Outline

1. Introduction: Nanocarriers and Trandermal Drug Delivery Systems (TDDS) 2. Structure of skin and absorption mechanism 3. Nanocarriers for transdermal drug delivery 4. Applications of nanocarriers in TDDS 5. Advantages and limitations 6. Conclusion

Nanotechnology
An integral part of the twenty first century. NANOCARRIERS: (NC)

Colloidal systems having structures below a particle or droplet size of 500 nm. Nano materials(Nanostructures)- Capable to carry drugs through the body, made of a lot of different materials and very different in structure and chemical nature. So small to be detected by immune system and they can deliver the drug in the target organ

NCs applied to the skin are in the center of attention

Nanocarriers (NCs)

Valuable alternative for delivering lipophilic and hydrophilic drugs

The desired effects:

The local effect within the skin (Dermal

drug delivery)

The systemic
the

effect accompanied by
through the skin

permeation

(Transdermal drug delivery)

Methods of Nanotechnology Based on Drug Delivery

NANOCARRIERS

Transdermal Drug Delivery Systems (TDDS)

Self contained, discrete dosage forms which, when applied to the intact skin, deliver the drug, through the skin at controlled rate to the systemic circulation. An integral part of novel drug delivery systems. Application of a pharmacologically active compound

on to the skin to achieve therapeutic blood levels in

order to application. treat diseases remote from the site of

Current transdermal therapeutics formulations Traditional formulations (Gels) Advanced delivery systems (Patches) Novel physical technologies (Microporation, iontophoresis, and sonophoresis).

ADVANTAGES
1.

DISADVANTAGES
significant
1. 2.

Avoidance

of

Limited to potent drug molecule. Pharmacokinetic, pharmacodynamic characteristics (sustained, slow input ).

presystemic

metabolism,

thus

the need for a lower daily dose

2.

Reduced dosage related sideeffects.

3.

Physicochemical

properties

of

3.

Drug input can be terminated simply by removal of patch.

4.

drug should allow to be absorbed

percutaneously.
Drugs must not be locally

4.

Longer

Duration of

of

action, is
5.

irritating or sensitizing. Drugs with short biological halflives cannot be delivered

Frequency decreased.
5.

dosing

Patient compliance and acceptability of the drug therapy.

STRUCTURE OF THE SKIN

SCHEMATIC REPRESENTATION OF PENETRATION ROUTES (PATHWAYS) OF DRUGS THROUGH THE SKIN

CLASSIFICATION OF NANOCARRIERS USED FOR TRANSDERMAL DRUG DELIVERY

INFLUENCE OF MAIN PHYSICOCHEMICAL PROPERTIES OF NANOCARRIER SYSTEMS ON CELL UPTAKE

LIPOSOMES

Most popular nano drug carrier. Spherical vesicles that comprise one or several lipid bilayer(s) without surface tension enclosing an aqueous core Protect encapsulated drugs from degradation

Conventional liposomes:
Stiff bilayers (To prevent undesirable drug leakage) An average diameter above 75 nm

Exterior lipid bilayer is very chemically reactive, -a means to conveniently couple tags (antibodies,

antigens, cell receptors, nucleic acid probes, etc.)on a

covalent basis.

LIPOSOMEScontd Lipoplexes : That encapsulate DNA or RNA in their aqueous space for delivery to cells. Unilamellar liposomes: unilamellar (one bilayer) Large (SUV and LUV) Spherical concentric structures Small and

Multilamellar liposomes: Spherically multilamellar (many bilayers) structures

concentric

TRANSFERSOMES

Highly Deformable (Elastic or Ultraflexible) liposomes Presence of surfactants as an edge activator that destabilizes the vesicle, - more flexibility and deformability. Surfactants : Tween 20, tween 80, sodium cholate, sodium deoxycholate, dipotassium glycyrrhizinate, and oleic acid Range in size from 200 to 300 nm. Squeeze through skin pores (2030 nm) and reach deeper layers in the skin. Penetrate the skin intact .

