parenterals Flashcards
Parenterals “injectables” are ____ and ____ preparations injected through skin into one or more layers of skin, or into internal body compartments.
sterile and pyrogen-free
Parenterals is Greek word “para = ____” and “enteron = ___”.
beside
intestine
this term means free from viable microorganisms e.g. bacteria
Sterile
Sterile and pyrogen free preparations are: (5)
parenterals irrigation solutions dialysis solutions biological preparations ophthalmics.
When are parenterals indicated? “Advantages”
emergency conditions fast onset local action for uncooperative or unconscious patient almost complete bioavailabilty Avoids GI less patient control
What are the drawbacks for parenterals?
- Require healthcare professional for drug administration, except for self-administered injectables e.g. insulin.
- pain, discomfort, and fear of needle.
- The drug cannot be retrieved or removed once administered.
- Contaminations and infections (aseptic technique is required).
- Manufacturing and preparation requirements / cost.
This route of administration requires the following:
injected into a VEIN using needles (venipuncture) or indwelling catheters (butterfly needle or catheter over needle)
IV
The sites of injection for IV are:
- Peripheral: arm (front of elbow), hand, leg, foot; for infants: scalp veins
- Central: vena cava, subclavian vein
The needle is inserted with the bevel facing ___.
The plunger of the syringe must be withdrawn before injection to ensure that the needle is inserted in the vein. The blood backflow into the syringe is the indicator.
upward
I.V. administration can be injected by:
____ or ____, or _____ (IV Push) injection
continuous or intermittent infusion, or bolus injections
Characteristics of IV dosage form:
-suitable for both small and large-volume injectable preparations.
-No drug absorption is required
-fast onset of action
-suitable for emergency and critical conditions.
-Large-volume injectables “500-1000 mL”
-containing nutrients, electrolytes, and/or
-therapeutic agents are administered by continuous infusion through indwelling catheters or needle.
-infusion rate of 42-150 mL/hour, or at a lower rate to keep the catheter open.
-Only clear, aqueous, non-precipitating, isotonic, pyrogen-free, sterile SOLUTIONS, and
EMULSIONS can be injected.
IV preparations should be free from particulate matter: USP limits are:
•Large Volume:
For particles size ≥10μm, the limit is ≤50 particles/mL
For particles size ≥25μm, the limit is ≤5 particles/mL
•Small Volume:
For particles size ≥10μm, the limit is ≤10,000 particles
For particles size ≥25μm, the limit is ≤1000 particles
Risks of IV routes of administration
–Bacterial infection
–Phlebitis due to irritation or rapid infusion
–THROMBUS “blood clot” due to the needle or catheter touching the vein wall, irritating solution, slowing of the blood circulation, altering the blood or vessel wall.
–EMBOLISM “blood vessel obstruction” due to the circulation of the formed thrombus
automated I.V. delivery system
for intermittent and self-administration of analgesics for chronic pain management.
provide constant and uniform analgesia
Patient Controlled Analgesia (PCA) Device
Patient Controlled Analgesia (PCA) Device can be used for ___, ____, and epidural administration.
IV
SC
The _____ injection technique is used for drugs that stain the skin and upper tissue, e.g. iron dextran, or irritating drugs e.g. diazepam.
Z-track
characteristis of IM injection
–Aqueous or oleaginous “oily” solutions, and suspensions can be injected.
–Absorption and elimination are slower than I.V.
–Variable absorption rates based on physiochemical properties of the drug and the formulation.
In the case of IM, drugs in solution formulation are more rapidly absorbed than in ___ or ____ formulations and less variable.
suspension
oleaginous
The type of the IM formulation depends on the _____ of the drug and the therapeutic goals.
properties
Risks of IM injections
Injuries due to incorrect administration technique that can result in neural damage “paralysis”, infection, embolism, hematoma
Injected into a skeletal muscle.
–Limited volume can be injected, up to __ ml (each side) using 20-22G, 1½” needle into the upper outer quadrate of gluteus maximus “buttock” area for adults and __ mL in the deltoid muscle “upper arm” or vastus lateralis “lateral thigh” for children and infants.
IM
5
2
Injected into the loose interstitial tissue under the skin (between the skin and the muscle tissue) of the upper arm, thigh, or abdomen.
Injection site should be rotated when frequent injections are required e.g. insulin.
If blood appears in the syringe after plunger is withdrawn, a new location should be selected.
Sub Q/hypodermic
In Sub Q, a small volume can be injected, up to ___ mL, using 24-26G, 1- ½”needle.
