Parenteral Preparations in Pharmacy

Sterile Pharmaceutical Preparations

• Sterile preparations encompass various forms, including parenteral, ophthalmic, dialysis solutions, radiopharmaceuticals, and plasma expanders.

Parenteral Preparations

• Parenteral preparations are sterile dosage forms administered outside the alimentary canal, via injection, infusion, or implantation.

• The term "parenteral" is derived from the Latin words "para" (beyond) and "enteron" (intestine).

• Parenteral preparations are essential for administering medications that are unstable in the gastrointestinal tract, irritating to the gastrointestinal tract, or for use in unconscious or uncooperative patients.

• They also allow for rapid correction of fluid and electrolyte imbalances, or for cases needing a rapid onset of action.

• Parenteral preparations' advantages include rapid onset of action, suitability for drugs with instability or poor absorption in the gastrointestinal tract, suitability for urgent situations, and lower side effects due to lower necessary doses.

• Disadvantages include invasiveness, possible pain, and potential for injury from needle or catheter insertion

• Also, potential risks due to errors regarding drug dosage, contamination, or incorrect use.

Types of Injections

• Intramuscular (IM): Injections into muscles (volume typically around 5 mL)
• Intravenous (IV): Direct injection into veins for immediate systemic effect (used for SVP, and LVP)
• Subcutaneous (SC): Injections under the skin; used predominantly for insulin injections (volume typically around 1.5 mL)
• Intradermal (ID): Injections into the skin's dermis layer; used mostly for allergy testing
• Intraspinal (Intrathecal): Injections into the spinal fluid; often used for spinal anesthesia
• Intraperitoneal (IP): Used in animal studies involving injection into the peritoneal cavity.

Common Types of Injections: Intravenous Route

• The IV route is the fastest method of systemic administration.
• It's the preferred route in emergency situations
• Large volume parenteral infusions (LVPs) enable the delivery of large doses of fluids, electrolytes, nutrients, and medications to hospitalized patients and individuals with severe gastrointestinal problems.

Administration and Precautions

• IV administration carries risks related to pyrogens, toxic agents, and microorganisms entering the bloodstream.
• Solutions must be free of particulates or air bubbles, as these can result in embolisms (blockage of blood vessels).
• IV infusions are not suitable for suspension-based injections or oily injections due to challenges in administration and restriction.
• IV injections cannot achieve depot effect.
• IV administration requires expertise to avoid infiltration damage (leakage into surrounding tissues).

Classification of Parenterals

• Pharmaceutical classification: Categorizes parenteral solutions (as solutions, suspensions, emulsions, or dry powders) according to their physical and chemical properties.

• Volume-based Classification: Categorizes parenterals based on volume.

How to Achieve Controlled Drug Delivery in Parenteral Preparations

• Controlled-release mechanisms are employed via various methods.
  • Controlling particle size (suspensions and oil-based), viscosity
  • Using implants or less-soluble salts: such as Insulin-Zn.
  • Formulating drugs in crystalline forms instead of amorphous forms: eg, Insulin lente

Insulin Lente

• A suspension of intermediate-acting human or porcine insulin.
• The suspension is formulated in a specific ratio (7:3) of crystalline to amorphous insulin for controlled delivery.

Assignments

• Assignment 1: Investigate different formulations of insulin on the market with varying durations and onsets of action.
• Assignment 2: Collect examples of different pharmaceutical forms of parenteral products from the market, including dry powder for reconstitution, oily injections, long-acting injections, and emulsion-based parenterals. Details should include the active ingredient, diverse doses, labeling information (excipients used), and reconstitution methods.