Do not penetrate through the transappendageal

pathways

Degree of penetration depends on amount of applied per

surface area of the skin

Mechanism of skin penetration of deformable vesicles

Transfersomal insulin (Transfersulin) Insulin incorporated into lipid-based transfersomes (Phosphatidylcholine-based drug carriers) is applied to intact skin Reduce plasma glucose concentration by ~20%; within 34 h. Effect lasts for 10 h, hypoglycaemic is equivalent to 75100 % of

ETHOSOMES
Ethanol (20% to 45%) containing phospholipid vesicles, by mixing them with a constant stream of aqueous solution in a sealed container Imparts high flexibility to the vesicles, enhanced solubility Enhance drug delivery through skin under both nonoccluding and occluding conditions Release of ethanol from the ethosomes- fluidizes the skin lipids to increases skin permeation

LIPID NANOPARTICLES (LNs)

Superior physical stability Made of solid lipids or a combination of solid and liquid lipids

Solid Lipid Nanoparticles(SLNs)

Nanostructured lipid carriers (NLCs)

Advantages: Solid lipid shell prevents drug leakage and degradation . Increased surface area from the lipids increases their adhesiveness to the skin. Increased skin hydration, which, in turn, reduces the corneocyte packing and increases skin penetration

SLN

NLC for

Delivery

systems

Flexibility in modulating drug encapsulation and drug release

hydrophobic drugs

Versatility - various routes of administrations : oral,

Higher
encapsulation

drug

parenteral, dermal, ocular

NIOSOMES
The hydrophobic part of the surfactant whereas the face toward the core, hydrophilic groups interface with the surrounding

aqueous medium.

Niosomes. Contd

Mainly localized in the Stratum Corneum (SC), can also penetrate deeper layers of the skin.

More stable and less expensive than liposomes. Potential for controlled and targetted drug delivery. Thermoresponsive (Polyhedral niosomes) and

release the encapsulated drug when heated above 35C.

Useful for sunscreen formulations Delivery of antimonials for Leishmaniasis

MICELLE / MICELLAR NANO PARTICLES (MNP)

An aggregate of amphipathic molecules in water, with the nonpolar portions in the interior and the polar portions at the exterior surface, exposed to water. Can accommodate both water-soluble and poorly watersoluble Active Pharmaceutical Ingradients( APIs) .

Schematic representation
Micro/nanostructures within an MNP formulation showing the different API components
Deposition and disposition of MNP structures within skin layers showing stratification of API.

MNPs contd

Attractive alternatives for systemic drug

delivery via topical application.

Deliver drugs topically (skin being the site

of action) or transdermally (systemic

availability).

Functionally create a drug depot in the SC and epidermis.

NANOEMULSION

A thermodynamically stable and visually clear disperse system of oil and water with a high proportion of surfactants. Typically contain 20500 nm large droplets

Use hydrophobic and hydrophilic drugs.

Non-toxic and non-irritant systems . Used for skin or mucous membranes, parenteral and non parenteral administration( in cosmetic field). Higher skin penetration ,penetrate through the hair follicles Stability. ???...Lesser use nowadays.

NANOPARTICLES

Nanoparticles are smaller than 1,000 nm.

Possible to insert many types of materials such as drugs, proteins, peptides, DNA, etc. into the nanoparticles. Constructed from materials designed to resist pH, temperature, enzymatic attack, or other problems.

Nanospheres (Solid-core structures ) Nanocapsules (Hollow-core)

Polymers used : Polymethacrylate polybutyl cyanoacrylate, polycaprolactone, chitosan

DENDRIMERS

Highly branched polymers with a controlled threedimensional structure. around a central core. Accommodate more than 100 terminal groups The particle size - 1 to 10 nm. Multivalent interactions with the biological membranes . Unique architecture Drugs can be encapsulated Inside the core (Nanocontainers). Complexed, or conjugated to the surface functional groups (Nanoshells).

Dendrimers: Schematic representation

ADVANTAGES OF DENDRIMERS
Suitable for targeting solid tumours due to increased

permeability, limited drainage in tumour vasculature which will lead to accumulation of macromolecules in tumour (Enhanced permeation rate).

Increase in therapeutic efficacy, decrease in side effects. Drugs easily made to remain within layers of skin and not penetrate in systemic circulation.

