Topical drug delivery
Karunya Kandimalla, Ph.D.
Assistant professor, Biopharmaceutics and drug delivery
E-mail: karunya.kandimalla@famu.edu
Office phone: 850-599-3581
Skin: Functions
With a thickness of only 3mm skin performs
1. Containment function
2. Protective function
• Microbial barrier
• Chemical barrier
• Radiation barrier
• Mechanical barrier
• Heat barrier
3. Temperature regulation
The skin: microscopic structure
Hair follicle
Sebaceous gland
Stratum corneum
(0.8mm – 0.006mm)
Epidermis
Dermis
(3 – 5mm)
Hypodermis
Hair matrix
Endocrine sweat
gland
Stratum corneum: transdermal drug delivery barrier
Transport Pathways
The drug permeation pathways across the SC include:
1. Intercellular pathway: across the lipid matrix
2. Transcellular pathway: across keratinized cells
3. Transappendageal pathway: across hair follicles
and sweat ducts
Intercellular and transcellular pathways are only accessible to
non-polar molecules
Transappendageal pathway is accessible to polar molecules it
occupies only 0.1% of the skin surface area. Hence its
contribution as a drug transport route is limited
Approaches to topical treatment
(1)
(2)
(3)
(1) Manipulate the barrier
(2) Direct drugs to viable skin
tissues
(3) Skin treatment for systemic
conditions
Target regions of topical treatment
Interfacial boundries
(1) Surface
(2) Stratum
corneum
Penetration routes
Drug dissolves
diffuses, releases
from vehicle
Partition/diffusion
stratum corneum
(3) Appendages
Pilosebaseous unit
Some treatments
1. Camouflage
2. Protective layer
3. Insect repellant
4. Antimicrobial
1. Emoliency
2. Keratosis
Ecrine 1. Antiperspirant
gland 2. Exfolient
3. Antibiotic
4. Depilatory
Interfacial boundries Penetration routes
Some treatments
(con’t)
(4) Viable
epidermis
Partition/diffusion
viable epidermis
1. Antiinflammatory
2. Anaesthetic
Dermis
corneum
(5) Circulation
Partition/diffusion
dermis
Removal via
circulation
3. Antipruritic
4. Antihistamine
1. Transdermal delivery
Transdermal drug delivery
systems (TDDS)
• Pharmaceutical formulations that are designed to deliver an
active drug across the skin into systemic circulation.
• Substances that possess both aqueous and lipid solubility
characteristics are good candidates for diffusion through
skin.
• Types of transdermal control released systems.
1. Membrane controlled systems.
2. Adhesive diffusion - controlled systems.
3. Matrix controlled systems.
TDD Patch Construction
Matrix
Nitro-Dur (Key Pharma)
Reservoir
E.g.Transderm-NitroTM
(Ciba/Pharmaco)
Drug-in-Adhesive
Multi-Layer
DeponitTM
(Pharma-Schwartz)
Backing
Drug
Drug-in-Adhesive
Single-Layer
Nitrodisc (Searle Pharma)
Membrane
Adhesive
Liner/Skin
Currently marketed TDDS
Drug
Applications
Scopolamine
Nitroglycerin
Estradiol
Clonidine
Testosterone
Isosorbide dinitrate
Fentanyl
Nicotine
Estradiol/ Norethisterone Ac.
Estradiol/Norethindrone
Motion Sickness
Angina Pectoris
Post menopausal symptoms
Hypertension
Hypogonadism
Angina pectoris
Pain
Smoking cessation
Hormone deficiency
Hormone deficiency and
Post menopausal symptoms
Birth control
Norelgestromin and
ethinyl estradiol
Topical preparations
1. Retinoic acid (acne)
2. Tetracycline (sores)
3. Corticosteroids (psoriasis)
4. Bacitracin (eczyma)
5. Coal tar extracts (contact dermatitis)
6. Cromatin (scabies)
7. Zinc oxide (general healing)
Why transdermal drug delivery?
• Continous IV administration at a constant rate of
infusion is a superior mode of drug delivery
• IV administration avoids hepatic first-pass
metabolism and maintain constant therapeutic
drug levels in the body
• TDD can closely duplicate continuous IV fusion.