1.3 - 2
In Sub Q injections, irritating solutions and ___ _____ should not be injected to avoid pain and abscess.
thick suspensions
Absorption and elimination are slower than I.M. This route describes ____
Sub Q
What route of administration is an injections into the skin “dermis” of the anterior surface of the forearm.
Intradermal (I.D.)
in intradermal injections, very small volumes (___ ml) can be injected using short 3/8”, 23-26G needle.
0.1
The injected substances via intradermal are used what 3 things?
diagnostic purposes (allergy)
desensitization
immunization
Intra-arterial:
Injected into arteries.Intra-arterial:
Intra-atricular:
Injected into the joints.
Intracardiac:
Injected into heart chamber (for life threatening conditions).
Intraspinal:
Injected into spinal column.
Intrasynovial:
Injected into joint-fluid (synovial fluid).
Intrathecal:
Injected into spinal fluid.
types of medications administered via S.C., IM, IV, and parenterals
insulin
vaccines
nearly all drug classes
types of medications administered via Intra-arterial
radiopaque media, anti-neoplastics, antibiotics
types of medications administered via intrathecal (intra-spinal)
local anesthetics, analgesics, neurolytic agents,
types of medications administered via intra-epidural
local anesthetics, narcotics, alpha 2 agonist, steroids
types of medications administered via intra-articular (joints)
morphine, local anesthetics, steroids, NSAIDs, antibiotics
types of medications administered via intra-cardial
cardiotonic drugs, calcium
types of medications administered via intra-pleural
local anesthetics, narcotics, chemotherapeutic agents
what are some formulation constraints for sub Q injections
need to be isotonic
what are some formulation constraints for Intramuscular injections
can be solutions, emulsions, oils or suspension.
isotonic preferably
what are some formulation constraints for intravenous injections
solutions, emulsions, liposomes
what are some formulation constraints for intra-arterial injections
solutions and some emulsions
solutions (parenteral dosage forms)
- most injectable products are solutions
- vehicle can be aqueous or non-aquaeous
- contain drug, water or solvent, and excipients
suspension (parenteral dosage forms)
- the most difficult dosage form to formulate
- Requires delicate balance of several physical and rheological factors
- They contain drug, excipients
A dispersion of one immiscible liquid in another using emulsifying agent are
emulsions (parenteral dosage forms)
two types of emulsions
W/O emulsions for SC Injection
O/W emulsions for IM Injection
Lipid emulsions mostly to provide fatty acids along with dextrose and amino acids for TPN preparations.
this type of parenteral dosage form is a drug that is formulated as a powder to be reconstituted with Water for Injection or other vehicle before administration.
Dry Powders (parenteral dosage forms)
this type of parenteral dosage forms is used when the drug is physically or chemically unstable, which allows for formulating the drug as a solution, suspension, or emulsion.
Dry Powders
Official “USP” Types of Injections (5)
[DRUG] Injection [DRUG] for injection [DRUG] Injectable Emulsion [DRUG] Injectable Suspension [DRUG] for Injectable Suspension
Ready LIQUID PREPARATION of drug substances in a solution form (e.g. Insulin Injection, USP).
[DRUG] Injection
DRY SOLIDS that require the addition of suitable vehicle “reconstitution” to yield solution similar to Injection (e.g. Cefamandole Sodium for injection).
[DRUG] for injection
Ready LIQUID PREPARATION of drug substances dissolved or dispersed in a suitable emulsion medium (e.g. Propofol).
[DRUG] Injectable Emulsion
Ready LIQUID PREPARATION of solid drug substances suspended in a suitable liquid medium (e.g. Methylprednisolone Acetate Suspension).
[DRUG] Injectable Suspension
DRY SOLIDS that require the addition of suitable vehicle “reconstitution” to yield preparation similar to Injectable Suspension (e.g. Imipenem).
[DRUG] for Injectable Suspension
Requirements for Injectable Vehicles and Products (Parenterals)
vehicle or solvent must meet certain PURITY level and STANDARDS
•ADDITIVES can be USED to enhance parenteral formulation
•Parenteral product or vehicles must be STERILIZED and PYROGEN FREE.
•solutions must meet the COMPENDIAL LIMIT for particulate matter
•products must be prepared under environmentally CONTROLLED AREAS (sanitation) and by specially TRAINED personnel with specific clothing.
•products are packaged in special hermetic (airtight) containers.
•Containers are slightly overfilled to permit withdrawing accurate labeled volumes.
•The volume of injection permitted is restricted to the type of the container (single-dose or multiple-dose).
