540 - Drug Delivery Systems - Exam Ii - Parenteral Drug Delivery

Front 1

Define SVPs

Back 1

Small Volume Parenterals
Vol < 100 mL

Front 2

Define LVPs

Back 2

Large Volume Parenterals
Vol > 100 mL

Front 3

Parenteral Drug Delivery Facts

Back 3

1) Require high standards for preparation, quality control and purity. 2) Circumvent the skin and mucous membranes. 3) Injected material, including contaminants, cannot be recovered. 4) Must be free from microbes, pyrogens and particulates

Front 4

Major Reasons to use Parenterals?

Back 4

1) Achieve the most direct access to the vascular system.
2) Provide highly predictable drug levels
3) Provide an alternative to the GI route (stability, unconscious patient)
4) Replace fluids, electrolytes, agents to maintain acid-base balance, whole blood, blood fractions, plasma and plasma expanders
5) Therapeutic Advantages - access, reliability, controllability and quantity

Front 5

Limitations to Parenteral Administrations

Back 5

1) Need for controlled processing envirorment and special skills for formulation, handling and clinical use
2) Real/Psych pain or discomfort associated with injection
3) Latrogenic Problems: thrombus, embolus, infection, pyrogenic rxn, phlebitits, extravasation, tissue granulomas
4) Relatively high cost
5) Transmission of disease

Front 6

Product Components of Parenterals

Back 6

1) Aqueous Vehicles
2) Non-aqueous Vehicles (Cosolvents)
3) Solutes
4) Container

Front 7

What are the solutes in Parenterals?

Back 7

1) Drugs
2) Antimicrobial Agents
3) Tonicity Adjusting Agents
4) Antioxidants and Buffers

Front 8

Water for Injection (WFI)

Back 8

*Most widely used and important vehicle for injectable preps.
*Made by distillation or reverse osmosis
*USP monograph states specifications
*Used in manuf. of inj. products, which are then sterilized

Front 9

Sterile Water for Injection, USP

Back 9

*Packaged in single 1 L container to be used as a vehicle for a product before administration. Used for reconstitution of multiple antibiotics

Front 10

Bacteriostatic Water for Injection, USP

Back 10

Sterile water for injection containing antimicrobial agent(s). Pre-filled syringes or vials <30 mL

Front 11

Solvents and Vehicles for Injection

Back 11

1) Sterile Water for Injection, USP
2) Bacteriostatic Water for Injection, USP
3) Sodium Chloride Injection, USP
4) Bacteriostatic Sodium Chloride Injection, USP

Front 12

Nonaqueous Vehicles

Back 12

Cosolvents and immiscible vehicles. Limited number have a low level of toxicity or sensitizing property to utilized for injection

Front 13

List four co-solvents commonly utilized in parenterals.

Back 13

Glycerin, Ethanol, Propylene Glycol, and Polyethylene Glycol [Increase drug solubility and perhaps stability]

Front 14

Water Immiscible Vehicles

Back 14

Limited to fixed oils and their derivatives such as ethyl oleate.

Front 15

[Drug] Injection

Back 15

Liquid preparation that are drugs or solutions thereof

Front 16

[Drug] for Injection

Back 16

Dry solids that, upon addition of suitable vehicles, yield solutions conforming to all requirements for Injections

Front 17

[Drug] Injectable Emulsion

Back 17

Liquid preparation of drugs dissolved or dispersed in a suitable emulsion medium

Front 18

[Drug] Injectable Suspension

Back 18

Liquid preparations of solids suspended in a suitable liquid medium

Front 19

[Drug] for Injectable Suspension

Back 19

Dry solids that yield preparations conforming in all respects to the requirements for Injectable Suspensions after addition of a suitable vehicle

Front 20

List Six Key Features of the Intravenous (IV) Route

Back 20

1) Most common and important route
2) Rapid effect owing to direct delievery into circulation
3) Easily facilitates desired blood levels
4) Major route for toxic or irritating drugs
5) Precludes recall of inadvertent drug overdose
6) Carries risk of embolus & thrombus

Front 21

List Four Key Features of the Intramuscular (IM) Route

Back 21

1) Solution, suspension, or emulsion injected directly into the muscle
2) Injected bolus forms a depot that releases drug over a period of time
3) Absorption Factor Types: A) Drug & Dosage Form Factors, B) Physiologic Factors
4) Common Sites: Buttocks, Lateral Thigh, Deltoids

Front 22

List Two Key Features of the Subcutaneous (SC) Route

Back 22

1) Fluid injected under the skin in a small vol bolus (< 2 mL). 2) Since blood flow to area is limited, absorption rate and onset of action are typically slower than with IM or IV injection.

