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Drug Delivery > Controlled delivery > Flashcards

Controlled delivery Flashcards

1
Q

Explain the rationale behind the development of controlled release drug delivery systems.

A

In the traditional oral formulation, all the drug is effectively released at once. This can result in side effects due to peaks in the plasma concentration going above the MTC.
This type of delivery necessitates repeated dosing for many medicines leading to compliance issues.

Controlled delivery allows many different release profiles to be achieved:

  • Pulsed
  • Delayed
  • Prolonged
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2
Q

Describe an implantable microchip drug delivery device:

A

Indicated for: chronic infusions of baclofen for spasticity, methotrexate for cancer, morphine sulphate for pain.

Release occurs by application of a current through a rupturable membrane and very long periods of delivery are possible if implanted SC.

Multiple drug reservoirs, tight control over timing of doses, protection of the drug prior to release.

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3
Q

What types of conditions may benefit from treatment via an implantable microchip?

A

Spasticity: chronic infusions of baclofen can be delivered.
Cancer: methotrexate.
Chronic pain: morphine sulphate.

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4
Q

How does drug release from biodegradable polymer matrix devices occur?

A

Either bulk or surface erosion.
Different factors influence the release rate/amount of degradation of the drug such as the physiochemical properties of the polymer, excipients and the drug itself.

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5
Q

What are the advantages of using implantable microchips? [5]

A
  1. Drug is protected prior to release. No premature clearance, drug degradation, metabolism etc.
  2. Multiple drug reservoirs containing different drugs are possible: one device could contain a range of drugs to be released over different timeframes and at different rates.
  3. Tight control of doses is possible: could wifi link to your phone etc.
  4. The release occurs via application of a current through a rupturable membrane and very long periods of delivery are possible if implanted SC.
  5. Useful for: Baclofen - for spasticity.
    Methotrexate - cancer.
    Morphine sulphate - chronic pain,
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6
Q

Describe implantable devices for drug delivery in general. [7]

A
  1. Polymer-based or pumps.
  2. Deliver controlled levels of drug over an extended time period.
  3. Increased compliance, convenience and control
  4. Do require invasive surgeries and can fail (potency issues).
  5. Dose dumping can potentially occur.
  6. Fibrous encapsulation of the device can occur.
  7. Device explantation can occur
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7
Q

What are the disadvantages to using implantable drug delivery devices? [5]

A
  1. Requires surgery.
  2. Devices can fail spontaneously
  3. Dose dumping can occur.
  4. Device can become fibrously encapsulated.
  5. Device can become explanted
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8
Q

How does drug release occur from implantable microchips?

A

The release occurs via application of a current through a rupturable membrane and very long periods of delivery are possible if implanted SC.

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9
Q

What factors affect the rate of release and/or the amount of degradation a drug will undergo in a biodegradable polymer matrix device?

A

Physiochemical properties of the drug itself.
Physiochemical properties of the excipients in the formulation.
Physiochemical properties of the polymer matrix itself.

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10
Q

What are the downsides to using biodegradable polymer matrix devices?

A

The interfaces, solvents etc. found in the formation of polymer-based devices and the products of acidic degradation can cause denaturation and aggregation of the proteins.

Microchip devices can offer protection to lyophilised proteins.

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11
Q

Describe an osmotic pump and describe its main features.

A

DUROS implant.

  • Zero-order release for up to 12 months.
  • Drug is protected from premature release/clearance/degradation
  • subcutaneous implant.

Main features:
Thin cylinder containing the drug in a reservoir, a small orifice for release, a piston, an osmotic agent and a semipermeable membrane.
Water (liquid) enters the pump via the semipermeable membrane at a preset known rate.
This causes the osmotic agent to expand at a controlled rate pushing the piston which in turns forces quantities of drug out of the drug reservoir into the surrounding tissue via the small orifice.

Another example: Viadur (Bayer) Leuprolide acetate for the pain, urinary problems and symptoms associated with advanced bladder cancer.

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12
Q

Describe a diffusion controlled reservoir DDS:

A

Water-insoluble polymer membrane surrounding a solid or concentrated solution drug core.
The membrane is either non-porous or micro-porous.
The drug reservoir is saturated.
The rate-controlling membrane has a constant thickness (so pathlength ‘h’ is always the same), diffusivity (D) and solubility coefficient (k?),.
Effectively zero order release.

