PHT 612 Selected Topics in Drug Delivery I 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 Controlled 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 Controlled Enteral Sustained Extended Parenteral Pulsatile drug delivery systems (PDDS) have attracted attraction because of their multiple benefits over conventional dosage forms. They deliver the drug at the right time, at the right site of action and in the right amount, which provides more benefit than conventional dosages and increased patient compliance. These systems are designed according to the circadian rhythm of the body, and the drug is released rapidly and completely as a pulse after a lag time. These products follow the sigmoid release profile characterized by a time period. Site-specific Other Pulsatile

Oral Administration Advantages Disadvantages 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) pH pKa - ionization Temperature Concentration Crystalinity Particle size State of hydration

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

Plasma Concentration Toxicity Therapeutic window No therapeutic effect (mg/mL) Time (min) Therapeutic window Toxicity No therapeutic effect

Unsuccessful therapy Successful Time (min) Plasma concentration (mg/mL) Unsuccessful therapy Successful

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

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 Single compartment with absorption Two compartments 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) t C/C0 C, Vd absorption elimination k, C

One-Compartment Model with Absorption Low absorption occurs Absorption is the rate- limiting 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 t M/D0 t M/D0

Two-Compartment Model k1, C1 Drug rapidly injected Drug distributed instantaneously throughout one compartment and slowly throughout second compartment Describes drug concentration in plasma injected IV C1, V1 k12 k21 k2, C2 C2, V2 Compartment 1 Compartment 2 t Concentration after ingestion Concentration with slow absorption C/C0

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 is the only route log P(octanol/water) <1: transcellular route

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.