PR5217: Injectables I

Course Information

• Course name: PR5217: Injectables 1
• Instructor: Associate Professor Matthias G. Wacker, PhD
• Department: Department of Pharmacy, Faculty of Science
• Contact: [email protected]
• University: National University of Singapore (NUS)

Learning Objectives

• Understand how different injection sites affect drug performance
• Identify regulatory requirements for parenteral products
• Explain the roles of excipients in various injectables
• Describe the processes used for sterilizing liquids and solids in drug products

Parenteral Drug Delivery

• Often an invasive treatment requiring healthcare professionals
• Frequently used in emergencies for rapid drug delivery with immediate onset of action
• Sometimes used to formulate depot formulations of degradable and poorly permeable compounds
• Very high cost of production due to sterility requirements (clean room or closed process)

Parenteral Preparations

• Sterile preparations administered via injection, infusion, or implantation
• Examples of types: injections, infusions, concentrates, powders, implants

Injection Sites

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

Volume of Distribution

• Pharmacokinetic parameter indicating the presence of a drug in blood plasma
• IV injections are commonly used to determine distribution volume

IV Injection Case Study: Liposomes

• Myocet™ has more unbound doxorubicin compared to Doxil™ compared to conventional doxorubicin.

Influence of Biologics

• Parenteral route accounts for 92% of administrations
• Oral, topical, subcutaneous, and other routes account for the rest of the percentages (oral and topical both constitute a small part) of routes

Subcutaneous Tissue

• Explains the process of drug release, metabolism, and tissue retention following injection.

Pharmacokinetic Profiles

• Plasma concentrations provide insights into the extent and rate of drug absorption
• Cmax and AUC (area under the curve) are key parameters used to evaluate these absorption parameters.

Dissolution

• Poorly soluble drugs with varying particle sizes affect dissolution rates, which in turn influence the speed of drug absorption (measured by Cmax and AUC).

Excipients - Tonicity

• Sodium chloride and buffer salts (e.g., histidine, citrate, phosphate) are used to adjust tonicity
• Small molecules (e.g., dextrose, glucose, mannitol, sorbitol) are also used

Excipients - pH

• Buffered solutions (phosphate, acetate, citrate, histidine) are used to maintain pH
• Sodium hydroxide and hydrochloric acid are used for pH adjustment

Excipients - Stabilization

• Surfactants (polysorbate, poloxamer), and steric stabilizers (dextran, albumin), are used for physical stability
• Antioxidants (ascorbic acid) are used for chemical stability
• Preservatives (metacresol) are used for microbiological stability

Insulin Solution

• Includes zinc chloride, glycerol, metacresol, sodium hydroxide, hydrochloric acid, and water for injections as excipients

Infusions

• Sterile, aqueous solutions or emulsions primarily intended for large-volume administration
• No preservatives are generally added
• Solutions and emulsions are practically free of particles and do not show any phase separation, and all infusions must be tested for pyrogens.

Concentrates for Injections or Infusions

• Sterile solutions intended for dilution and use
• Prepared in prescribed volumes

Antibody Concentrate

• Contains polysorbate 80, sodium chloride, tri-sodium citrate dihydrate, and water for injections

Powder for Injections or Infusions

• Sterile solid substances that readily form clear or uniform suspensions.
• Often made via freeze-drying.
• Additional excipients aid in the drying process

Implants

• Sterile, solid preparations designed for implantation and sustained-release drug delivery
• Methods of manufacture includes hot melt extrusion

Sterility

• Sterility and the absence of pyrogens are essential requirements of all injectable preparations.

Sterility Testing

• The testing is summarized by the pharmacopeia and filtration method is use to count microorganisms

Pyrogens

• Historical development of pyrogen testing methods, including RPT (Hort & Penfold), LAL, and MAT

Sterilization Methods (Moist Heat Sterilization)

• Achieved using saturated steam under pressure
• Suitable for aqueous and thermostable solutions, as well as lab instruments.

Sterilization Methods (Dry Heat Sterilization)

• Suitable for thermostable powders, water-free, thermostable ointments and other objects (dishes, etc.)

Sterilization Methods (Gamma Radiation Sterilization)

• Utilize gamma radiation for sterilization.
• The process involves a specific product packaging and treatment procedure.

Summary

• Injectables, with varying characteristics, encompass a wide range of administration sites and preparations
• The pharmacopeia categorizes preparations based on their tolerance regarding pH, particle concentration, tonicity.
• Key considerations include preparing injectable formulations that are sterile and free from pyrogens, and ensuring stability (physical, chemical, and microbiological)

Thermodox®

• Rapid doxorubicin release triggered by heat
• Combining radiation therapy with specific liposomal delivery for tumor targeting.
• Preclinical findings do not always translate into clinical efficacy improvements.

This quiz covers essential concepts of parenteral drug delivery, focusing on injection sites, regulatory requirements, excipient roles, and sterilization processes. It aims to deepen the understanding of injectable preparation and performance in healthcare settings.