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13
Q

Describe a monolithic matrix DDS:

A

The drug is uniformly dispersed or dissolved in the polymer, and is released by diffusion. Release rate is function of time and distance.
As more drug is released the distance between unreleased drug particles and ‘outside’ is increased. Hence ‘h’, pathlength and thus flux will have an inverse correlation: as h increases flux will decrease.
Release rate from a monolithic matrix DDS will decrease over time.

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14
Q

Release rate from which type of diffusion controlled device will decrease with time?

A

A monolithic diffusion device.

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15
Q

How can drugs be released from implantable devices?

A
  1. Passing current though a rupturable membrane: Microchips.
  2. Degradation of the polymer: cleavage of monomer bonds, cleavage of crosslinks between polymer chains to free soluble polymer molecules and drug. Conversion of side groups from hydrophobic to hydrophilic species, rendering the polymer soluble.
  3. Bulk erosion: PLA, PGA, PLGA.
  4. Surface erosion: Polyanhydrides.
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16
Q

Variables that affect release rate from implantable devices. [6]

A
  1. Moleculer weight of the polymer.
  2. Ratio of the monomers (PLGA etc.) and the effect of the polymer’s chemical structure on the hydrophobicity.
  3. Individual excipients can alter the hydrophobiciy, pH in solution and the effect of pH on the degradation of the polymer.
  4. Modification of the polymer structure for autocatalysis can occur.
  5. The geometry of the device itself can affect the release rate - the surface area of an eroding polymer can vary with time, changing the release rate.
  6. Rate-controlling membranes can be potentially used.
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17
Q

How can the geometry of an implantable/controlled release device influence the release rate of a drug?

A

The surface area of an eroding polymer (polyanhydrides) can vary with time.

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18
Q

The drug is uniformly dispersed in which type of diffusion controlled drug delivery device?`

A

In a monolithic/matrix device.
Drug is uniformly dispersed or dissolved in the polymer, and is released by diffusion.
-Release rate is a function of time and distance.
-As more drug is released the distance between unreleased drug particles and outside is increased.
Hence h, pathlength, in Ficks first law will increase with time. -Release rate will decrease over time.

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19
Q

Polymers typically used to create bulk erosion - releasing controlled delivery systems.

A

PLA
PGA
PLGA

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20
Q

Surface erosion polymer

A

Polyanhydrides, polyorthoesters

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21
Q

What are the 4 main reasons behind developing controlled drug delivery systems?

A
  1. Reduce fluctuations in drug plasma levels.
  2. Reduce dosing frequency - improve patient compliance
  3. Control the delivery site.
  4. Timed release.
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22
Q

What role to enteric coatings play in controlled drug delivery?

A

Coatings for a tablet that are insoluble in the highly acidic environment of the stomach but dissolves in the small intestine.

They can be used to protect the drug from the stomach: Erythromycin.

Or to protect the stomach from the drug: NSAIDs.

Numerous polymers availble such as cellulose derivatives and methacrylic acid co-polymers (Eudagrit).

Release area can be tailored depending on pH/solubility profile.

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23
Q

PLA, PGA and PLGA are commonly found in:

A

Bulk erosion controlled release devices.

Surface erosion: polyanhydrides.

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24
Q

How can we protect the stomach from damage by NSAIDs?

A

Enteric coatings:
Coatings for a tablet that are insoluble in the highly acidic environment of the stomach but dissolves in the small intestine.

They can be used to protect the drug from the stomach: Erythromycin.

Or to protect the stomach from the drug: NSAIDs.

Numerous polymers availble such as cellulose derivatives and methacrylic acid co-polymers (Eudagrit).

Release area can be tailored depending on pH/solubility profile.

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25
Q

What are the four main classes of mechanisms for controlling drug release?

A
  1. Water Penetration-Controlled DDS: Swelling/Osmosis
  2. Diffusion-Controlled DDS: reservoir + monolithic devices.
  3. Chemically-Controlled DDS: monolithic devices - surface or bulk erosion. Pendant systems.
  4. Responsive DDS: physical or chemical.
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26
Q

What polymers can be used to enterically coat a drug?

A

Cellulose derivatives
methacrylic acid co-polymers.
Eudagrit

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27
Q

HPMC is commonly found in:

A

Swelling- controlled release devices.

HPMC: Hydroxypropyl methylcellulose.

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28
Q

In a water penetration-controlled DDS, what is the erosion front?

A

Erosion front: boundary between dissolution medium and matrix.

