implants advance drug delivery

Question 1

what are the two different strategies for advanced drug delivery technology?

explain each.

Answer 1

rate-controlled : being able to deliver a drug in the correct time frame. (immediate release or a delayed release or continued release

targeted: systems that are able to deliver the drug to only where the drug is required

Question 2

what are the advantages of controlled drug delivery

Answer 2

it helps to avoid periods of ineffective activity of the drug and toxicity of the drug and maintain the drug at concentration that is within its therapeutic window.

it is effective and it reduces problems to non effective dose concentration and toxic effect

Question 3

what are the therapeutic and commercial advantages of using advanced drug delivery.

Answer 3

CONVENIENCE & COMPLIANCE
Slower release 🡪 less administrations 🡪 better compliance
The patient will prefer a form with controlled release especially in asymptomatic conditions such as hypertension

2. EFFICACY
   Ibuprofen (4-6h effect) 🡪 non effective overnight need for SUSTAINED RELEASE
   Brufen retard, tablets
   Fenbid, capsules
3. PROTECTION OF FRANCHISES
   patents on drugs expire in about 20 years, after that any manufacturer can produce that drug
4. ADDING VALUE TO GENERICS
   Generic is a product for which the original patent has expired and can now be sold to other companies for production, it can be sold at low prices; advanced technologies can be applied to generics to differentiate them from those produced in other companies
5. MARKET EXPANSION
   advanced technologies can make it possible to administer drugs by different routes, above all drugs that were traditionally injected, self-administration increases the population that can benefit from that drug and therefore increases the size of the market
   ex. Nasal route for peptides
   Calcimar Intranasal, calcitonin (Aventis)
   nasal Insulin will enter the market in UK in May 2006
6. CREATING NEW MARKETS
   sense of developing drug delivery system for novel type of drugs (e.g. in gene therapy where there are not many drug delivery systems yet developed, therefore making it difficult to deliver this type of therapy)

Question 4

explain the following terms.

Prolonged/sustained release

delayed release

repeat action

prolonged release

sustained release

rate controlled

targeted drug delivery

Bio-responsive release

Zero-order release

Variable release

Answer 4

delayed release: release does not occur immediately

repeat action: more than one dose is released

Prolonged release: slow onset and slow release

sustained release: initial release plus gradual release

targeted drug delivery: drug released in a specific location.

Prolonged/sustained release: the delivery system prolongs therapeutic blood or tissue levels of the drug for an extended period of time

Zero-order release: the drug release does not vary with time; thus the delivery system maintains a relatively constant effective drug level in the body for prolonged periods

Variable release: the delivery system provides drug input at a variable rate, to match, for example, endogenous circadian rhythms, or to mimic natural biorhythms

Bio-responsive release: the systems modulates drug release in response to a biological stimulus (e.g. blood glucose levels triggering the release of insulin from a drug delivery device.

Modulated/self regulated release: the system delivers the necessary amount of drug under the control of the patient.

Rate-controlled release: the system delivers the drug at some predetermined rate, either systemically or locally, for a specific period of time.

Targeted drug delivery: the delivery system achieves site-specific drug delivery

Question 5

what are the advantages of using rate controlled implants?

Answer 5

covinence and compliance

flexibility in dosage rate

no 1st pass or enzymatic metabolism

commercially covinent

Question 6

what are the disadvantages of using rate controlled implants?
5

Answer 6

Invasive
Termination Failure
 Limited loading: only a certain amount can be loaded
 Biocompatibility issues
 Commercially expensive

Question 7

what does Diffusion-controlled release depend on?

Answer 7

The release depends on the diffusion of the drug through:

- polymeric membrane
- polymeric matrix
- lipid matrix

Question 8

what is Fick’s law?

Answer 8

Fick’s Law describes the relationship between the rate of diffusion and the three factors that affect diffusion. It states that ‘the rate of diffusion is proportional to both the surface area and concentration difference and is inversely proportional to the thickness of the membrane’.

Question 9

Knowing that the release kinetic follows fick’s first law, how do you think you can modify the release rate from this system (reservoir devices )?

Answer 9

thickness of the membrane
surface area
type of polymer which changes partition
diffusion coefficient

Question 10

How do you expect the release to change in time (reservoir devices)?

Answer 10

constant because the membrane does not change

Question 11

What is the rate limiting factor for drug release from reservoir devices?

Answer 11

the membrane

Question 12

What is the rate limiting factor for drug release from matrix devices?

Answer 12

the diffusion path length

Question 13

How do you expect the release to change in time (matrix devices)?

Answer 13

slowing down in time as the diffusion path becomes greater; because there is no membrane and there is no control meaning that it would take longer for particles at the core to get to the intended site.

it slows down in proportion to the square root of time. M=Kt^1/2

Question 14

what do you think are the factors controlling drug release in this type of systems (matrix devices)

Answer 14

initial concentration of the drug in the matrix

Porosity: can be evenly (straight forward and quick release or randomly distributed (scattered and slow release)

Tortuosity: when the drug release is random and scattered

Polymer employed: if there is high affinity between the drug and the polymer used to hold the drug then this would cause a slow release of the drug.