Front 23

Explain the Intradermal (ID) Route and list three applications for which it is used?

Back 23

A small amount of fluid (< 0.2 mL) injected into the most superficial skin layer. ID injections are used for allergy tests, local anesthesia, and certain immunizations.

Front 24

What is an Epidural and how is it used?

Back 24

Injection into the epidural space, between the dura mater and the vertebral column. It is an effective means of controlling and relieving chronic pain. [Low doses, fewer side effects, no preservatives]

Front 25

What is the Intrathecal (IT) Route and why is it used?

Back 25

Injection into the CSF (140 mL). May drugs do not reach adequate therapeutic levels in the CSF upon IV injection. [No preservatives]

Front 26

What is the Intraarticular Route? [Provide an example]

Back 26

Injection into the synovial cavity of a joint, usually to obtain a local action. Example: steroids for anti-inflammatory action in arthritic joint.

Front 27

What is the Intracardiac Route? [Provide an example]

Back 27

An injection directly into a chamber of the heart or into the myocardium. Example: 0.5 to 1 mL of Epi solution used for heart stimulation in cardiac arrest

Front 28

What is the Intraspinal Route?

Back 28

Injection into the spinal column.

Front 29

What are the four general requirements for parenterals?

Back 29

1) Sterility, 2) Pyrogen-Free, 3) Clarity, and 4) Isotonicity

Front 30

What is a nosocomial infection?

Back 30

A nosocomial infection is one acquired in a hospital.

Front 31

What is the major cause of nosocomial infections?

Back 31

Unclean hands are the major cause of nosocomial infections.

Front 32

What are four categories of patients at greater risk of infection?

Back 32

Children, Pregnant Women, Elderly, and Immunocompromised Patients

Front 33

Define the term "D value."

Back 33

D value is the time in minutes required to destroy 90% of the microbes exposed under a standard set of conditions.

Front 34

What are the major methods of sterilization?

Back 34

1) Steam Sterilization, 2) Dry Heat Sterilization,3) Filtration, 4) Gas Sterilization, and 5) Radiation Sterilization

Front 35

What is the mechanism of microbial destruction in steam sterilization?

Back 35

Moist heat causes denaturation and coagulation of proteins essential to the microorganism.

Front 36

What is the USP standard for Steam Sterilization?

Back 36

120 C at 15 psi for 20 min.

Front 37

What is the mechanism of microbial destruction in dry heat sterilization?

Back 37

Dry heat dehydrates and slowly burns (oxidizes) microbes.

Front 38

What is the USP standard for Dry Heat Sterilization?

Back 38

160 to 170 C for more than 2 hrs.

Front 39

What is the mechanism by which filtration achieves sterilization?

Back 39

Physical removal of microorganisms by adsorption on the filter medium or by a sieving mechanism.

Front 40

What is the mechanism of microbial destruction in gas sterilization?

Back 40

Under hot, moist conditions, ethylene oxide acts as an alkylating agent, "interfering with cell metabolism."

Front 41

What is the mechanism of microbial destruction in radiation sterilization?

Back 41

"Ionizing radiation, such as gamma radiation, creates highly reactive ions that can react with biological macromolecules, especially DNA, leading to cell damage and death."

Front 42

List some types of products that cannot be sterilized with steam.

Back 42

Oils, fats, oleaginous preparations, and powders damaged by moisture cannot be sterilized with steam.

Front 43

For what types of items is dry heat sterilization the method of choice?

Back 43

Dry heat sterilization is the method of choice for dry items, such as containers, apparatuses, and certain chemicals that do not undergo thermal degradation.

Front 44

When is filtration the preferred method of sterilization?

Back 44

Filtration is the preferred method of sterilization for solutions that are degraded via thermal, chemical, or radiation methods.

Front 45

List some of the materials for which gas sterilization is utilized.