Hence it is helpful in delivering drugs that
undergo significant first pass metabolism and/or
have narrow therapeutic index
Principles of diffusion through membranes
Homogenous
membrane
Aqueous
pores
Cellulose
fibres
(1) Diffusion - random molecular motion. Must have concentration gradient.
K
D
C0
Donor
solution
h
Cd
C1
C2
Donor
Cr
Receptor
Fick’s law of diffusion
dM SDC1  C2 
J

dt
h
Since K = C1 = C2
Cd Cr
Where, dM = change in mass transferred
dt in change of time t
D = diffusion constant
C1 = concentration in donor
compartment
C2 = concentration in receptor
compartment
S = surface area of membrane
dM SDK Cd  Cr 

dt
h
Under sink conditions and rearranging all constants,
M r  PSC d t
Where, P = permeability constant
Complex diffusional barriers
Stratum corneum
Epidermis
Dermis
Subcutaneous
1
1
1
1
R  

...
t P DK
D K
D K
t
1 1
2 2
n n
Where, Rt = Total diffusing resistance
Pt = Thickness – weighted
permeability coeff.
Parrallel
dM SDK Cd  Cr 

dt
h
FOR EACH
Factors influencing the rate of percutaneous
diffusion
1. Diffusant solubility (C0)
2. Partition coefficient (K)
3. pH variation (K)
4. Co-solvents (K and C0)
5. Surface activity and micellization (C0)
6. Complexation (K)
7. Diffusivity (D)
Factors that effect percutaneous absorption
Biological factors
1. Skin age
2. Skin condition
3. Regional skin sites
4. Skin metabolism
5. Circulatory effects
Physicochemical factors
1. Skin hydration
2. Drug/skin binding
3. Temperature
4. Penetration enhancers
5. Drug/vehicle interaction
Attributes of a Passive TDD Drug Candidate
•
•
•
•
•
•
Daily dose (< 20 mg/day)
Half-life (10 hours or less)
Molecular weight (< 500 Daltons)
Melting point (< 200 oC)
Skin permeability
Lipid solubility
[partition coefficient (Log P) between –1.0 and
4]
• Toxicology profile
(non-irritating and non-sensitizing to skin)
Factors Important for Transdermal Drug
Delivery
• Physical and chemical properties of drug
• Molecular weight, solubility, partitioning coefficient and
pKa
• Nature of the carrier vehicle
• Condition of the skin.
• Drug concentration is a important factor. The amount of
drug percutaneously absorbed per unit of surface area
per time interval increases as the concentration of the
drug substance in the TDDS is increased
• More drug is absorbed through percutaneous
absorption when the drug is applied to a larger
surface area (e.g. a larger size TDDS).
Requirements..contd.
• The drug substance should have a greater physicochemical attraction to the skin than to the vehicle in
which it is presented. Solubility of drug in both lipid
and water is though to be essential for percutaneous
absorption.
• The aqueous solubility of a drug determines the
concentration presented to the absorption site and the
partition co-efficient influences the rate of transport
across the absorption site. Drugs penentrate the skin
better in its unionized form. Non-polar drugs tend to
cross the cell barrier through the lipid rich regions
(transcellular route) whereas polar drugs favor
transport between cells (intercellular route).
Requirements….
• Drugs with molecular weight between 100-800 with
adequate lipid and aqueous solubility can permeate skin.
The ideal molecular weight of a drug for transdermal
delivery is 400.
• The skin hydration favors percutaneous absorption. TDDS
act as occlusive moisture barriers through which the sweat
from the skin cannot pass resulting in increased skin
hydration.
• In General, the longer the time the medicated application
is permitted to remain in contact with the skin, the greater
will be the drug absorption.
• In cases the skin is abraded or cut will permit drugs to gain
direct access to subcutaneous tissues and the capillary
network obviating the designed function of the TDDS.
Skin permeation enhancement
• Physical approach
–
–
–
–
Stripping of stratum corneum
Hydration of stratum corneum
Iontophoresis or phonophoresis
Thermal energy
• Chemical approach
– Synthesis of lipophilic analogues
– Delipidization of stratum corneum
– Coadministration of skin permeation enhancer
• Biochemical approach
– Synthesis of bioconvertible prodrugs
– Coadministration of skin metabolism inhibitors.
