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Biopharmaceutics 2 > Parenteral Drug Delivery > Flashcards

Parenteral Drug Delivery Flashcards

1
Q

What is special about parenteral drug delivery?

A

Can gain easy access to the systemic circulation with complete drug absorption & therefore reaches site of action rapidly.

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2
Q

Parenteral administration has rapid absorption and ____ decline. How can this be altered?

A

Rapid, unless given through continuous IV infusion (needs hospitalization and supervision)

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3
Q

Explain depot injection.

A

Can be aqueous suspension or oleaginous solution.
After SC or IM injection, they can form a spot at the site of injection, acting as a drug reservoir that releases the drug molecules continuously at a rate determined by the characteristics of the formulation.

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4
Q

These properties reduce the inherent disadvantage of conventional Parenteral dosage forms.

A

Controlled release properties of depot injections

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5
Q

What are some additional advantages of depot injections?

A

Reduced drug dose
Decreased side effects
Enhanced patient compliance and improved therapeutic outcomes

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6
Q

What are some examples of several controlled release parenteral products?

A

Depo-Medrol: Glucocorticoid (lasts from 1 week to several)
Depo-Provera: Progesterone (3 months)
Modecate Concentrate: antipsychotic (2-3 week)
Norplant: Contraceptive implant (5 years)

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7
Q

List the 7 commonly used techniques for the development of parenteral sustained or controlled release formulations.

A

1) use of viscous, water-miscible vehicles (gelatin and PVP)
2) use of water immiscible vehicles (vegetable oils, plus water-repelling agent)
3) formation of thixotropic suspension
4) use of water insoluble drug derivatives
5) formation of polymeric microspheres or microcapsules
6) formation of liposomes
7) coadministration of vasocontrictors

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8
Q

The drug absorption rate in this type of depot formulation is controlled by dissolution of drug particles in the formulation or in tissues surrounding the fluid.

A

Dissolution-Controlled Depot

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9
Q

What are you looking for in a formulation for Dissolution-Controlled Depot to produce the desired effects?

A

A selection of salts or complexes with low aqueous solubility or formulation of macrocrystal suspensions

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10
Q

What are the major drawbacks of the Dissolution-Controlled Depot formulation?

A

Not zero-order kinetics
Due to either:
- the surface area of the drugs particles diminishes with time because of increased drug dissolution
-the saturation solubility of the drug at injection site cannot be easily maintained because of rapid absorption

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11
Q

This preparation is formed by binding drug molecules to adsorbents such as aluminum hydroxide gel and only unbound drug is available for absorption. When unbound drug is absorbed, fraction of bound drug is released to maintain equilibrium.

A

Adsorption-Type Depot

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12
Q

This preparation is made by encapsulating drug solids within a permeation barrier or dispersing drug particles in a diffusion matrix, with drug release rate controlled by permeation rate.

A

Encapsulation-Type Depot

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13
Q

What materials are used in the Encapsulation-Type Depot?

A

Biodegradable or bio absorbable macromolecules such as gelatin, dextran, polylactate, phospholipids.
Formulations include microcapsules, liposomes, and microbeads.

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14
Q

This type of formulation is produced by esterifying the drug to form a bioconvertible prodrug ester and then preparing it in an injectable.

A

Esterification-Type Depot

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15
Q

What is the drug absorption rate controlled by in the Esterification-Type Depot?

A

It is controlled by the interfacial partitioning of drug esters from the reservoir to the tissue fluid and the bioconversion of inactive drug esters to active drug molecules.

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16
Q

Why are parenteral emulsions being increasingly used as drug carriers?

A

Du to their ability to incorporate dugs within the internal phase, resulting in better solubility and stability.
Not in direct contact with body fluids

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17
Q

How can we prolong the delivery of drug in parenterals?

A

Through the use of multiple emulsions by introducing an extra partitioning step

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18
Q

What are the common oils used in oil phase emulsion injections?

A

Long chain triglycerides from vegetable sources such as soybean and safflower oil, which contains a significant percent of linoleum acid.

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19
Q

What is involved in the purification of oil?

A

May involve treatment with silicic acid or silica gel to remove undesirable components such as peroxides, pigments, thermal and oxidative decomposition
Natural oils must also be checked for the presence of aflatoxins, herbicides and pesticides (inadvertent contamination)

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20
Q

What must natural oils be checked for?

A

Aflatoxins, herbicides and pesticides

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21
Q

What eliminates most emulsifying options?

A

Hemolytic reactions

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22
Q

What is the most frequently used emulsifier in injectables? And what is its advantages?

A 
Natural lecithins (egg yolk, soybeans).
It is metabolized the same way fats are and is not renally excreted.
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23
Q

What is another option for emulsifiers?

A

Phosphatide, very stable, resisting hydrolysis and oxidation if processed under inert conditions

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24
Q

Why are substances added to the aqueous phase?

