Pharmaceutical Excipients and Parenteral Preparations

Course Information

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

Learning Objectives

• Understand how different injection sites affect drug performance
• Identify regulatory requirements for different parenteral products
• Understand the roles of excipients in formulating injectables
• Learn how sterility is achieved in drug products (liquid and solid)

Parenteral Drug Delivery

• Invasive treatment, often requiring a healthcare professional
• Commonly used in emergency medicine for rapid drug delivery with immediate action
• Often used to formulate depot formulations for degradable and poorly permeable compounds
• High production cost due to sterility requirements (clean rooms, closed processes for all product handling)

Parenteral Preparations

• Sterile preparations for injection, infusion, or implantation into the human or animal body
• Types include: injections, infusions, concentrates, powders, implants

Injection Sites

• Intravenous (IV) administration has stricter requirements compared to subcutaneous (SC) or intramuscular (IM)
• SC/IM have higher tolerance for:
  • Particles
  • Oily liquids
  • Hypotonic or hypertonic solutions
  • pH variations

Volume of Distribution

• Pharmacokinetic parameter indicating drug presence in blood plasma
• IV injections commonly used to determine volume of distribution
• Includes intravascular, intracellular, interstitial volumes, and fat (several percent).

IV Injection Case Study: Liposomes

• Liposomes and conventional doxorubicin distribute into tissues.
• Myocet™ comprises a larger amount of unbound doxorubicin than Doxil™™

Influence of Biologics

• Parenteral administration route comprises 92% in all administration routes
• Administration routes:
  • Other: 4%
  • Oral: 3%
  • Topical: 1%
  • Subcutaneous (SC): 35%
  • Other: 3%
  • Intramuscular (IM): 15%
  • Intravenous (IV): 47%

Subcutaneous Tissue

• Diagram illustrates drug release, tissue retention and metabolism in subcutaneous tissue, lymphatic drainage, and blood flow through capillaries

Pharmacokinetic Profiles

• Plasma concentrations provide information on the extent and rate of drug absorption
• Cmax and AUC are key parameters to evaluate this effect

Dissolution

• Poorly soluble drugs exhibit varying dissolution rates depending on particle size
• Faster dissolution leads to faster absorption

Subcutaneous Fluid

• Data table detailing total protein content (g/L), albumin content (g/L), IgG content (g/L), and A/TP & IgG/TP ratios for different animal models (mouse, rat, minipig, Landrace pig, non-human primate (NHP), human).

Tissue Retention - Molecular Volume

• Diagram and data for studying tissue retention and molecular volume in animals

Lymphatic System

• Particles and molecules larger than 100 nm typically do not enter the lymphatic system
• Higher molecular weight molecules may enter lymphatic capillaries, which are 15-20 nm wide

Immune Responses - Anti-Drug Antibodies (ADAs)

• ADA formation creates less predictable pharmacokinetics
• Best strategy is to avoid ADA during preclinical evaluation of molecules

Key Learning Points

• Data from preclinical studies doesn't always translate to clinical advantages for injectables
• Different formulations may be needed for different applications

Injectables and Disadvantages

• Advantages:

  • Rapid onset of action
  • Lower absorption barriers compared to oral routes (proteins, peptides)
  • Long-acting treatment possible without "missing out a pill"
  • High knowledge barrier for market competitors

• Disadvantages:

  • Invasive treatment
  • High safety requirements to avoid physical, chemical and microbiological contaminations
  • Long-acting formulations are very challenging to develop
  • Sterile formulations are more expensive to manufacture

Preparations

• General information on injectable preparations

Injections

• Sterile solutions, emulsions, or suspensions prepared by dissolving, emulsifying, or suspending active substances in Water for injections.
  • Solution must be clear, practically free from particles.
  • Emulsions must not show signs of phase separation.
  • Sediment from suspensions must be easily redispersable.
• Multidose container (preservative possible) and single-dose vial (preservative not always possible)

Excipients - Tonicity

• Sodium chloride
• Buffer salts (e.g., histidine, citrate, phosphate)
• Small molecules (e.g., dextrose, glucose, mannitol, sorbitol)
• 288 mOsmol (0.9% sodium chloride solution)
• Acceptable tonicity range is ~225-430 mOsmol

Excipients - pH

• Buffered conditions
  • Phosphate buffer (pK_A2 = 7.2)
  • Acetate buffer (pK_A = 4.76)
  • Citrate buffer (pK_A1 = 4.76, pK_A2 = 6.4)
  • Histidine (pK_A = 1.8)
  • pH adjustment
    • Sodium hydroxide
    • Hydrochloric acid

Excipients - Stabilization

• Physical stability: surfactants (e.g., polysorbate, poloxamer), steric stabilizers (e.g., dextran, albumin)
• Chemical stability: antioxidants (e.g., ascorbic acid)
• Microbiological stability: preservatives (e.g., metacresol)

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.
• Usually isotonic with blood
• Intended for administration in large volume
• No preservatives added
• Solutions are practically free from particles
• Emulsions show no phase separation
• All infusions must be tested for pyrogens

Concentrates for Injections or Infusions

• Sterile solutions intended for injection after appropriate dilution to prescribed volume
• Diluted solution must meet injection/infusion requirements

Antibody Concentrates

• Polysorbate 80
• Sodium chloride
• Tri-sodium citrate dihydrate
• Water for injections

Powder for Injections or Infusions

• Solid sterile substances distributed in containers
• Manufactured by freeze-drying
• Contain additional excipients for facilitated drying

Implants

• Sterile, solid preparations of suitable size and shape, for parenteral implantation/release of active substance(s) over time
• Provided in a sterile container

Implants - Hot Melt Extrusion

• Diagram showing hot melt extrusion process for implant production

Sterility

• Importance of sterility and absence of pyrogens in injectable preparations

Sterility and Pyrogens

• Sterility and absence of pyrogens are general requirements for all injectable preparations
• High death rate of sepsis in the US each year.

Sterility Assurance Level (SAL)

• Indicates probability of one viable microorganism in a certain number of drug products
• Defines acceptable safety levels relative to pharmacopeial standards
• Common methods include heat sterilization, sterile filtration, aseptic product production, radiation sterilization, and chemical sterilization

Sterility Testing

• Media for incubation of preparations summarized by pharmacopeia guidelines
• Filtration method involves filtration and incubation of the filter used to determine microorganism counts

Pyrogens

• Historical timeline of developing pyrogen testing methods including different tests.

Sterilization Methods — Moist Heat

• Sterilization achieved using dry, saturated steam under pressure
• Appropriate for aqueous, thermostable solutions, instruments, and lab equipment

Sterilization Methods — Dry Heat

• Sterilization through direct energy input, without evaporation
• Suitable for water-free, thermostable ointments, fat, oil, longer-chain alcohols with low vapor pressure, and laboratory equipment

Sterilization Methods — Gamma Radiation

• Diagram showing gamma radiation sterilization process

Summary

• Injectables are diverse, grouped by injection site/biopharmaceutical characteristics
• Pharmacopeia categorizes them based on administration route tolerances for factors like pH, concentration, etc.
• Typical excipients adjust tonicity, pH, presence contaminants
• Key requirement of injectables is obtaining sterility by various processes, such as moist heat sterilization and gamma radiation.

Thermodox®

• Release of doxorubicin triggered by heat.
• Radiation produces heat locally, for ablation
• Selectively targets solid tumors

This quiz tests your knowledge of excipients used in parenteral formulations, including preservatives and pH regulators. Explore the characteristics that differentiate various types of parenteral preparations and their roles in drug delivery. Perfect for students and professionals in pharmaceutical sciences.