Diffusion front: boundary in the gel between solid and dissolved drug.

Swelling front: Boundary between glassy and rubber polymer.

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29
Q

What is the release rate of a water penetration-controlled DDS affected by?

A

Polymer MW, concentration and chemical structure.

Drug concentration, solubility and location.

Geometry of tablet and modifications.

30
Q

Describe the Geomatrix technology of SkyePharma:

A

Tablet with a hydrophillic HPMC core containing the drug.

One or two drug-free barrier layers which control swelling and surface area of the core.

31
Q

In a water penetration-controlled DDS, what is the diffusion front?

A

Erosion front: boundary between dissolution medium and matrix.

Diffusion front: boundary in the gel between solid and dissolved drug.

Swelling front: Boundary between glassy and rubber polymer.

32
Q

What us the TIMERx Controlled Release Delivery System?

A

A water penetration-controlled DDS.

Locust Bean Gum (LBG) and Xantham.

One smooth region per molecule results in across-linked network.

LBG + Xantham + Drug = TIMERx system.

33
Q

What does drug release from the TIMERx system depend on?

A

LBG:X:Drug ratio
Drug concentration
Additional components - salts and sugars
Construction of the tablet

34
Q

In a water penetration - controlled DDS, what is the diffusion front?

A

Erosion front: boundary between dissolution medium and matrix.

Diffusion front: boundary in the gel between solid and dissolved drug.

Swelling front: Boundary between glassy and rubber polymer.

35
Q

What excipients are found in the TIMERx system?

A

Drug
Locust Bean Gum (LBG)
Xantham.

36
Q

What is the major advantage behind GEMINEX technology? What type of DDS is it?

A

Water Penetration-controlled DDS.
Advantage is the ability to develop a combination drug product that has two unique release profiles,

Different granules are made for each drug component.

The two drugs are then compressed as standard.

37
Q

What is the SyncroDose system?

A

Ability to vary lag time by variations in the two polysaccharides, xantham gum and locust bean gum, found in the TIMERx coating.

Delivery system works by controlling rate of water ingress into coating and subsequent disintegration of the core.

38
Q

How do swelling/burst water penetration-controlled DDS work?

A

So there is a drug in a soluble polymer matrix with a rupturable membrane coating.

Water will ingress into the polymer through the membrane.

The device will swell and then rupture/burst releasing the drug.

Can allow delayed release.

39
Q

Alginate gel can be found in:

A

Swelling/burst DDS.

Alginate gel and Na+ –> alginate solution.

40
Q

What is the OROS system?

A

Osmotic water penetration-controlled DDS.

Drug is mixed with water-soluble core material such as polymer or inert salt like KCl.

Core is surrounded by water-insoluble semi-permeable polymer membrane, in which is laser-drilled a small orifice.

Water diffuses into the core through the outer membrane to form a concentrated solution inside.

Osmotic gradient established across semi-permeable membrane and drug is pushed out of hole.

41
Q

What are the benefits of OROS technology? [5]

A

Provides precise, controlled drug delivery for up to 24 hours.

Can be used with a range of compounds, including poorly soluble or highly soluble drugs.

Can target specific areas of GI tract to improve bio availability.

Can be tailored for patterned drug delivery profiles.

Protects the drug until release.

Can be used to deliver high drug doses.

42
Q

How are chemically controlled DDS typically produced? [6]

A 
Compression and melt molding. 
Solvent casting
Extrusion
Emulsions e.g. micro and nano particles.
Electrospinning 
3D printing .
43
Q

What natural polymers are found in chemically-controlled DDS? [6]

A

Collagen, Fibrinm Gelatin, Hyaluronan, Chitin, Silk.

44
Q

What synthetic polymers can be found in chemically-controlled DDS? [4]

A

Polyesters
Polyanhydrides
Polyorthoesters
Polyphosphoesters

45
Q

Why is the same injection moulding technology found in the plastics industry used to create chemically-controlled DDSs? [4]

A 
Results in:
Accuracy
Reproduciblility 
Reduced costs
Rapid device development
46
Q

What are pendant systems?

A

Pendant-chain systems have degradable linkages that release drug molecules upon exposure to water.

In pendant-chain systems, the drug molecules are covalently attached to the main polymer chain via degradable linkages. So, as the polymer is exposed to water or chemicals, the linkages break down releasing the drug.

47
Q

What are the factors affecting the drug release rate from a reservoir DDS?