A

To adjust/control osmolality, pH, oxidation and Microbial growth.
Because oils exert no osmotic effect, additives are also for isotonicity.

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25
Q

What additives don’t work in the aqueous phase of the injectable and which do work?

A

Sodium chloride, glucose, dextrose due to their interaction with the emulsifier
Glycerol is good

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26
Q

How do antioxidants contribute to emulsions? Give some examples used.

A

May be added to prevent per ideation of unsaturated fatty acids.
Alpha-tocopherol, deferoxamine mesylate or ascorbic acid

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27
Q

This is usually adjusted with a small quantity of sodium hydroxide prior to sterilization

A

pH

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28
Q

Why does the pH of the formulation fall during autoclaving and storage?

A

Hydrolysis of glycerine and phosphatide produces free fatty acids

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29
Q

What does pH effect as far as particle size?

A

Surface charge of particles causing coalescence and generation of large particles
A low pH can reduce the electrostatic repulsion between emulsified oil particles

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30
Q

What characteristics of the lipid globules have a direct effect on toxicity and stability?

A

Particle size
Greater than 4-6micrometers= increase the incidence of emboli and BP changes
Small particle size has increased physical stability

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31
Q

What do ionized lipids have a favourable effect on?

A

Emulsion particle size and stability through increased surface charge.

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32
Q

A ______ in the electrical charge can _____ the rebate of flocculation and coalescence.

A

Reduction, increase

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33
Q

How can we optimize surface charge?

A

By choosing lecithins with varying amounts of negatively charges phosphatides such as phosphatidic acid, phosphatidylserine or phosphatidylinositol.

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34
Q

List what can influence the stability of emulsions.

A

Processing conditions
Autoclaving storage conditions
Excessive shaking
Addition of electrolytes or drugs

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35
Q

Particle size changes, flocculation, creaming, coalescence and oil separation are all indicators of what?

A

Physical instability

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36
Q

Oxidation and hydrolysis of the oil or emulsifier, change in the pH value and increase in free fatty acid content are all indicators of what?

A

Chemical instability

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37
Q

Heterogenous systems consisting of a solid phase dispersed in a liquid phase that may be either aqueous or nonaqueous.

A

Injectable suspensions

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38
Q

What are the requirements of injectable suspensions?

A

Should be sterile, pyrogen free, stable, resuspendable, syringeable, injectable, isotonic, and non-irritating

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39
Q

What is the recommended particle size for IM or SC administration of injectable suspension?

A

5 micrometers

40
Q

What is the purpose of flocculating agents and what are some agents used?

A

Forms loosely bound aggregate or flocs that rapidly settle but redisperse easily.
Electrolytes, surfactants, and hydrophilic colloids

41
Q

What is an alternative to flocculating agents is using viscosity increasing agents to do what?

A

To thicken and maintain dispersion of the flocculating agents, reducing the rate of sedimentation.

42
Q

What is the purpose of wetting agents and their normal concentration?

A

Wetting agents reduce the contact angle between the surface of the particle and the wetting liquid.
0.05- 0.5%

43
Q

What does the solvent system in suspended injections depend on?

A

Solubility, stability and desired release characteristics of the drug.

44
Q

Define syringeability and injectablility.

A

The ability of the injectable suspension to pass through the needle before and during injection. They are closely related to viscosity and particle size of the suspension.

45
Q

Define resuspendability.

A

The ability of the suspension to uniformly disperse with minimal shaking after it has stood for some time. Related to particle size, crystal growth and viscosity of vehicle

46
Q

How are injectable suspensions normally administered?

A

Intravenously.

47
Q

Mixing order should be strictly observed for IV infusions. What should normally be added last?

A

Electrolytes should be added last or mixed with amino acid/dextrose injections, then transfer into the emulsion.

48
Q

How are injectable suspensions normally administered?

A

Limited to IM or SC application for prolonged/controlled therapy. Must watch for possible irritation and toxicity.

49
Q

What is the issue in IV administration of suspensions?

A

Could result in vasoocclusion and pulmonary embolism with particles larger than 5 micrometers

50
Q

A type of parenteral drug delivery system for prolonged effect.

A

Medical Implant

51
Q

What are the seven requirements controlled release drug implants need to fulfill?

A

1) Facilitate and maximize patient compliance.
2) Deliver drug at controlled rate throughout treatment period, with maximal dose-response-duration relationship and minimal adverse effects.
3) Readily implanted with major surgical procedure.
4) Free of potential medical complication.
5) Minimal risk of misuse or unauthorized termination of medication.
6) Readily removed by medical personnel when necessary
7) Manufactured with simple processing cost

52
Q

Describe the membrane permeation controlled devices.

