Pharmaceutical Sciences Quiz: Drug Phases

Chapter 2: Drug Delivery Approaches

• This chapter covers approaches in drug delivery
• Course: Drug Delivery Systems
• Course Code: 070114120
• Fall 2023
• Instructor: Msc Suhad Anabousi
• University: Arab American University, Palestine

Approaches in Drug Delivery

• Chemical Approach/Prodrugs
  • Used for drug optimization through chemical modification
  • Two common chemical derivatives used for modification
    • Analogs
      • New drugs with new pharmacological and pharmacokinetic characteristics (e.g., fentanyl vs. morphine)
    • Prodrugs
      • Same pharmacological characteristics as parent compounds, but different pharmacokinetic properties (delivering the drug itself)
• Biological Approach
  • Involves using biological materials for controlled drug delivery
  • Effective drug targeting and side effect reduction
  • Biological carriers (e.g., albumin, antibodies, DNA, lipoproteins, glycoproteins) are used
    • Methotrexate and Adriamycin are examples of drugs incorporated into these carriers
    • Carriers are used for enhancing drug effectiveness in the body
• Polymeric Approach
  • Also discussed in the presentation

Prodrugs

• Defined as an alteration in the physicochemical properties of a drug via bio-reversible chemical modification
• The prodrug is inactive, and the parent drug is regenerated in vivo
• It's used to overcome barriers that hinder a drug from reaching its target site
• The drug is modified chemically to improve its usefulness

Drug Action & Barriers

• Pharmaceutical phase: In vitro analysis of drug development
• Pharmacokinetic phase: After drug administration in the body, its fate is analyzed.
  • Incomplete absorption can be affected by dosage form factors and physicochemical properties
  • Can cause transport problems across membranes (GI, other membranes)
    • Poor drug solubility
• Pharmacodynamic phase: Interaction between the drug and target receptors
• Prodrugs can overcome barriers in the pharmaceutical stage and pharmacokinetic phase, but they do not affect the pharmacodynamic stage.
  • Important to analyze drug action and how barriers might affect its usefulness

Drug Action & Barriers (continued)

• Pharmaceutical phase:
  • Deals with drug development into a delivery system
  • Includes economics and drug formulation aesthetics (appearance, taste)
• Barriers that represent issues in developing the formulation
  • Taste, pain (injection), texture (skin delivery )
  • Volatile drugs, heat-sensitive drugs, photosensitive ones
• Pharmacokinetic phase:
  • This deals with the fate of a drug after administration
  • Incomplete absorption of the drug due to:
    • Dosage form properties
    • Properties of the drug
    • Other membranes in the body.
    • Drugs are metabolized early (before circulation)
    • Toxicity during distribution to tissues or organs
    • Poor site specificity of the drug

Pharmacodynmic phase

• This focuses on the drug-receptor interactions, and not the drug delivery or the process of drug getting to the targeted location
• This is about how the drug works once it reaches its target.

The Prodrug Approach

• Used to overcome issues with drug molecules:
  • Absorption problems
  • Solubility problems
  • Toxicity problems
  • Formulation and stability issues

Synthesis of Prodrugs

• Before synthesizing a prodrug consider:
  • Modifying functional groups of the parent drug
    • Alcoholic, hydroxyl, thiol, and carboxylic acid groups
  • Availability of synthetic methods
  • Cost-effectiveness of the chemical intermediaries used in synthesis

Synthesis of Prodrugs (continued)

• Design considerations include:
  • Optimal synthesis and purification steps (ideally a minimal number of steps)
  • Chemical stability of the prodrug in its bulk form, along with the compatibility of the prodrug with the drug formulation itself.
  • Toxicity of the prodrug's derivative component
  • Bioreversibility of the prodrug in vivo (conversion back to the parent drug)

The Choice of a Derivative

• Physicochemical properties (prodrug design):
  • Masking bitter taste or odors
  • Improving absorption
  • Pain reduction during injections
• Rapid or decreased gastric distress
• Short half-life is needed for prodrugs to ensure they degrade quickly after passing barriers/ reaching their target location (short half-life in prodrugs reduces the need for prodrug to be active or be in use for a long time before working).

The Choice of a Derivative (continued)

• Modified physicochemical and pharmacological properties (e.g., enhancing drug bioavailability related to poor water solubility):
  • Phosphate esters (enhancing water solubility)
  • Adding bulky hydrophobic groups, which reduces water solubility
    • In general, increasing hydrophobic groups (with -CH2 units) reduces the water solubility

The Choice of a Derivative (continued)

• Drug molecule may undergo hydrolysis in specific locations, so these factors must be considered when a drug needs to be administered in specific locations for its effectiveness
• Using amides and phosphamides:
  • In the case of cancer treatment, there has been an effort to use amides because these can target cancer cells.

