Topical drug delivery

Karunya Kandimalla, Ph.D.Assistant professor, Biopharmaceutics and drug delivery

E-mail: karunya.kandimalla@famu.eduOffice phone: 850-599-3581

Skin: Functions

1. Containment function

2. Protective function• Microbial barrier• Chemical barrier• Radiation barrier• Mechanical barrier• Heat barrier

3. Temperature regulation

With a thickness of only 3mm skin performs

The skin: microscopic structure

Hair follicle

Stratum corneum

Epidermis

Dermis

Hypodermis

Hair matrix

Endocrine sweatgland

Sebaceous gland

(0.8mm – 0.006mm)

(3 – 5mm)

Stratum corneum: transdermal drug delivery barrier

Transport PathwaysThe drug permeation pathways across the SC include:

1. Intercellular pathway: across the lipid matrix2. Transcellular pathway: across keratinized cells3. Transappendageal pathway: across hair follicles and sweat ducts

Intercellular and transcellular pathways are only accessible to non-polar moleculesTransappendageal 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)

(1) Manipulate the barrier(2)

(2) Direct drugs to viable skin tissues

(3)

(3) Skin treatment for systemicconditions

Target regions of topical treatment

Interfacial boundries Penetration routes Some treatments

(1) Surface Drug dissolves 1. Camouflagediffuses, releases 2. Protective layerfrom vehicle 3. Insect repellant

4. Antimicrobial

(2) Stratum Partition/diffusion 1. Emoliency corneum stratum corneum 2. Keratosis

(3) Appendages Piloseba- Ecrine 1. Antiperspirantseous unit gland 2. Exfolient

3. Antibiotic4. Depilatory

Interfacial boundries Penetration routes Some treatments

(5) Circulation Removal via 1. Transdermal deliverycirculation 2. Nitroglycerin

(4) Viable Partition/diffusion epidermis viable epidermis

1. Antiinflammatory2. Anaesthetic

Dermis Partition/diffusion 3. Antipruritic corneum dermis 4. Antihistamine

(con’t)

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

MatrixNitro-Dur (Key Pharma) Reservoir

E.g.Transderm-NitroTM

(Ciba/Pharmaco)

Drug-in-AdhesiveMulti-LayerDeponitTM

(Pharma-Schwartz)

Drug-in-Adhesive Single-Layer

Nitrodisc (Searle Pharma)

Backing Drug Membrane Adhesive Liner/Skin

Currently marketed TDDSDrug ApplicationsScopolamine Motion SicknessNitroglycerin Angina PectorisEstradiol Post menopausal symptomsClonidine HypertensionTestosterone HypogonadismIsosorbide dinitrate Angina pectorisFentanyl PainNicotine Smoking cessationEstradiol/ Norethisterone Ac. Hormone deficiencyEstradiol/Norethindrone Hormone deficiency and

Post menopausal symptomsNorelgestromin and Birth controlethinyl 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

Homogenousmembrane

Aqueouspores

Cellulosefibres

(1) Diffusion - random molecular motion. Must have concentration gradient.

Donor Receptor

CdC1

C2

Cr

h

D

C0 Donorsolution Pe

rmea

ble

me m

bran

e

Blo

od

K

hCCSD

dtdMJ 21

Where, dM = change in mass transferred dt in change of time t

D = diffusion constantC1 = concentration in donor compartmentC2 = concentration in receptor compartmentS = surface area of membrane

Since K = C1 = C2

Cd Cr

dMdt

SDK C Ch

d r

Under sink conditions and rearranging all constants,

M PSC tr d Where, P = permeability constant

Fick’s law of diffusion

Complex diffusional barriers

Stratum corneum

Epidermis

Dermis

Subcutaneous

nKnDKDKDtP1...

22

1

11

11tR

Where, Rt = Total diffusing resistancePt = Thickness – weighted permeability coeff.

Parrallel

dMdt

SDK C Ch

d r

FOR EACH

Factors influencing the rate of percutaneousdiffusion

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

• 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)

Attributes of a Passive TDD Drug Candidate

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 physico-

chemical 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 co-solvent 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. No

Chemical class of enhancer

Examples1 Fatty acids Oleic acid, Lauric acid2 Fatty acid esters Isopropyl myristate,

Isopropyl palmitate, 3 Fatty alcohols Olyl alcohol, Lauryl alcohol

4 Fatty alcohol ethers -Monoglyceryl ether 5 Azone and related

compoundsAzone (laurocapram), N-Dodecyl-2-pyrrolidone,

6 Complexing agents Cyclodextrins and their derivatives, HPMC

7 Pyrrolidones and related compounds

2-Pyrrolidone, N-Me-2-pyrrolidone,

8 Classical surfactants Brij 36T, Tween 80, Cetrimide, Sodium lauryl sulphate

9. Dimethyl sulphoxide and related compds.

Decylmethyl sulphoxide, Dimethyl sulphoxide

10. Ionic compounds

Sodium hyaluronate, Ascorbate,

11. Macrocyclics Macrocyclic lactones, Ketones, Anhydrides

12. Amines and Amides

Olyl amine, Lauryl amine, Urea,

13. Solvents and related compds.

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 isopropylmyristate may help transport drugs via activeMechanisms, i.e. carrier – mediated transport.

cell membrane Cell interior

Drug

Drug + Carrier

Carrier Drug

Carrier

Carrier

N

O

(CH2)11 - CH3

1- dodecylazocycloheptane – 2- one

CH3

CH3

N C

O

H

N,N – dimethylformamide (DMF)

CH3

CH3

N C

O

CH3

N,N – dimethylacetamide (DMA)

CH3

CH3

S O

Dimethylsulphoxide(DMSO)

ON

2- pyrollidone

Methods for studying percutaneous absorption

11.1 In vitro methods

11.1.1 Without a rate limiting membrane

stirrer

Ointment

Alcohol in water

Chloroform sink

stirrer

support

Ointment

With a rate limiting membrane

Sampling port

Receptor compartment(mainly chloroform)

Donor compartmentWith formulation

Membrane(cellulose acetate,Silicone,Isopropyl myristate)

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