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Questions and Answers
Which of the following substances is primarily used as a preservative in insulin solutions?
Which of the following substances is primarily used as a preservative in insulin solutions?
What role does polysorbate 80 serve in antibody concentrates?
What role does polysorbate 80 serve in antibody concentrates?
Which excipient is responsible for regulating pH in insulin solutions?
Which excipient is responsible for regulating pH in insulin solutions?
What is the main characteristic that distinguishes infusions from other types of solutions?
What is the main characteristic that distinguishes infusions from other types of solutions?
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Which excipient in powders for injections is intended to facilitate the drying process?
Which excipient in powders for injections is intended to facilitate the drying process?
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What is a significant advantage of parenteral drug delivery in emergency medicine?
What is a significant advantage of parenteral drug delivery in emergency medicine?
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Which of the following administration sites has the most stringent requirements?
Which of the following administration sites has the most stringent requirements?
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What is one of the main reasons for the high production costs of parenteral preparations?
What is one of the main reasons for the high production costs of parenteral preparations?
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What type of parenteral preparation is intended for injection or infusion into the body?
What type of parenteral preparation is intended for injection or infusion into the body?
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Which of the following is NOT a type of parenteral preparation?
Which of the following is NOT a type of parenteral preparation?
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Which aspect of parenteral formulations is primarily influenced by the choice of excipients?
Which aspect of parenteral formulations is primarily influenced by the choice of excipients?
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Which of the following factors does not influence the performance of a drug product administered parenterally?
Which of the following factors does not influence the performance of a drug product administered parenterally?
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What is the expected tonicity for an acceptable injection solution?
What is the expected tonicity for an acceptable injection solution?
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Which of the following is a common excipient used for tonicity adjustment in injections?
Which of the following is a common excipient used for tonicity adjustment in injections?
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What is the role of buffer salts in injection formulations?
What is the role of buffer salts in injection formulations?
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Which of the following buffer systems has a pKA closest to physiological pH (7.4)?
Which of the following buffer systems has a pKA closest to physiological pH (7.4)?
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What is the primary function of sodium hydroxide in injection formulations?
What is the primary function of sodium hydroxide in injection formulations?
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Which of the following statements regarding multidose containers is correct?
Which of the following statements regarding multidose containers is correct?
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Which excipient is commonly used to prevent pain or irritation upon injection?
Which excipient is commonly used to prevent pain or irritation upon injection?
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What is the main characteristic of a single dose vial used in injections?
What is the main characteristic of a single dose vial used in injections?
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Which of the following substances is NOT typically a pH buffer for injection formulations?
Which of the following substances is NOT typically a pH buffer for injection formulations?
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What does a typical tonicity range of 250-300 mOsmol indicate about an injection?
What does a typical tonicity range of 250-300 mOsmol indicate about an injection?
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What parameter is NOT useful for evaluating absorption kinetics from plasma concentrations?
What parameter is NOT useful for evaluating absorption kinetics from plasma concentrations?
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Which factor is most influential in determining the rate of absorption of poorly soluble drugs?
Which factor is most influential in determining the rate of absorption of poorly soluble drugs?
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What is a characteristic of particles and molecules >100 nm regarding their interaction with the lymphatic system?
What is a characteristic of particles and molecules >100 nm regarding their interaction with the lymphatic system?
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Which administration route has the highest percentage of total usage for biologics?
Which administration route has the highest percentage of total usage for biologics?
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What pharmacokinetic parameter indicates the presence of a drug in the blood plasma?
What pharmacokinetic parameter indicates the presence of a drug in the blood plasma?
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In pharmacokinetics, Cmax is best defined as:
In pharmacokinetics, Cmax is best defined as:
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What type of injection is commonly used to determine the volume of distribution?
What type of injection is commonly used to determine the volume of distribution?
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Which of the following statements is false about the relationship between dissolution and absorption?
Which of the following statements is false about the relationship between dissolution and absorption?
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What aspect does AUC help to measure in pharmacokinetics?
What aspect does AUC help to measure in pharmacokinetics?
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Which formulation comprises almost no unbound doxorubicin?
Which formulation comprises almost no unbound doxorubicin?
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What effect does intravenous injection have on Cmax relative to other administration routes?
What effect does intravenous injection have on Cmax relative to other administration routes?
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Which factor do SC/IM routes have much higher tolerance for?
Which factor do SC/IM routes have much higher tolerance for?
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In what context are liposomes discussed?
In what context are liposomes discussed?
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Why is molecular volume important in pharmacokinetics?
Why is molecular volume important in pharmacokinetics?
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Which solution type presents a challenge to SC/IM administration due to osmotic balance?
Which solution type presents a challenge to SC/IM administration due to osmotic balance?
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Which of the following is a correct relationship between particle size and dissolution rates?
Which of the following is a correct relationship between particle size and dissolution rates?
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What is the significance of studying plasma concentration profiles?
What is the significance of studying plasma concentration profiles?
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Which type of biologic administration represents the least volume usage?
Which type of biologic administration represents the least volume usage?
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What does the abbreviation SC stand for in the context of injection types?
What does the abbreviation SC stand for in the context of injection types?
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Study Notes
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 (pKA2 = 7.2)
- Acetate buffer (pKA = 4.76)
- Citrate buffer (pKA1 = 4.76, pKA2 = 6.4)
- Histidine (pKA = 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
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Description
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.