A

The drug reservoir is encapsulated within a compartment that is totally enclosed by a rate controlling polymeric membrane.
Drug reservoir: drug solid particles, or dispersion of solid in liquid.
Polymeric membrane: homogenous or heterogenous non porous polymeric material or a microporous semipermeable membrane

53
Q

How is the drug release rate from membrane permeation controlled devices controlled?

A

By the permeation of drug solution from the system

54
Q

Describe the matrix diffusion controlled devices

A

This type of device has a drug reservoir that is formed by homogenous dispersion of drug solid particles throughout a lipophilic or hydrophilic polymer matrix.

55
Q

Describe the Membrane-Matrix Hybrid Devices?

A

Takes advantage of the constant drug release rate maintained by the permeation-controlled system while minimizing the risk of dose damping from the reservoir compartment of this type of delivery system.
Drug reservoir is intially formed as drug matrix but the matrix is encapsulated by a rate-controlling polymeric membrane.

56
Q

Describe the Microreservoir Partition Controlled Devices.

A

Drug reservoir is a suspension of drug crystals in an aqueous solution of a water-miscible polymer. Creates homogenous dispersion of microscopic reservoirs in a polymer matrix. Device can be further coated with a layer of biocompatible polymer to modify release.

57
Q

Describe Pressure Activated Devices.

A

Osmotic pressure used as energy source to deliver drugs. Drug reservoir is contained within semipermeable housing with controlled water permeability. Drug release rate is controlled by water permeability, surface area and thickness of semipermeable membrane.

58
Q

Describe Vapor Pressure Activated Devices.

A

The drug reservoir, a solution, is contained inside a infusate chamber, seperate from the vapor chamber which contains fluorocarbon.

59
Q

Describe Magnetically Activated Devices.

A

Electromagnetic energy is used to activate drug delivery and control release rate. Amount released varies on magnitude and duration electromagnetic energy is applied.

60
Q

The interaction between membrane molecules such as phospholipid and water forming a unique structure.

A

Liposomes

61
Q

What are vesicles made of?

A

Hydration of the polar head groups of the lipid results in a heterogenous mixture of structures

62
Q

Liposomes that contain multiple lipid bilayers are called:

A

Multilamellar vesicles

63
Q

Liposomes with a single bilayer with diameters ranging 25-50nm

A

Small uni lamellar vesicles (SUV)

64
Q

Liposomes with a single bilayer with a size range of 100-500nm in diameter

A

Large uni lamellar vesicles (LUVs)

65
Q

What are the most commonly used components of liposome formulations?

A

Glycerol-containing phospholipids, with the general chemical structure of these types of lipids being exemplified by phosphatidic acid.

66
Q

What is the most abundant glycerol phosphatides in plants and animals?

A

Phosphatidylcholine (lecithin) and phosphatidylethanolamine (cephalin)

67
Q

List the three roles of cholesterol in liposome structures.

A

1) Decreasing the fluidity or microviscosity of the bilayer
2) Reducing the permeability of the membrane to water soluble molecules
3) Stabilizing the membrane in the presence of biological fluids such as plasma.

68
Q

Liposomes (with) or (without) are known to interact rapidly with plasma proteins such as albumin, transferrins and macroglobulins?

A

Without.

These proteins extract bulk phospholipids, depleting the outer mono layer of the vesicles (physical instability)

69
Q

What determines the location of the drug within the liposome?

A

Partition coefficient of the drug between aqueous compartments and lipid bilayers.
The amount of drug within liposome is dependant on solubility of each phase.

70
Q

The internal or trapped volume and encapsulation greatly depend on what?

A

Liposomal content, lipid concentration, method of preparation and the drug used.

71
Q

Incorporation of what in the bilayers increases the volume of the aqueous compartments by separating adjacent bilayers, resulting in increased volume?

A

Charged lipids(phophatidylserine), seperated adjacent bilayers due to charge repulsion

72
Q

What is the most frequently used lipid for liposome formulations?

A

Lecithin

73
Q

Why is sphingomyelin used a substitute for lecithin?

A

Produces more rigid structure (longer T1/2)

74
Q

What is added to “toughen” liposomes up, and reduce leakage of entrapped drug?

A

Cholesterol

75
Q

What is considered an effective antioxidant to prevent unsaturated phospholipids from being oxidized?

A

Alpha-tocopherol

76
Q

What is included in the Positive and Negative Liposome kit?

A

Positive: Egg lecithin, stearlamine, Cholesterol
Negative: Egg lecithin, Dicetylphoshate, Cholesterol

77
Q

List the 3 liposome preparation methods and what must be done to all of them after preparation?

A

Hydration Method (excess volume of aqueous buffer to a thin film of lipid under pressure)
Solvent Injection Method (injection of lipids dissolved in organic solvent)
Reverse Phase Evaporation Method (formation of W/O emulsion of phospholipids and buffer, followed by removal of organic phase under pressure)
- further size reduction must be performed

78
Q

What are the three approaches to control particle size distribution of liposome preparations?

