Pharmacokinetics: Volume of Distribution Quiz

Course Information

• Course code: PR5217
• Course name: Injectables 1
• Instructor: Associate Professor Matthias G. Wacker, PhD
• Department: Department of Pharmacy, Faculty of Science, National University of Singapore
• Email: [email protected]
• Website: www.pollev.com/mgwacker

Learning Objectives

• How do different injection sites affect drug performance?
• What are the regulatory requirements for parenteral products?
• What excipients are used for different injectables and what are their roles?
• How is sterility achieved in drug products (liquid and solid)?

Parenteral Drug Delivery

• Invasive treatment, often needed in emergencies.
• Rapid onset of action is a key advantage, but this is often balanced by high production costs due to sterility requirements.
• Often used for degradable and poorly permeable compounds.

Parenteral Preparations

• Sterile solutions, emulsions, or suspensions for injection, infusion, or implantation.
• Types include injections, infusions, concentrates, powders, and implants.

Injection Sites

• Intravenous (IV) administration has stricter requirements compared to subcutaneous (SC) or intramuscular (IM) injections.
• SC/IM injections have higher tolerance to particles, oily liquids, hypotonic and hypertonic solutions & pH variations.

Volume of Distribution

• Pharmacokinetic parameter that describes the drug's presence in blood plasma.
• IV injections are commonly used to determine distribution volume of drugs.

IV Injection Case Study: Liposomes

• Conventional doxorubicin distributes into tissue well with Myocet™, which has a larger amount of unbound doxorubicin.
• Doxil™ has minimal unbound doxorubicin.

Influence of Biologics

• Parenteral administration accounts for 92% of total administration routes.
• Intravenous (IV) injections are the most frequent injection type (47%).

Subcutaneous Tissue

• Shows the lymphatic drainage, metabolism, and immune response processes around the injection site.

Pharmacokinetic Profiles

• Plasma concentrations reflect absorption extent and rate.
• Cmax and AUC (area under the curve) are key parameters to assess absorption.

Dissolution

• Poorly soluble drugs exhibit varying dissolution rates depending on particle size.
• Faster dissolution often corresponds to faster absorption (as indicated by Cmax and AUC).

Subcutaneous Fluid

• Data table showing total protein content, albumin content and others in various mammals(Mouse, Rat,... Human)
• Note that there are differences in parameters between species

Tissue Retention Molecular Volume

• Images showcasing different time-points of tissue retention of labeled molecules.
• A way of quantifying tissue retention of molecules

Lymphatic System

• Particles over 100nm typically do not enter the lymphatic system.
• Smaller molecules can diffuse through tissue and enter the lymphatic capillaries (around 15-20nm wide).

Immune Responses Anti-Drug Antibodies

• Anti-drug antibodies (ADAs) can make pharmacokinetics less predictable.
• Preclinical testing usually avoids ADAs to improve predictability.

Injectables Advantages and Disadvantages

• Advantages: Rapid onset of action, lower barriers for absorption of proteins/peptides, long-acting formulations possible.
• Disadvantages: Invasive treatment, high safety requirements regarding purity, sterility is a challenge, and costly formulation.

Preparations

• Categorization of various types of preparations.

Injections

• Sterile solutions, emulsions, or suspensions.
• Prepared by dissolving, emulsifying, or suspending active substances and excipients in water for injections.
• Clear solutions, free of particles, and no phase separation.
• Suspension sediments must easily redisperse.

Injections - Multidose and Single Dose Vials

• Multidose vials often use preservative (like benzyl alcohol).
• Some single-dose vials can be preservative-free.

Excipients Tonicity

• Includes sodium chloride, buffer salts (e.g., histidine, citrate, phosphate), small molecules (e.g., dextrose, glucose, mannitol, sorbitol), and 288 mOsmol solution (0.9% NaCl).
• Acceptable tonicity range is approximately 225-430 mOsmol, with a typical range of 250-300 mOsmol.

Excipients pH

• Buffered pH conditions using phosphate buffer (pKA2 = 7.2), acetate buffer (pKa = 4.76), citrate buffer (pKA1 = 4.76, PKA2 = 6.4), and histidine (pKa = 1.8).
• pH adjustment accomplished with sodium hydroxide and hydrochloric acid.

Excipients Stabilization

• Stabilizers can improve physical, chemical, and microbiological stability during storage.
• Some examples are surfactants (polysorbate, poloxamer), steric stabilizers (dextran, albumin), antioxidants (e.g., ascorbic acid) and preservatives (e.g., metacresol).

Insulin Solution

• List of ingredients for insulin solution - Zinc chloride, Glycerol, Metacresol, Sodium hydroxide, Hydrochloric acid, Water for injections.

Infusions

• Sterile, aqueous solutions or emulsions with water as the continuous phase, made isotonic and administered in high volumes.
• No preservatives typically added, and solutions are particle-free and show no phase separation.
• Must be tested for pyrogens.

Concentrates for Injections or Infusions

• Sterile solutions intended for later dilution and intended use.
• Dilute according to prescribed volume and liquid.

Antibody Concentrate

• Example of an antibody concentrate including Polysorbate 80 (stabilizer), sodium chloride (tonicity), tri-sodium citrate dihydrate (pH / buffer), Water for injections (Vehicle).

Powder for Injections or Infusions

• Sterile solid substances intended for dissolution or suspension in liquid before use.
• Usually produced by freeze-drying including added excipients to facilitate drying.

Implants

• Sterile, solid preparations for implantation, releasing active substance over an extended period of time.
• The size and shape are suitable for parenteral implantation.
• An example mentioned is Implanon (Etonorgestrel 68 mg).

Implants Hot Melt Extrusion

• Process used for preparing Implants.

Sterility

• Sterility is a key requirement for injectables.

Sterility and Pyrogens

• Sterility and absence from pyrogens are required for all injectables.
• Key point - sepsis is a serious health problem with high death count
• Data about causes of death.

Sterility Assurance Level (SAL)

• SAL indicates the probability of one viable microorganism in a certain number of drug products.
• Defines an acceptable safety level according to pharmacopeiad standards, including heat sterilization, sterile filtration, aseptic production, radiation sterilization, and chemical sterilization methods.

Sterility Testing

• Methods for testing sterility, including incubation media summary, and filtration to determine microorganism counts.

Pyrogens

• Traceback to dates when pyrogens were identified and tested, with particular mention of the LAL method in 1980.

Sterilization Methods

• Different techniques for ensuring sterility, including moist heat and dry heat for different product types.

Moist Heat Sterilization

• Use of saturated steam and pressure.
• Suitable for aqueous and thermostable solutions instruments/lab equipment.
• Procedures for using autoclaves.

Dry Heat Sterilization

• Direct heat input.
• Suitable for thermostable powders, water-free ointments, and objects requiring dry air. (like laboratory dishes)

Gamma Radiation

• High-energy radiation used for sterilization, with a diagram of the sterilization setup.

Summary

• Injectables are a varied group of preparations suited to a diverse range of injection sites, differentiated by their biopharmaceutical traits and classified by pharmacopeia based on their tolerance to pH, concentration parameters.
• Excipients adjust tonicity and pH, and prevent physical, chemical, or microbiological degradation (instability).
• Key to success for injectables is their sterility achieved through various processes including moist heat, gamma radiation, etc.

Thermodox®

• Thermodox® delivers doxorubicin triggered by heat following radiation therapy, selectively targeting areas of solid tumors.
• Data suggest that pre-clinical data does not result in consistent clinical improvement.