DRUG DELIVERY TO NAILSFORMULATIONS AND

EVALUATIONS

By:Ch. Pradeep kumar

170209881021

UNDER THE GUIDANCE OFAsst.Prof. Monika Nijhawan M. Pharm

1

2

Contents:IntroductionAnatomy of nailDiseases of nailChallenges of nail drug delivery Per ungual drug absorption Factors effecting penetration of drug through nail plate Enhancement of nail penetrationFormulationsEvaluations of nail lacquersAdvance techniques Conclusion

3

INTRODUCTIONDrug 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.

4

Topical therapy can be optimized by the use of Potent drugs to ensure that effective drug concentration are acheived at the site of actionDrugs with the correct physico-chemical properties for permeation into nail platePenetration enhancers are facilitate ungual drug permeationAppropriate 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.

5

ANATOMY OF NAILThe 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.

6

Anatomy of nail

7

DISEASES EFFECTING THE NAILOnchomycosis

Psoriasis

Yellow nail syndrome

Pitting of nail

Hyper keratosis

Paronychia

ONCHOMYCOSIS:

a)Distal and lateral subungual onchomycosis

b)Superficial onchomycosis

c)Total dystrophic onchomycosis.

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

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

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

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.

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

membrane

13

Permeability coefficient is defined as the product of drug’s diffusion coeffient

(D) through the nail/hoof barrier and the drug’s partition coefficient(K) between

the vehicle and the barrier. P = DK

Units:cm2/s

14

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

Nail lacquer as perungual drug delivery:

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

16

Relationship between log of permeability co-efficient (p) and the molecular sizeHuman nail permeability coefficient (∆), hoof permeability coefficient (o)

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

denser network of keratin fibers , this result

in greater chain-chain interactions, it leads

to smaller ‘pores’.

 

Fig 2

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 (C10

and C12) with increasing lipophilicity was suggested to

occur through a lipidic pathway.

Fig 3

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.

 

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 PH

and charge of drug on its permeability coefficient.

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.

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.

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

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

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

25

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 .

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.

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

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.

30

Example Formula:

Ingredients Percentage

Nitro cellulose 10%

Ethyl acetate 50%

Butyl acetate 20%

Diethyl phthalate 15%

Camphor 4.5%

Color(dye) 0.5%100%

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.

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.

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 g 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.

Fig 6

34

ADVANCE TECHNIQUESFor 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

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.

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.

37

Thank you