Skin penetration enhancers
Agents that enhance skin permeability.
They act by:
– Disruption of the highly ordered stratum corneum lipids
– Interaction with cellular proteins
– Improved partitioning of drug co-enhancer or cosolvent into the stratum corneum.
Skin penetration enhancers
Contd …
The amount of drug transported through unit area of
skin per unit time (Flux, J) is the product of
diffusion coefficient of drug in the skin (D), the
skin-vehicle partition coefficient (K) and the drug
concentration in the vehicle or delivery system (C),
divided by the thickness of skin (h).
Flux (J) = (DKC)/h
Skin penetration enhancers
Contd …
In principle enhancers act by:
• Increasing drug partitioning (DK) in the stratum
corneum by acting as solvents to dissolve the skin
lipids or to denature skin proteins.
• Increasing the drug solubility (C) in the
transdermal formulation / patch
S. Chemical class of
Examples
No
enhancer
1 Fatty acids
Oleic acid, Lauric acid
2
Fatty acid esters
Isopropyl myristate,
Isopropyl palmitate,
3
Fatty alcohols
Olyl alcohol, Lauryl alcohol
4 Fatty alcohol ethers
-Monoglyceryl ether
5 Azone and related
Azone (laurocapram), NDodecyl-2-pyrrolidone,
compounds
6 Complexing agents
Cyclodextrins and their
derivatives, HPMC
7 Pyrrolidones and
2-Pyrrolidone, N-Me-2pyrrolidone,
Brij 36T, Tween 80, Cetrimide,
Sodium lauryl sulphate
related compounds
8 Classical surfactants
9.
Dimethyl
sulphoxide and
related compds.
Decylmethyl sulphoxide,
Dimethyl sulphoxide
10.
Ionic
compounds
Macrocyclics
Sodium hyaluronate, Ascorbate,
11.
12.
13.
Amines and
Amides
Solvents and
related compds.
Macrocyclic lactones, Ketones,
Anhydrides
Olyl amine, Lauryl amine, Urea,
Ethanol, Polyethylene glycol,
Propylene glycol
14.
Biologicals
Lecithin, Sodium deoxychloate
15.
Enzymes
Papain, Acid phosphatase
16.
Others
Terpenes (Menthol, Eucalyptol,
etc.), Cardamom oil, Anise oil,
Euginol, Bisabolol,Cysteine HCl
Penetration enhancers
Enhance transport of polar drugs via;
(1) Extraction of stratum corneum lipids,
lipoproteins, and nucleoproteins.
(2) Loosening of the polymeric structure of
the keratinocyte of the cytoplasmic
matrix.
(3) Changing the solvent properties of the
stratum corneum.
Enhancement of skin transport
Surfactants
Enhance transport of polar drugs via;
(1) Solubilization and removal of
intercellular lipids.
(2) Interaction and binding to keratin
filaments of intracellular matrix resulting
in disruption of cell order.
Non passive transport?
Compounds like disopropanolamine and isopropyl
myristate may help transport drugs via active
Mechanisms, i.e. carrier – mediated transport.
cell membrane
Cell interior
Drug + Carrier
Drug
Carrier
Carrier
Carrier
Drug
O
(CH2)11 - CH3
N
1- dodecylazocycloheptane – 2- one
O
CH3
N
C
CH3
N,N – dimethylformamide
(DMF)
H
O
CH3
N
C
CH3
CH3
N,N – dimethylacetamide
(DMA)
CH3
S
O
CH3
Dimethylsulphoxide
(DMSO)
N
O
2- pyrollidone
Methods for studying percutaneous absorption
11.1 In vitro methods
11.1.1 Without a rate limiting membrane
stirrer
stirrer
Ointment
Alcohol in water
Ointment
Chloroform sink
support
With a rate limiting membrane
Donor compartment
With formulation
Membrane
(cellulose acetate,
Silicone,
Isopropyl myristate)
Sampling port
Receptor compartment
(mainly chloroform)
Bar magnetic stirrer
In vivo methods
11.2.1 Direct methods
Measurement of Pharmacological response
•
Antihypertensives by means of measuring blood pressure
•
Antihistamines by means of measuring the reduction in swelling
11.2.2 Indirect methods
• Transepidermal water loss
• Thermal determinations
• Analysis of body fluids