Back 45

Medical devices, such as catheters, needles, certain heat-labile enzymes, and certain antibiotics and other drugs are sterilized with ethylene oxide. Some heat- or moisture-sensitive materials can be sterilized by ethylene oxide as well.

Front 46

What is one of the notable limitations of radiation sterilization?

Back 46

Ionizing radiation can accelerate drug degradation.

Front 47

Beyond what pH range can most microorganisms not grow?

Back 47

Few microorganisms can grow below a pH of 3 or above a pH of 9.

Front 48

By what mode of action do quaternary ammonium salts and phenols act as a preservative?

Back 48

They modify cell membrane permeability, causing leakage of cellular constituents.

Front 49

By what mode of action do benzoic acid, boric acid, and mercurial compounds function as preservatives?

Back 49

They cause irreversible coagulation of cytoplasmic constituents, e.g. denaturation and precipitation of proteins.

Front 50

What are pyrogens?

Back 50

Pyrogens are substances that induce fever. [Pyrogens from microbial contamination are often responsible for febrile reactions in patients following injections.]

Front 51

What is one of the most prominent classes of pyrogens?

Back 51

Lipoploysaccharides (LSP), found on the outer membrane of many gram-negative bacteria, acts as an "endotoxin," which is to say that it is recognized the immune system and elicits a response.

Front 52

Name and describe two methods of testing for pyrogens?

Back 52

1) Rabbit Febrile Reaction: A sample is injected into the ear vein of a rabbit and the rectal temp is taken during 3 hrs. An elevation of more than 0.6 C above normal is the criterion for test failure. 2) Limulus Amebocyte Lysate Test: A sample is incubated for 1 hr at 37 C with the lysate of the blood of a horseshoe crab. A gel forms in the presence of a pyrogen.

Front 53

Why do we worry about particles and what are some sources of them?

Back 53

Particles in parenterals may act as emboli, matter carried in the blood which lodge in blood vessels, resulting in blockage or occlusion (an embolism). Some sources of particles include incompletely dissolved drug, precipitate from incompatible admixtures, glass particles from ampoules, particles from rubber stoppers, and particles from plastic.

Front 54

Why is isotonicity important for parenteral drug delivery?

Back 54

Hypotonic and hypertonic solutions can cause cell damage or "the build up of pressure which causes pain, irritation, inflammation, and necrosis, e.g. destruction of a peripheral vein."

Front 55

What is the difference between osmolality and osmolarity?

Back 55

Osmolality is the number of osmols per kg of solvent, while osmolarity is the number of osmols per liter of solution.

Front 56

How do the calculations of osmolality or osmolarity differ from simple calculations of molality or molarity?

Back 56

Osmolality and osmolarity account for all of the discrete species in solution, such as the number of dissociated ions. In other words, a 1 molar solution of sucrose would have an osmolarity of 1, while a 1 molar solution of NaCl would have an osmolarity of 2 owing to the fact that 1 mole of NaCl contains 1 mole Na+ plus 1 mole Cl-.

Front 57

What are "two key requirements for injectable formulations?"

Back 57

Sufficient drug concentration and sufficient shelf-life (time for 10% degradation is 2 yrs).

Front 58

What are the properties of an ideal injectable formulation?

Back 58

Isotonicity & Neutral pH

Front 59

What are the major ways of formulating drugs having poor water solubility for parenteral administration?

Back 59

pH adjustment, salt formation, co-solvents, inclusion complexes, nanosuspensions, micellar dispersions, emulsions, and other lipid systems.

Front 60

What pH range is allowable for IV and IM formulations? For SC formulations?

Back 60

pH of 3 to 11 for IV and IM, pH of 3 to 6 for SC.

Front 61

What cation salt of weak acids is utilized for > 90% of parenteral formulations?

Back 61

Sodium

Front 62

What anion salt of protonated weak bases is most common among parenteral formulations?

Back 62

Chloride

Front 63

List some common parenteral formulation co-solvents utilized to dissolve drugs having poor water solubility.

Back 63

Glycerol, Ethanol, Propylene Glycol, Polyethylene Glycol, and Dimethylacetamide

Front 64

List three adverse reactions associated with the use of propylene glycol as a co-solvent for rapid IV infusions.

Back 64

Hypotension, Arrhythmia, and Thrombophlebitis

Front 65

Name two common nonionic surfactants utilized in parenteral formulations.

