King Saud University College of Pharmacy Department of

King Saud University College of Pharmacy Department of Pharmaceutics PHT 612 Selected Topics in Drug Delivery I Fundamentals of Drug Delivery Systems

Outlines • Introduction • Theoretical Aspects of TDD • Experimental Design • Chemical Modulation of TDD • Physical and Technological Modulation of TDD • Topical and Transdermal Formulations

Introduction

Drug Delivery Definition The appropriate administration of drugs through various routes in the body for the purpose of improving health It is highly interdisciplinary It is not a young field It has recently evolved to take into consideration Drug physico-chemical properties Body effects and interactions Improvement of drug effect Patient comfort and well being Controlled Drug Delivery

Drug Delivery Conventional Enteral Parenteral Controlled Sustained Extended Site-specific Other Pulsatile

Oral Administration Advantages Patient: Convenience, not invasive, higher compliance Manufacture: well established processes, available infrastructure Disadvantages Unconscious patients cannot take dose Low solubility Low permeability Degradation by GI enzymes or flora First pass metabolism Food interactions Irregular absorption

Factors Influencing the Selection of the Delivery Route Drug physico-chemical properties Drug molecular size (molecular weight) Half-life Chemical stability Loss of biological activity in aqueous solution Proteins Denaturation, degradation

Factors Influencing the Selection of the Delivery Route Solubility in aqueous solution (hydrophobicity/hydrophilicity) p. H p. Ka - ionization Temperature Concentration Crystalinity Particle State size of hydration

Pharmacokinetics and Pharmacodynamics Pharmacokinetics Design of dosage regimen • Where? • How much? • How often? • How long? Pharmacodynamics Plasma Concentration Effects Plasma refers to the clear supernatant fluid that results from blood after the cellular components have been removed

Plasma concentration (mg/m. L) Plasma Concentration Toxicity Therapeutic window No therapeutic effect Time (min)

Plasma concentration (mg/m. L) Unsuccessful therapy Successful therapy Time (min)

Intravenous Injection Gastrointestinal Tract Circulatory System Intramuscular Injection Subcutaneous Injection Tissues Metabolic Sites Excretion Oral Administration

Absorption of drugs could vary within different administration routes 500 mg dose given intramuscularly orally **to the same subject on separate occasions Biological barriers greatly affect the extent of drug absorption

Absorption of drugs could vary within the same administration route

Important Concepts Volume of distribution apparent volume into which a drug distributes in the body at equilibrium direct measure of the extent of distribution V = amount of drug in the body/Plasma drug concentration

Mathematical Modeling of Drug Disposition Single compartment with absorption Two compartments with absorption Physiological Models

Single Compartment Model Assumptions: Body one compartment characterized by a volume of distribution (Vd) Drug is confined to the plasma (small V) C/C 0 absorption C, Vd elimination k, C t

One-Compartment Model with Absorption Low absorption occurs Absorption is the ratelimiting step Slow absorption may represent drug entry through GI tract or leakage into circulation after SC injection Drugs require multiple doses to maintain drug concentration within therapeutic window M/D 0 t

Two-Compartment Model Drug rapidly injected Drug distributed instantaneously throughout one compartment and slowly throughout second C/C compartment Describes drug concentration in plasma injected IV k 1, C 1, V 1 k 12 k 21 k 2, C 2, V 2 C/C 0 0 Compartment 1 Compartment 2 t Concentration after ingestion t Concentration with slow absorption

Where to Find PD and PK Information United States Pharmacopeia www. usp. org It is also paper published Provides standards, chemical properties, and protocols to perform pharmacological experiments Federal Drug Administration – if it has already being approved www. fda. org

Transdermal Drug Delivery

Disadvantages of TDDS

Disadvantages of TDDS…(cont. ) b) Stratum corneum is hydrophobic: (limits drug penetration) c) Epidermis is hydrophilic d) Main entry to vasculature via pores: (small % of surface) e) Drugs bind to skin: desorption becomes rate-limiting step f) Allergic reaction: triggered by adhesive

Theoretical Aspects of TDD a) Partition coefficient: a permeant must first partition into the membrane log P(octanol/water) It is considered that rate limiting step in the permeation process. - According to the oil and water phases solubility: § log P(octanol/water) 1 -3: intercellular route predominates § log P(octanol/water) > 3: intercellular route § log P(octanol/water) <1: transcellular route is the only

Theoretical Aspects of TDD b) Molecular size: the second major factor in determining the flux of a material through human skin is the size and shape of the molecules. Selected candidate for TDD should fall within (100 -500 Dalton). c) Solubility/melting point d) Ionization e) Other factors: binding forces, particle size, …etc.

Experimental Design Preparation of skin membranes: - In vitro/in vivo studies - Animal membrane: hairless mouse, guinea pig and mammalian skin - Artificial membrane: - More simplistic model - No regional variability - Advantages of reproducibility and control - Simple permeation process - Used for quality control purposes or for testing formulation variables

Experimental Design…(cont. ) Diffusion cell for in-vitro studies: - Comprise of two compartments: donor and receptor sections - The receptor section of a fixed volume is kept at controlled T at 37 ºC and the fluid is agitated - A portal from the receptor compartment allows removal of receptor fluid at required time intervals.