•Specific labeling regulation is applied
•Sterile powders for solution or suspension injection are packaged as lyophilized powders for reconstitution.
The selected vehicles for parenteral use must be:
- Sterile and pyrogen-free
- Nonirritating and not sensitizing
- Non-toxic in the amounts administered
- Have no pharmacological activity
- Do not interact with the medicinal agents used
- Have suitable physiochemical properties (e.g. pH, viscosity, fluidity, boiling point, vapor pressure, purity, miscibility with body fluids)
Obtained by distillation or reverse osmosis (solids contents ≤ 1 mg per 100 mL)
•To be used for RECONSTITUTION by aseptic technique
Sterile Water for Injection, USP: aqueous vehicles
- Contains one or more suitable antimicrobial agents
- “Not for Use in Newborns” labeling is required.
- When used as vehicle, added drugs should be compatible with preservative contained
Bacteriostatic Water for Injection, USP
- Contains no added substances
- Not isotonic
- Not for I.V. administration by itself.
- Packaged in ≤ 1 L size containers.
Sterile Water for Injection, USP
- Not isotonic
- Packaged in ≤ 30 mL size containers.
- To be used for reconstitution of only small volume injectables ≤ 5 mL (if larger quantities are required use Sterile Water for Injection)
Bacteriostatic Water for Injection, USP
Examples of solubilizers
co-solvants
surfactants
cyclodextrins
examples of this solubilizer are ethanol, glycerin, PEG
co-solvants
amphiphilic organic compounds that lower the interfacial tension between two liquids and
form micelles e.g. tween 80
Surfactants:
______ ______ adjust the tonicity to the physiological levels
(284 mOsm/L)
Tonicity modifiers
Added to form a complex and inactivate metals like copper, iron, zinc that catalyze oxidation of the drug
Chelating Agents
An example of a chelating agent is:
EDTA (ethylenediaminetetraacetic acid) derivatives
Used to protect against the degradation of drugs (like proteins, liposomes, vaccines) or drug loss due to adsorption (like insulin)
Protectants
sucrose and trehalose (lyorotectants) and HSA (for adsorption) are examples of:
protectants
The complete destruction or removal or all living organisms and their spores
Sterilization
two types of thermal sterilization:
dry heat
steam
involves temp and time using oven
•170 C for 120 min
•Mostly used for oily preparations (nonaqueous), glassware, and surgical tools
Dry-Heat
involves moisture, temp.,
pressure, time using autoclave
•121 C for 15 min
•Not suitable for oily preparations.
Steam
•Mechanism: dry then burn organisms
•Not efficient neither practical for most
of drugs
Dry-Heat
- Mechanism: denature and coagulate proteins
* Mostly used for partially sealed (steam-permeable) or unsealed aqueous preparations, glassware, surgical tools.
Steam
Remove microorganisms by adsorption
to filter membrane or sieving.
–Suitable for heat-sensitive liquid
preparations with small volumes
Mechanical “Filtration” Sterilization
Membranes can be hydrophilic or hydrophobic
Drug loss due to adsorption might occur (problem for high potency drugs)
Mechanical “Filtration” Sterilization
Two types of chemical sterilization methods
Gas
Ionizing radiation “y-rays”
- Interferes with the chemicals within the cell
- Suitable for heat and moisture-sensitive materials, and for plastics and surgical supplies.
- Expensive and requires specialized equipments
- Might not be suitable for all drugs.
Ionizing radiation “γ rays”
involves ethylene oxide, time (4-16 hrs), temp. (60 C), humidity (60%).
Gas
- interferes with cell metabolism.
- Suitable for heat and moisture-sensitive materials, and for plastics and surgical supplies.
- Expensive and requires specialized equipments
Gas
the different types of sterilization methods
Thermal - dry heat and steam
Mechanical Filtration
Chemical - gas and ionizing radiation “y-rays”
___ and ___ should be terminally sterilized if contains no preservative.
–If the product can’t be terminally sterilized or intended for multiple use, it should contain preservative even for ___.
LVP
SVP
SVP
The dry powder is prepared by _____ (freeze drying) to facilitate dissolution or suspension and prevent caking upon storage. Also, can be prepared by aseptic ____, or _____ followed by powder filling.
lyophilization
crystallization
spray-drying
It is impossible in practice to withdraw the entire volume of a single-dose container or the last dose in a multiple-dose container into a syringe (T/F)
true
The ___ allow for overages in excess of the labeled size or volume
USP
____ must not interact physically or chemically, including the closures, with the preparation and should be made of unleaching materials.