Back 65

Tween 80 & Cremophor-EL

Front 66

Name an anionic surfactant utilized in parenteral formulations.

Back 66

Sodium Deoxycholate (a bile salt)

Front 67

What are two general disadvantages of surfactant formulations?

Back 67

1) Surfactant formulations are often diluted below their Critical Micelle Concentration prior to administration, creating supersaturated solutions that may precipitate, 2) Surfactant formulations are not always biologically inert (may cause hemolysis)

Front 68

What is the most widely used nonionic surfactant in IV formulations?

Back 68

Cremophor-EL

Front 69

What effect does Cremophor-EL have on PVC containers and administration sets?

Back 69

It enhances the leeching of additives.

Front 70

What clinical consideration limits the amount of Cremophor-EL used in IV formulations?

Back 70

Serious or fatal hypersensitivity reactions.

Front 71

What effect does Cremophor-EL have on the drug efflux pump, P-glycoprotein, responsible for multi-drug resistance?

Back 71

Cremophor-EL inhibits P-glycoprotein.

Front 72

What are cyclodextrins?

Back 72

Cyclodextrins are relatively nontoxic, cyclic oligomers of dextrose that form inclusion complexes with hydrophobic drugs due to hydrophobic interaction.

Front 73

What is the average particle diameter and range of particle diameters in oil-in-water emulsions?

Back 73

The average is 0.3 to 0.5 micrometers, while the range is from 0.1 to 1.0 micrometers. [These particles are small enough to clear the capillary bed of the lungs.]

Front 74

How are oil droplets cleared from circulation?

Back 74

Oil droplets are cleared from circulation via metabolism and phagocytosis by cells of the reticuloendothelial system.

Front 75

What are prodrugs?

Back 75

Prodrugs are pharmacologically inactive compounds that are converted to an active drug by enzymes or hydrolysis.

Front 76

List 12 Chemical or Physical Factors Affecting Drug Stability

Back 76

1) Nature of Drug
2) Concentration of Drug
3) pH
4) Temp
5) Light
6) Solvent/Vehicle
7) Preservatives
8) Tonicity Adjusting Agents
9) Antioxidants
10) Complexing Agents
11) Surfactants
12) Containers

Front 77

Why are some injectables packaged as dry solids?

Back 77

Due to their instability in the presence of water

Front 78

How do you sterilize drug powders?

Back 78

Dry heat or another method that is appropriate for the particular drug

Front 79

What are common solvents for reconstituting dry-packaged injections?

Back 79

Sodium chloride injection and sterile water

Front 80

How are drug powders packaged?

Back 80

In containers designed to be reconstituted with liquid prior to use, usually to form a solution or, less frequently, a suspension.

Front 81

Notable Features of Freeze-Drying (Lyophilization)

Back 81

It is one means of preparing a dry powdered drug for reconstitution as an injectable product. It is a three stage process resulting in a "solid cake" with the same shape as the frozen liquid, but with a honeycomb structure. Bulking agents (ex. Mannitol) enhance the physical and chemical stability of the solid plug.

Front 82

Stages of Freeze-Drying

Back 82

1) Freezing: Prepare an aqueous solution of drug, filter, and freeze (-40 to -20 C)
2) Primary Drying: Sublimation of ice by reduced pressure
3) Secondary Drying: Sublimation of water bound to solutes

Front 83

Four Advantages of Freeze-Drying

Back 83

1) Reduced Water Content (enhanced drug stability)
2) Reduced Oxidation (when sealed under vacuum or in an inert gas)
3) Rapid and Complete Reconstitution (due to honeycomb structure)
4) Fewer Particles than Sterile, Dry-Filled Powder (due to filtering)

Front 84

Two Disadvantages of Freeze-Drying

Back 84

1) Risk Associated with Reconstitution (ex. Spillage, Spray)
2) Drug Degradation

Front 85

Seven Questions to Ask when Reconstituting Drugs

Back 85

1) Properly Diluted?
2) Correct Dose?
3) Aseptic Technique Used?
4) Reconstituted in accordance to manufacturer's instructions?
5) Labeled Properly?
6) Stored Properly?
7) ROA considered?