Medication to the affected part inside a patient's body directly. Controlled and sustained release of drugs.

NANOCRYSTALS

Large insoluble drug crystals are milled to form nano-sized particles with less than 2000 nm.

The decrease in drug particle size to nanoscopic crystals

results in an increased surface area to volume ratio.

Explored to increase oral bioavailability of sparingly water soluble drugs.

NANODIAMONDS

Nano-sized tetrahedral network Potentially protect drugs trapped inside ND agglomerates due to high surface energy relative to their small size.

Potential in drug nanoformulations for melanoma therapy

CUBOSOMES

Honeycombed (cavernous) structures separating two internal aqueous channels and a large interfacial area. Nanoformulations for melanoma therapy Encapsulate hydrophobic, hydrophilic and amphiphilic substances, targeting and controlled release of bioactive agents

POLYMERSOMES

Nanostructures composed of amphiphilic block copolymers Size range from 50 nm to 5 m Encapsulate drugs inside vesicle membrane. Potentially offers a protective barrier to proteins peptides, DNA and RNA fragments against deleterious factors that may be present in the biological environment. Potential in melanoma therapy

APPLICATIONS
Liposomes :
Moisturizing and smoothening effect To deliver skin protectants, antioxidants, and skin-whitening agents. For DNA delivery in gene therapy. For many antifungal and anticancer agents. Eg: Melatonin, indinavir, methotrexate, amphotericin B, ketoprofen, estradiol, clindamycin and lignocaine.

Vesicular systems : To deliver hydrophilic ,hydrophobic cosmetic agents Improve skin retention, sustain release of the agents. Lipid nanoparticles: To deliver sunscreen agents. SLNs improve the skin protection from UV radiation. Deformable liposomes, ethosomes, and niosomes : Topical and transdermal applications in : dermatitis, acne, psoriasis, skin carcinomas.(melanoma),where

Transfersomes Improve in vitro skin delivery of drugs Efficiency comparable to subcutaneous administration. Eg: Diclofenac, insulin, tetanus toxoid, corticosteroids, superoxide dismutase, DNA, triamcinolone and ketoprofen Ethosomes In atopic dermatitis, Parkinsonian syndrome Eg: Tacrolimus, clotrimazole, ketoprofen and testosterone Niosomes In hair loss. They increase the residence time of drugs in the stratum corneum and epidermis, while reducing systemic absorption of drug. Eg: Minoxidil and ellagic acid. Dendrimers Gene therapy, Delivery of contrast agents, controlled drug delivery, Used in antiviral and anticancer pharmaceutical therapies, including vaccines.. Eg: Tamsulosin, indomethacin, ketoprofen, diflunisal and

ADVANTAGES AND DISADVANTAGES OF NANOCARRIER SYSTEMS Nanoparticles Made of a lot of biodegradable materials. Both hydrophilic and hydrophobic drugs Not enough toxicological assessment has been done. Difficult to develop an analytical method for drug delivery. Niosomes, Transfersomes, Ethosomes Biodegradable and low toxicity., Easy to prepare. Softness, malleability. Predisposition to oxidative degradation. Purity of natural phospholipids.? Formulations are expensive Nanoemulsions Can be formulated as foams, liquids, creams, and sprays. Nontoxic and nonirritant. Easily applied to skin and mucous membranes Surface charge has a marked effect on stability.

Veterinary Applications
Nanoemulsions :

Controlled release of injectable poorly water-soluble

drugs In the delivery of controlled amounts of drugs in breeding animals.

Other potential applications of nanotechnology in veterinary medicine and animal health. Treatment of Feline Hyperthyroidism. Utilization, modification of animal waste as expelled from the animal. Pathogen detection, sensory and surgical aids.

CONCLUSION
Nanocarriers Increasing treatment efficiency Reducing side effects, An increased activities as prolonged activities

well as

Presently,

Polymeric

nanoparticles,

liposomes,

dendrimers,

cubosomes,polymersomes and niosomes Potential in treatment of skin cancers

The risk ratio for many drugs included in nanocarriers; and nano toxicity ??.