If glass, must be __ and ___ or light amber to permit inspection
Containers
clear
colorless
Hermetic container intended for single dose, once
opened cannot be resealed with assurance of
maintained sterility. Maximum volume is 1 L.
Single-dose container
Can be ampoule, single-dose vial, or prefilled syringe
and bottles for irrigation solutions
Single-dose container
Have narrow neck
Sealed by fusion under aseptic condition
withdrawn using 5 μm filter needle
cannot be resealed or used later
Ampoule
which ampoule glass types are suitable for parenteral products
type I, II, or III are
Glass type that is borosilicate glass (most chemically and temperature resistant glass)
Types I
Glass type that is soda-lime treated glass
Type II
Glass type that is side-lime glass
Type III
Hermetic container that permits withdrawal of successive portions of the contents without changing the strength, quality, purity of the remaining portion
Multiple-dose container
Multiple dose container (hermetic container) can e ___ or ____ _____
Sealed by a ____ closure that permit the
penetration of needle multiple times without
removal or destruction of the closure
vials
plastic bags
rubber
in a multiple dose container, withdrawals more than __ mL are not permitted to
avoid injecting excessive amount of preservative
30
Usually, multiple-dose container contains
___ doses for withdrawal
10
What are the Labels Requirements? (10)
- official name
- name of prep
- for liquid prep, the % or amount of drug in a specified volume
- for dry prep, the amount of drug present and the volume of liquid to be added for reconstitution
- route of admin
- storage conditions and exp date
- name of manufacturer and distributer
- lot number (yields manufacturing history)
- veterinary injections, dialysis, or irrigation solution are also labeled
- sufficient area must remain free of label to permit visual inspection
This types of testing confirms the absence of microorganisms using USP standards “biologic indicators”
Sterility Testing, USP
in sterility testing, ___ indicators are spores either in a form of a strip of filter paper or can be added to a representative sample.
Specific spores are selected based on their _____ to a specific sterilization method
Biologic
resistance
____ are thermostable and remain in water even after autoclaving or filtration (sterilization).
pyrogens
Pyrogens are removed from water by ___ them, using e.g. potassium permanganate, to gases or solids that can be removed from water by distillation.
oxidizing
Types of Pyrogen Testings
Rabbit’s Test, USP
Bacterial Endotoxin Test, USP
This test is done by measuring the elevation of rectal temperature of 3 healthy rabbits after the administration of 10 mL/kg of the parenteral preparation.
Rabbit’s Test, USP
if rectal temperature does not increase by 0.5 ºC or more than it is
Pyrogen free
if rectal temperature increases by 0.5 ºC or more then _ additonal rabbits are used
5
Temperature of only 3 rabbits or less out of the 8 rabbits increased by 0.5 ºC
pyrogen free
The sum of temperature increase of the 8 rabbits did not increase more than 3.3 ºC
pyrogen free
Limulus amebocyte lysate (LAL) is used for this test (modified from Limulus Polyphemus found in crab’s blood cells)
Bacterial Endotoxin Test, USP
This test contain an enzyme and protein system that coagulates in the presence of low levels of lipopolysaccharides.
It is more sensitive to endotoxin that the _____ test. However, some drugs interfere with the LAL test
Bacterial Endotoxin Test, USP
rabbit’s
Because LAL is very sensitive, the small-volume parenteral product can be diluted more than ___ to avoid drug interference.
twofold
Sources of particulate matter in particulate matter testing
- dust
- Cloth fibers
- Glass fragments
- Materials leaching form the glass or plastic container or seal
Individual final products must be inspected visually or automatically in a ______ ____ testing.
The final product is positioned against light source with a black background to observe any mobile particles (≥50 μm and ≥25 μm) or by microscopic examination
particulate matter testing
This types of testing is for for ampoules sealed by fusion.
They are tested by immersing the ampoule in dye solution, 1% methylene blue
Apply negative pressure (vacuum) for 15 min then release rapidly to apply stress on weak seals
if the ampoule is leaky the content will be colored.
Container/Closure Integrity Testing
Vial and bottles are not subjected to this test
Container/Closure Integrity Testing
Vial and bottles are tested for:
- Proper fitting that prevents any leak
- Physical characteristics
- Proper lubrication for easy closure
- The capping pressure
Clean room (grade __ air) for the production of parenteral products is used
A
____ filters are used for incoming air
Produce laminar air flow with uniform
velocity
HEPA
HEPA filters needs to be 99.99% efficient to remove __ μm particles
0.3
Aseptic ares must allow _____, with disinfectants
sanitization
This support area can be designed with less standards (clean room grade ____)
D