A

Fractionation (from heterogenous liposome preparation)
Homogenization of a liposome dispersion
Extrusion of a heterogenous preparation through capillary pore membranes

79
Q

Physical instability of liposome formulations (aggregation/fusion, phase change) is dependant on what?

A

Mechanical: liposome membranes, thermodynamics, colloidal properties
Chemical: hydrolysis and oxidation

80
Q

MLVs are most stable and SUVs are least. Why?

A

MLVs only have a portion of the phospholipid exposed to invivo attack
SUVs have stress imposed on their curvature.

81
Q

How can we stabilize liposomes in blood circulation?

A

Cover them with hydrophilic, nonionic polymers.

Nonionic water-compatible, flexible polymers like polyethylene oxide are preferred.

82
Q

What is the proposed major mechanism of liposome uptake an disintegration in plasma?

A

The reaction with proteins of the immune system, which absorbs foreign colloidal particles and tag them for macrophage uptake.

83
Q

Define Stealth liposomes.

A

Liposomes with surface attached polymers, reducing immunoglobulin and lipid exchange.

84
Q

What are some highlights of liposomes as a drug delivery system?

A

Drug dispersers for difficult to solubilize drugs
Sustained release system for micro encapsulated agents
Penetration enhancers
Site-specific delivery vehicles
Reduced toxicity (no accumulation in kidneys and heart)

85
Q

What are the five most promising liposomal drug delivery areas?

A 
Site-specific delivery
Site-avoidance delivery
Sustained or Controlled release
Passive drug targeting
Gene therapy
Can also be used as a signal carrier in diagnostics
86
Q

What is the other colloidal system, besides liposomes, that’s possess controlled release and site specific characteristics?

A

Nanoparticles

87
Q

Define nanoparticles and explain the difference between a nanaocapsule and nanosphere

A

Colloidal particles with a size smaller than 1mm
Nanocapsule: core-shell structure, drug reservoir
Nanosphere: matrix system

88
Q

What are the three ways the active compound can be presented in nanoparticles?

A

Dissolved in polymeric matrix
Encapsulated
Absorbed or attached to surface of colloidal carrier

89
Q

What materials are commonly used to prepare nanoparticles?

A

Polyesters, cellulose derivatives and natural polymers

Sometimes, nanoparticles can be prepared by polymerization of monomers

90
Q

What are the unique methods to prepare nanoparticles?

A

1) Emulsion-evaporation method: preformed polymer (water-insoluble and -soluble polymers) are dissolved in chlorinated solvent and emulsified in an aqueous phase containing surfactant
2) Salting-Out Method: an electrolyte-saturated solution is added to acetone solution of polymer to form O/W emulsion. Sufficient water is added to allow diffusion of acetone into the aqueous phase
3) Emulsion-Diffusion Method: aqueous gel added to polymer solution dissolved in benzoyl alcohol to form W/O. Large amount of water added
4) Precipitation Method: polymer is dissolved in a water-miscible solvent and mixed into a nonsolvent, resulting in percipitation

91
Q

Why is a purification of step necessary in parenteral nanoparticles?

A

Many potentially toxic and undesirable preparation additives can be present in raw suspension.

92
Q

What are the five normal purification steps of nanoparticles?

A

1) Ultracentrifugation(supernatant is discarded and particles resuspended in water, done several times)
2) Centrifugal Ultrafiltration (ultrafiltration membrane seperate particles from dispersion)
3) Cross-flow Flitration (directed tangentially to the surface of the membranes to prevent clogging of the filters and water is added at same rate as filtration)
4) Gel Permeation (seperate free drug from particle bound)
5) Dialysis (nanoparticle suspension dialyzed against poloxamer solution

93
Q

What can occur if nanoparticles are kept in an aqueous medium during storage? How would you improve the physiochemical stability?

A

Biodegradation of polymers
Drug leakage
Degradation
- Drying increases stability (freeze-drying is most common, in nitrogen)

94
Q

What does redispersion depend on after freeze drying?

A

Depends on particle coating
Poloxamer, Polysorbates, and sodium dodecyl sulfate are all easily redispersed.
Can add a cryoprotective(dextrose, lactose) if not easily redispersed

95
Q

What is the method of choice for nanoparticle sterilization and why?

A

Gamma-radiation because:
High temps= irreversible fusion of nanoparticles
Gas= residual concentrations within the product
Aseptic processing: costly and risky in regards to contamination

96
Q

List the general parameters used to characterize nanoparticles.

A

Particle size, morphology, surface charge, drug loading, entrapment efficiency, drug release profile, physiochemical state of polymer and in vitro biodegradation

Biopharmaceutics 2 (7 decks)

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