The Choice of a Derivative (continued)

• In cases where a drug is meant to undergo slow hydrolysis or provide depot activity
  • Long aliphatic chains and sterically hindered derivatives In cases where drugs need a specific amount of absorption in tissues
  • Adjusted HLB (hydrophilic-lipophilic balance) in order to enhance partitioning between biological membranes and water
• Drug ionization may be altered (e.g., using hydrophobic moieties) to improve absorption in biological membranes

Selection of a Prodrug Linkage

• Requires understanding of enzymes/enzyme systems that catalyze prodrug hydrolysis
• Different enzymes active in the gut, liver, and blood of the body.
• Site-activated prodrugs: tailored for specific target tissue

Prodrug Derivatives

• Include:
  • Aliphatic and aromatic esters (improving absorption and duration of action)
  • Carbonate esters (rapid hydrolysis)
  • Hemiesters (increased water solubility)
  • Phosphate esters (high water solubility, used for localization of action)
  • Amides (relative stability in vivo)
  • Peptides (hydrolyzed by peptidases/proteolytic enzymes)
  • Azo products (hydrolyzed by azo reductases, often used in colon)
  • Phosphamides (cancer chemotherapy, selective activity on receptors)

Prodrug Examples

• Overcoming absorption problems:
  • Poor lipid solubility, very low water solubility
  • First-pass metabolism (the initial metabolism of a drug when it first enters the body) should be addressed or bypassed
• Poor patient acceptance:
  • Unpleasant taste (e.g. acetaminophen)
  • Chewing tablets for pediatric patients (conversion to better prodrug form under acidic stomach conditions), making it more compatible with the stomach

Prodrug Examples (continued)

• Site-specific delivery:
  • Formaldehyde and its prodrug Methenamine (site-specific for urinary tract)
• Prolonging and Sustaining drug release (in prolonging the action to provide longer duration of action):
  • Steroid therapy (e.g., testosterone), acylation of hydroxyl group

Prodrug Examples (continued)

• Stability and formulation issues:
  • Penicillins (instability in aqueous solutions due to B-lactam ring hydrolysis)
• Improving efficacy of ophthalmic drugs
  • Dipivefrin (prodrug of epinephrine)

II. The Biological Approach

• Includes using biological materials for controlled drug delivery
• Targeting drugs to biological carriers to enhance effectiveness and reduce side effects:
  • Albumin, antibodies (IgG), lipoproteins, DNA, glycoproteins
  • Drugs incorporated into biological carriers: methotrexate and Adriamycin, enzymes, nucleic acids.

Drug Carriers

• Localized drug action by introducing the carrier into the target organ
• Controlled drug release
• Drug targeting
  • Protection from degradation
  • Reduced nonspecific cytotoxicity
  • Modified solubility, antigenicity of enzymes
• Combination of drug carriers with antibodies to develop more specific target drug carrier complexes (e.g. liposomes)

Properties of a Carrier System

• General characteristics are necessary for a drug-carrier system
• The carrier must retain the agentís activity at the site of action
• Biocompatible (nontoxic, nonimmunogenic)
• Biodegradable
• Retains its desirable characteristics in a conjugated form

Types of Carriers

• Specific carriers (high specific binding to cell surface receptors, used to direct drugs or enzymes to cells with specific receptors, such as antibodies)
• Non-specific carriers (do not have high specificity of binding, usually taken up by phagocytosis -cells in the body and blood stream take up the drug and other material, cells that take up unwanted material or material not required by the body should absorb that material - macrophages)

Example: Phagocytosis of Micro-Particles

• SEM images showing phagocytosis of microparticles by macrophages

Types of Carriers (continued)

• Cross-linking between carrier and drug molecules can be:
  • Covalent binding (strong bonding, low leakage, but may delay release)
  • Non-covalent binding (easier but higher leakage)

Types of Carriers (continued)

• Desirable characteristics for cross-link reactions:
  • Effective control of the drug-carrier complex size
  • Maintaining the target specificity of the carrier
  • Maintaining the normal activity of the drug or enzyme
  • Readily broken for drug release

Distribution of Non-Specific Carriers

• Distribution depends on:
  • Size and size distribution of the carrier
  • Lipophilicity/hydrophilicity of the carrier
  • Surface charge of the carrier

Test your knowledge on the various phases of drug development in pharmaceutical sciences. This quiz covers topics like drug delivery systems, pharmacokinetics, and pharmacodynamics. Explore the barriers and characteristics that affect drug absorption and interaction.