN NAIL DRUG
DELIVERY
Nail lacquers mainly used formulation in the ungual drug delivery system
Nail lacquers (varnish, enamel) have been used as a cosmetic for a very long time to
protect nails and for decorative purposes
Nail lacquers containing drug are fairly new formulations and have been termed
transungual delivery systems.
Functional scheme for nail lacquer : release,penetration,permeation of
drug.
Fig 4
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26. FORMULATION
Nail Lacquer consist following components
Film former
Resins
Plasticizers
Solvents
Pigments
FILM FORMER
These substance forms the film over the nail plate, number of film forming agents are
available
Example: cellulose acetate, cellulose acetate butylate, ethyl cellulose, vinyl
polymers,
Nitrocellulose .
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27. RESINS :
Resins impart adhesion , improve gloss and improves the resistance
detergents solutions.
Examples:: santolite MHP , santolite MS 80 percent ,styrene alkyds,melamine
formaldehyde, urea formaldehyde and acrylics.
PLASTICIZERS:
Plasticizers are used for impart the flexibility and adhesive properties to
the
film. Plasticizers are two types:
i) Solvent plasticizers
ii) Non-solvent plasticizers
Plasticizers used in proportion of 1:1, it produces a very flexible film.
Examples: Tricresyl phosphate,Benzyl benzoate,Tributyl phosphate, Butyl
acetyl ricenoleate, Camphor, Castor oil. Among these castor oil is widely used
plasticizer.
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28. SOLVENTS:
Solvents are extremely important in lacquer ,they are responsible for its brushability
and for regulating the drying time.
Solvents must have following characteristics:
1.They must be completely and sequentially evaporate as quickly as possible.
2.They compactable with the all ingredients of lacquer.
3.They must have good evaporation characteristics.
The solvents can be placed into three inter –related categories:
Active solvents
Couplers
Diluents
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29. PIGMENTS:
Pigments used to give the colour to the nail lacquer, to easily distinguish from the
one to other product.
Pigments used in nail lacquers should have following properties:
These should be non-staining
These should be substantially insoluble in lacquers
These should not exhibit bleeding tendency
Example for inorganic pigments : Titanium dioxide ,yellow iron oxide, red iron
oxide.
SUSPENDING AGENTS:
Suspending agents used for prevent the settling of inorganic and insolule matter
Examples: Benzyl dimethyl hydrogenated tallow, Dimethyl dioctadecyl
ammonium bentonite.
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31. MANUFACTURE OF NAIL LACQUERS
Manufacture of nail lacquers consists of mainly two steps.
i)Manufacture and compounding of base nail lacquer
ii)Coloring of base lacquer
Next step is filling and packing in suitable containers.
Add 75% of the solvent and total amount of diluent in a mixer.
Mix well with agitation
Add nitro cellulose while agitating
Add resin and plasticizer and remaining amount of solvent
Stir it and check the viscosity
Perform the clarification and add the color.
Steps involved in nail lacquer formulation.
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32. Evaluation of nail lacquers:
1)Non –volatile content :
1gm of the sample in a tared, flat dish which is about 8cm in diameter.The
sample is evenly spread with tared wire and placed in an oven at 105±2C for
one hour. After removing from oven sample is weighed ,lose weight from the
total weight gives amount of non-volatile content.
2)Drying time :
Apply the sample with 0.006 inch applicator under the controlled temperature
and humidity conditions, at 250c and 50%RH, to a completly non-porous
surface ,such a plate of glass. Note the time required to form a dry-to-touch
film using a stop watch.
3)Gloss :
Gloss of an applied film can determined visually or by using an instrument
based on the principle of reflection of light.
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33. 4)Invitro transungual permeation studies:
Invitro transportation studies carried using Frazn diffusion cell volume of 25ml, at
37±5oc, using phosphate buffer solution( pH7.4) fitted with the custom made teflon
nail holder .
Drug solution equivalent to 100 µg prepared in buffer was placed in the
donor compartment.
The receiver compartment was filled with phosphate buffer (pH 7.4) volume was 2
5 ml. The active diffusion area was 0.25cm2. The receiver compartment was stirred
at 600 rpm with a 3-mm magnetic stir bar.
Intermittent samples of 2 ml are drawn,
at 2hrs and 36 hrs ,amount of drug
determined by using the UV
spectroscopy.
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Fig 6
34. ADVANCE TECHNIQUES
For treatment of nail disorders Photodynamic therapy using with bioadhesive
patchs are available.
Photodynamic therapy (PDT) is defined as a medical treatment by which a
combination of a sensitising drug and visible light causes destruction of
selected cells.
Example: Bioadhesive patch-based delivery of 5-aminolevulinic acid to the
nail for photodynamic therapy of onychomycosis
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35. CONCLUSION
The permeability of the compact, highly keratinised nail plate for topically
applied drugs is poor and drug uptake into the nail apparatus is extremely
low.
Topical application may be divided into three approaches
(i) understanding the physico-chemical factors that influence drug permeation
into the nail plate;
(ii) the use of chemical enhancers which cause alterations in the nail plate,
thus
assisting drug permeation;
(iii) the use of drug-containing nail lacquers which are brushed onto nail plates
and which act as a drug depot from which drug can be continuously
released into the nail.
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36. REFERENCES:
Sudaxshina Murdan’s, Drug delivery to nail following topical
application ,IJP, 2002,pg no:1-26.
Rania Elkeeb, Ali Alikhan ,Laila Elkeeb’s, Transungual drug
delivery:Current status, IJP, 2010,pg no:1-8.
P.P.sharma,Cosmetics-Formulations,Manufacturing&Quality
control,2005,pg no:467-483.
Sanju Nanda, Arun Nanda,Roop K.Khar , Cosmetic
Technology,2006-07,pg no:317-329.
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