Specifications of Parenteral Preparations

• Sterility: Absence of microorganisms and contaminants, crucial for IV administration as pathogen presence can be fatal. Preservatives are used to maintain product sterility.
• Clarity: Absence of foreign particles (dust, glass, fiber) preventing accumulation in tissues (IM: granuloma; IV: embolism).
• Absence of Pyrogens: Solutions must be non-pyrogenic (pyrogen-free), as they contain fever-producing endotoxins.
• Tonicity: Parenterals must be isotonic to blood, meaning same osmotic pressure, preventing cell damage (hypertonic: shrinkage, damage; hypotonic: lysis, fatal)
• pH: Ideal pH is usually 7.4, though some injected drugs may necessitate different values.

Methods of Sterilization

• Moist heat: Sterilization using steam
• Dry heat: Sterilization using dry heat
• Ionizing radiation: Sterilization using ionizing radiation
• Gaseous sterilization (ethylene oxide): Sterilization using gaseous sterilization
• Filtration: Using bacterial filters to remove microbes

Preservation

• Preservatives are added to multi-dose vials to prevent contamination during production, use, and storage. Single-dose LVPs do not usually require preservatives.
• Preservatives that interfere with injection should not be used. Suitable preservatives must prevent bacteria contamination, be non-toxic, stable, compatible, and not interact with the injection components.
• Preservatives are more significant in natural or neoprine rubber, whereas less effective in butyl rubber closures.

Clarity

• Parenteral solutions must be clear, devoid of dust or foreign particles such as glass, fibers.
• Particles not easily degraded can accumulate.
• IV injections, if contaminated, lead to fatal embolisms, while intramuscular (IM) injections or subcutaneous (SC) injections result in potentially damaging granuloma formations.

Absence of Pyrogens

• Pyrogens are fever-inducing endotoxins found in the outer membrane of Gram-negative bacteria.
• Endotoxins are lipopolysaccharides consisting of lipid A and a central polysaccharide core.
• Pyrogens contaminate solutions from solvents, equipment, packaging materials, and raw materials.
• Highly concentrated pyrogen doses can cause serious problems, including fever, shock, and even death.. Pyrogen removal is achieved using various methods.

Depyrogenation

• Depyrogenation eliminates pyrogens from solvents, equipment, and raw materials for parenteral solutions. Methods involve either pyrogen removal or inactivation.

Water Depyrogenation

• Distillation, reverse osmosis, and ultrafiltration techniques are used to depyrogenate water.

Packing Materials and Equipment

• Pyrogens can be removed by rinsing surfaces with non-pyrogenic water.
• Equipment materials and packing materials are heat-sterilized.

pH

• Optimal pH for parenteral preparations is 7.4, though certain drugs may require different pH values for stability or solubility.

• For non-neutral solutions, the buffer system is designed to allow quick neutralization while maintaining low buffering capacity, as high buffering capacity for large volumes of IV fluids can result in toxicity.

• Acceptable pH values for non-neutral SVPs (Solutions for intramuscular, subcutaneous, and intravenous injections in smaller volumes) range from 4 to 9, while for larger volumes, the solutions should be within 3 to 10.5 pH for parenteral injection.

Tonicity (Osmotic Pressure)

• Tonicity represents the osmotic pressure required by a solution to prevent water from moving to another solution through a semi-permeable membrane.

• Solutions that have the same osmotic pressure as blood plasma are isotonic, avoiding harm or distress to cells.

• Hypertonic solutions, with higher osmotic pressure than plasma, can cause cellular shrinkage and damage.

• Hypotonic solutions, having lower osmotic pressure than plasma, can lead to cell lysis, posing a life-threatening intravenous risk.

Hypertonic and Hypotonic Parenteral Solutions

• Hypertonic solutions can be made isotonic through dilution, used for IM or SC injections, but for intravenous infusions should be administered slowly or via a central catheter. These solutions are sometimes deliberately used in Total Parenteral Nutrition (TPN).

• Hypotonic solutions are made isotonic by adding electrolytes such as sodium chloride or osmotic agents such as mannitol or glucose.

Components of Parenteral Products

• The components of parenteral products include packaging containers, active ingredients, solvents (like water), and additives (stabilizers, buffers, preservatives). Different types of packaging containers are used, such as glass ampoules, rubber-stoppered vials, glass and plastic bottles, syringes, and pre-filled syringes.