Solubility of the drug: low solubility means smaller amounts of the drug is dissolved in water, therefore a slower release of the drug from the system.

Question 15

___ close to the surface are released quicker than the internal ones that have to travel longer distance in matrix devices.

Answer 15

molecules

Question 16

_____ do not give zero-order release rate

Answer 16

matrix devices

Question 17

_______subdermal implant

Contraceptive levonogestrel released for up to 5 years

Answer 17

Norplant

Question 18

what is the silicone rubber copolymer that is the membrane of norplant

Answer 18

dimethylsiloxane/methylvinylsiloxane

Question 19

give facts about Implanon

polymer?

system

drug?

Answer 19

has both a matrix and the membrane made of the same polymer which is polyethylene-co-vinyl acetate.

it uses a hybrid system of both reservoir and matrix. (using the same polymer for both)

and it’s technology is used in subdermal implant
Contraceptive etonogestrel released for up to 3 years at a rate of 40μg/day

Question 20

what are the limitations of non-degradable implants?

Answer 20

The implant must be surgically removed

• Water-soluble, highly-ionised and macromolecular drugs do not diffuse through hydrophobic membranes (the device)
• Release rate depends on the characteristics of the polymer and it is difficult to obtained varied release rates

Question 21

list two Degradation mechanisms

Answer 21

Bioerosion 🡪 gradual dissolution

Biodegradation 🡪 chemical or enzymatic processes
Biodegradation can occur by both methods at the same time, albumin is soluble and subject to enzymatic degradation

Question 22

list two Polymer degradation patterns

can they both happen at the same time? give an example.

Answer 22

• Bulk erosion: where the polymer breaks down from inside out therefore releasing the drug. (makes determining the release of the drug a bit more complicated).
• Surface erosion: where the polymer surface keeps shrinking and gradually releasing the drug. (it has to be spherical in geometry because it’s surface degradation over time is more predictable than flat geometry)

they can both happen at the same time e.g. albumin

Question 23

_________polymers are more stable against degradation

Answer 23

Lactid acid rich

Question 24

what are the Stages of polymer degradation?

4

Answer 24

Polymer hydration

• Rupture of ester linkages
• Loss of mass, small parts become soluble and are absorbed
• Phagocytosis of polymeric segments

Question 25

list facts about Zoladex (goserelin acetate)

it is a __________ implant
Used in the treatment of _______________

The drug is ______________________
Lag phase is due to _________________________

Answer 25

it is a biodegradable implant
Used in the treatment of sex-hormones responsive tumours and endometriosis.

The drug is dispersed in a bulk-eroding PLGA matrix moulded in cylindrical shape.

Release profile: initial rapid release – 4 days lag – constant release for prolonged period
Lag phase is due to hydration of polymer and beginning of degradation

Question 26

how do you think the swelling of the matrix or membrane is going to affect the release?

Answer 26

the swelling: - increases the amount of water available for dissolution of the drug

increases the path length for the diffusion

increases the mesh size of the matrix or membrane

Question 27

Biodegradation or dissolution of the polymer can occur according to two different patterns:

Answer 27

Bulk erosion/dissolution in which the process takes place in the bulk of the system, outside and inside

Surface erosion/dissolution in which the process occurs only at the surface

Question 28

how are these two biodegradable system patterns going to affect release?

Answer 28

Bulk process: changes diffusion path in shape and length, porosity increases and most internal molecules don’t have to diffuse through the whole system

Surface process: changes diffusion path in shape and length, both surface area and path length decrease, you can work on the geometry of the system to define which of the two parameters will be the prominent one, you will get different effects with a spherical system or a flat one

Question 29

how do biodegradable implants work?

Answer 29

1. the liquid product is injected into the subcutaneous space through a small gauge needle or placed into accessible tissue sites through a cannula
2. water in the tissue fluids causes the polymer to precipitate and trap the drug in a solid implant
3. The drug encapsulated within the implant is then released in a controlled manner as the polymer matrix biodegrades with time

Question 30

what are advantages of biodegradable implants?

Answer 30

Advantages:
- Compatibility with a broad range of pharmaceutical compounds

• Easy to be injected
• All current components of the Atrigel system are biocompatible and have independently established safety and toxicity profiles

Question 31

_________is a biodegradable implant for the delivery of carmustine for the treatment of recurrent brain tumour.

Answer 31

Gliadel

Question 32

what are advantages of glidel

Answer 32

Advantages:

• Circumvents BBB
• Can be applied during surgery
• Provides localised concentration of drug

Question 33

list steps for preparation of glidel?