Front 86

Define "Admixtures"

Back 86

Combined Parenteral Dosage Forms for Administration, including SVPs and LVPs. [Approximately 10-15% of hospital patients receive IV admixtures]

Front 87

Define "Incompatibilities"

Back 87

Any problems of dosage forms that result from compounding, dispensing, or administration.

Front 88

Define "Physical Incompatibilities"

Back 88

Occur after the combination of two or more drugs, or a drug in a vehicle, results in a change to the solution's appearance, color, clarity, or turbidity; precipitation of a solid; or evolution of gas.

Front 89

Provide an example of a predictable physical incompatibility.

Back 89

The addition of an IV fluid having an acidic pH to a sodium salt of a weak acid will protonate the acid, resulting in a less soluble species that may precipitate.

Front 90

Define "Sorption"

Back 90

From Lecture Notes: "Plastics and rubber may absorb lipophilic drugs, such as diazepam." [Technically, sorption is defined as the process by which one substance takes up another. The term is generic in that it can represent either absorption or adsorption]

Front 91

Define "Adsorbtion"

Back 91

From Lecture Notes: "Proteins may adsorb to plastic surfaces and filter membranes. Example: Insulin adsorbs to both glass and plastic surfaces." [Technically, adsorption refers specifically to the accumulation of one substance on the surface of another, as opposed to the accumulation of one substance within another, which is absorption]

Front 92

Negative Effect of Prolonged Storage of Frozen Parenteral Admixtures

Back 92

Can cause polymorphic crystalline changes resulting in insoluble particles since the stable polymorphs are less soluble than the metastable form

Front 93

Define "Chemical Incompatibilities"

Back 93

When a drug degrades more rapidly as a result of being combined with other drugs or formulations. Arise primarily from hydrolysis, oxidation and photolysis.

Front 94

What is the general order of Lability to Hydrolysis?

Back 94

1) Lactams (cyclic amides)
2) Esters
3) Imines
4) Amides

Front 95

What drugs have to be supplied as sterile powders due to chemical incompatibilities?

Back 95

Beta-Lactam antibioitics, penicillins & cephalosporins. All readily undergo hydrolysis.

Front 96

How does the stability of local anesthetics containing an ester functional group compare with one containing an amide during steam sterilization?

Back 96

Esters (Procraine) undergo hydrolysis, while amides (Lidocaine) remain intact

Front 97

Define Oxidation.

Back 97

Oxidation is a reaction with oxygen or a loss of electrons.

Front 98

What is a common type of oxidation catalyst?

Back 98

Trace metals are a common oxidation catalyst.

Front 99

Describe the typical coloring of intact drugs and their oxidized degradation products.

Back 99

The typical coloring of intact drugs is “colorless,” while oxidation products are typically colored (pink, amber, brown, or black).

Front 100

What is one strategy for preventing drug photolysis?

Back 100

Light degradation may be prevented by barriers (Amber vials, Al foil).

Front 101

How might photolysis of certain drugs affect the appearance of a solution?

Back 101

Some solutions will visibly change color on prolonged exposure to light.

Front 102

Which wavelength range of light, UV or visible, has a higher energy?

Back 102

UV light has higher energy, and thus a greater photolytic effect, than visible light.

Front 103

List Four Alternate Administration Techniques for Incompatible Drugs.

Back 103

1) Administer drugs separately at staggered time intervals.
2) Use a heparin lock.
3) Use an alternative ROA.
4) Flush line thoroughly between drugs so that problem drugs do not come into actual contact with each other.

Front 104

What makes up an IV fat emulsion?

Back 104

Vegetable oil - linoleic acid (10%, 20%), an emulsifier (1.2%), glycerin (2.5%) and water at a slightly alkaline pH

Front 105

What happens with a loss of charge?

Back 105

May result in flocculation, creaming, or coalescence.

Front 106

Random Notes from "Incompatibilities of IV fat emulsions" [Slide 2 of 3]

Back 106

1) Product is heat sterilized and does not require refrigeration
2) Shows small tendency to cream on standing, should be shaken before use
3) Additives (Salts, dextrose, a.a.) May influence stability
4) Do not use plastic containers
5) Can add drugs (example with anesthesiologists and propofol)

Front 107

Major Incompatibility of IV fat emulsions

Back 107

Pulmonary embolisms --> Insoluble CaHPO4 formed