Packing Materials

• The materials used for packing, including glass, rubber, and plastic, need to comply with specific standards and specifications to avoid contaminations and toxicity.

Ampoules

• Ampoules are single-dose glass containers.
• The glass neck needs to be scratched or self-breaking for easy opening.

Vials

• Vials are multi-dose or single-dose containers.
• They comprise glass bottles with rubber caps sealed with aluminum covers, with rubber materials either natural or synthetic (such as butyl rubber).
• Vials may need to be specially handled to avoid issues of complete sealing, air contamination.

Pre-filled Syringes Advantages/Limitations:

• Advantages: overcoming issues with particle and air contamination.
• Limitations: High expense. Need for specialized machines.

Plastic containers (LVP)

• LVPs often come in flexible PVC or semi-rigid PE containers, with advantages in handling and transportation but also potential for leaching of plasticizers or adsorption of drugs.

Glass Bottles

• Glass bottles are chemically inert , widely used for parenteral products.
• Disadvantages include risk of breakage during transport and the necessity of aeration lines.

Solvents for Injections

• A key component for injection formulation, solvents—both aqueous (water, co-solvents) and non-aqueous (oils)—must be chemically inert.

Grades of Water

• Water for injection (WFI): Free of pyrogens and high chemical purity, as potable water may contain organisms, particles, gases, or minerals; and it is necessary to sterilize water through various methods for proper functioning.

• Sterile water for injection (SWFI): WFI containing bacteriostatic agents and used in multi-dose products.

Co-solvents

• Water-miscible compounds like glycerin, ethyl alcohol, and propylene glycol are mixed with water to enhance solubility and act as stabilizers.

Non-aqueous Solvents (Oils)

• Non-aqueous solvents like vegetable oils are used to dissolve drugs poorly soluble in water. Example: digoxin, barbiturates, steroids.

Additives

• Substances needed to ensure stability, preservation, and effective handling of parenteral solutions. 
  • Antimicrobials:  Prevent contamination.
  • Buffers:  Maintain pH neutrality
  • Tonicity adjusters: Protect cells and blood vessels.
  • Antioxidants: Prevent degradation.
  • Surfactants: Improve wetting and ease of injection administration.

Antioxidants

• These are added to preserve parenteral solutions from degradation.
  • Examples are ascorbic acid, cysteine, sodium metabisulfite, and tocopherol.

Surfactants

• Substances to enhance wetting and syringeability of parenteral suspensions and emulsions.
  • Examples include polyoxyethylene sorbitan monooleate and sorbitan monooleate

Production of Parenteral Solutions

• Parenteral solutions are manufactured in clean rooms with high standards of cleanliness.
• Critical elements impacting sterility, absence of pyrogens, and clarity include raw materials, personnel, and the production area.
• Raw materials must be of pharmaceutical grade. Personnel undergo training and observe strict hygiene. The production area has sterile facilities (e.g., laminar flow hoods, HEPA filters) to eliminate microbial and particulate contamination to prevent pyrogenic, particulate and microbial contaminants.

Quality Control Testing (BP)

• Comprehensive quality control testing, adhering to comendial methodologies, is essential for ensuring the safety and efficacy of parenteral solutions. This includes tests on containers/packaging (e.g., glass, plastic, rubber closures), throughout the entire production batch, as well as individual samples.

Procedures for Testing

• Detailed procedures exist in compendia for assessing containers, complete batches, and individual samples, covering aspects like container strength, physical characteristics of the solution/components (clear, absence of particulates), biological effects, potential contamination or toxicity, and suitability of use.

This quiz focuses on the essential principles and practices of parenteral preparations in pharmacy. It covers topics like administration methods, quality control, and the characteristics of specific preparations. Test your knowledge on the advantages and limitations of parenteral drug delivery.