Polymer 🡪__________: ___________ 20:80

Polymer and drug dissolved in ______________

______________ produced spherical microparticles

Powder compressed into _________________

Answer 33

Preparation:
Polymer 🡪 biscarboxyphenoxy propane: sebacic acid 20:80

Polymer and drug dissolved in dichloromethane
Spray-dry of solution produced spherical microparticles

Powder compressed into disk-shaped wafers

Question 34

how is glidel degraded

constant release is guaranteed by ______________

Answer 34

Degradation:
The disk is degraded by surface erosion

Constant release is guaranteed by constant surface/volume ratio

Question 35

_____is dibotermin α

Answer 35

InductOS

Question 36

describe dibotermin α (InductOS) with its mechanism of action, indications

name?

Answer 36

Recombinant human Bone Morphogenic Protein (BMP) – osteoinductive protein

Indications: treatment of bone fractures

Mechanism of action:
BMP binds to mesenchymal cells receptors and induces differentiation into bone forming cells
Differentiated cells form trabecular bone
New blood vessels form
Matrix degraded and is replaced by new bone

Question 37

how is induct os formulated?

Powder:

Solvent:

Matrix:

Answer 37

Powder: sucrose, glutamic acid, NaCl, Polysorbate 80, NaOH

Solvent: water for injection

Matrix: Bovine Type I collagen

Question 38

what are the key features of osmotic pumps? with an example

Outer titanium alloy reservoir provides ____________, __________- and __________

2. Polyurethane membrane, permeable exclusively to ____________
3. Osmotic engine containing a tablet of ___________ and other excipients
4. Piston made of elastomeric material, separates the osmotic engine from the drug formulation
5. Exit port which design depends on the rheological properties of the drug formulation
6. Drug formulation in form of either a solution or a suspension aqueous or not, must be stable at 37°C for a period of __________, ___________ are more stable

Example: Viadur® containing ______________

Answer 38

Outer titanium alloy reservoir provides protection from enzymes, body moisture and cellular uptake

2. Polyurethane membrane, permeable exclusively to water
3. Osmotic engine containing a tablet of sodium chloride and other excipients
4. Piston made of elastomeric material, separates the osmotic engine from the drug formulation
5. Exit port which design depends on the rheological properties of the drug formulation
6. Drug formulation in form of either a solution or a suspension aqueous or not, must be stable at 37°C for a period of 3 months to 1 year, non-aqueous solutions are more stable

Example: Viadur® containing leuprolide acetate

Question 39

in osmotic pumps, constant rates can be achieved if _______ happens

Constant release-rate can be achieved if:
- ______________________, so that the osmotic pressure remains constant

• _________________, so that the concentration of drug remains constant

Answer 39

Constant release-rate can be achieved if:
- Sufficient amount of osmotic agent is present, so that the osmotic pressure remains constant

• The drug reservoir contains a saturated solution of drug, so that the concentration of drug remains constant

Question 40

mechanical pumps, list facts about them

Developed in the___________

• Titanium: ___________ and_________
• Inserted __________ between ___________ and subcutaneous fat, secured by suturing
• Release in the peritoneal membrane ensures__________ of insulin than subcutaneous injection
• Site of delivery can vary, it can be reached by a catheter

Answer 40

Developed in the 1980s

• Titanium: biocompatible and long-life
• Inserted intraperitoneally between muscular fascia and subcutaneous fat, secured by suturing
• Release in the peritoneal membrane ensures faster absorption of insulin than subcutaneous injection
• Site of delivery can vary, it can be reached by a catheter

Question 41

what are the three rate controlled parenteral drug delivery systems?

Answer 41

non degradable: diffusion controlled (matrix reservoir pore)

bio degradable: dissolution controlled (biodegradable

pumps

Question 42

what are the two different types of implantable systems?

explain them.

Answer 42

RESERVOIR DEVICES
The drug is surrounded by a rate-controlling polymer. it needs water in order to be released because the water has to dilute the drug at the core of the device and therefore the drug would be released through the polymeric membrane by diffusion

MATRIX DEVICES
The drug is distributed throughout a continuous phase comp. Here we have a polymeric matrix in which the drug is homogenously dispersed or dissolved. we would need water coming into the system to dissolve the drug and causing it to diffuse out.

Question 43

what are the two different geometry for a reservoir system?

Answer 43

spherical geometry: more common for implantable or oral systems

flat and layered geometry: which is found normally in transdermal systems.

Question 44

what is the advantage of implanon

Answer 44

since it uses a hybrid system, the having a matrix core makes it more polar therefore reducing the affinity of the polymer to the drug.

the reservoir membrane is used to limit the diffusion rate.

Question 45

PLGA list facts___________

what two monomers form it?

use frequency

full meaning

monomers

link break?

Answer 45

is one of the most used polymer that undergoes degradation, and it is used for biodegradable implants

full meaning of PLGA is poly-lactide-co-glycolide polymers (PLGA)

it is a co polymer formed by combination of two monomers, namely lactic acid and glycolic acid

you can also have only the lactic acid form the polymer (poly lactic acid)

the link holding the monomers is an ester link. which would break when in presence of water (hydrolysis)

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