A

Membrane thickness
Membrane porosity
Chemical nature of membrane material
Nature of drug and excipients.

48
Q

What are the factors affecting the release rate of drugs from a Matrix DDS?

A

Polymer properties
Diffusivity of drug in matrix
Nature of the drug and excipients.
Geometry

49
Q

What type of delivery system has linkages that break down releasing the drug?

A

In pendant-chain systems, the drug molecules are covalently attached to the main polymer chain via degradable linkages. So, as the polymer is exposed to water or chemicals, the linkages break down releasing the drug.

50
Q

How can drug release in responsive DDS be controlled?

A 
pH
Chemicals
Enzymes
Ultrasound
Magnetism
Light
51
Q

How can pH create a responsive DDS?

A

Changes in ionisation or cleavage of functional groups due to altered pH can affect sol-gel behaviour: for example poly(proylene imine) dendrimers. Acidic conditions can cause drug release.

52
Q

How are sepharose beads with immobilised glucose oxidase used to deliver insulin?

A

A polymer matrix containing crystalline insulin + sepharose beads with immobilised glucose oxidase are formulated.

As glucose is converted into gluconic acid (only when levels of glucose are high and thus insulin would be necessary) by the glucose oxidase the pH will drop causing the release of the crystalline insulin.

53
Q

What is the COLAL colonic drug delivery system?

A

Treats ulcerative colitis, Crohns.

Drug pellets are coated with ethylcellulose and “glassy” amylose. Ranitidine delivered this way.

54
Q

What are mesoporous silica nanoparticles?

A 
Inert. 
Thermally stable. 
Easy to functionalise. 
Controlled particle size. 
Homogenousm tunable porosity. 
Great potential for controlled delivery of traditional drugs, proteins and nucleic acids.

Following drug loading, pores can be capped with nanoparticles that can be selectively removed by pH, light, magnetism, antigen S-S reduction or saccharide.

55
Q

What are some examples of implantable devices for contraception?

A

Mirena - Diffusion controlled DDS.

Norplant and Jadelle rods - both Diffusion controlled DDS.

56
Q

How can ranitidine be delivered to treat Crohns and ulcerative colitis?

A

Via the COLAL colonic drug delivery system.

Drug pellets are coated with ethylcellulose and “glassy” amylose. Ranitidine delivered this way.

57
Q

What is the RETISERT implant?

A

Intravitreal to treat chronic noninfectious uveitis.
Fluocinolone acetonide.
PVA membrane.

58
Q

What coatings can be used to ensure colonic delivery?

A

Via the COLAL colonic drug delivery system.

Drug pellets are coated with ethylcellulose and “glassy” amylose. Ranitidine delivered this way.

Ranitidine.

59
Q

What is the I-vation implant, what does it treat?

A

Intravitreal implant to treat:
AMD, diabetic macular edema (DME) or Glaucoma.

Uses a Bravo (R) polymer matrix.

60
Q

What are Drug-Eluting Stents?

A

Stenosis is the narrowing of a blood vessel.
DES limit restenosis following removal of the stent.
Implanted in >6 million people worldwide.
Examples: CYPHER + TAXUS

Dissolving stents are a thing: polylactic acid backbone, polylactic acid/everolimus coating. Stent bioabsorbed in 2 years.

61
Q

How can timed release be achieved via swelling/bursting water penetration controlled DDSs?

A

We can formulate the membrane so that water ingresses at a known rate and therefore can time the release.

62
Q

What is eudragit?

A

Eudagrit is polymer coating (enteric) composed of either cellulose derivatives/methacrylic acid co-polymers.

63
Q

What are some examples of water penetration-controlled drug delivery systems?

A 
OROS
TIMERx
SyncroDose
GEMINEX 
GEOMATRIX -Skyepharma 
Duros implant?

Diffusion controlled devices: reservoir, monolithic matrix etc.

64
Q

CYPHER is an example of:

A

DES.
Stenosis is the narrowing of a blood vessel.
DES limit restenosis following removal of the stent.
Implanted in >6 million people worldwide.
Examples: CYPHER + TAXUS

Dissolving stents are a thing: polylactic acid backbone, polylactic acid/everolimus coating. Stent bioabsorbed in 2 years.

65
Q

What effect does the geometry of a DDS have on its rate of drug release?

A

The higher the surface area then the higher the drug release.
SA can be modified to control release rates.

66
Q

Fluocinolone acetonide is found in what?

A

RETISERT intravitreal implant to treat chronic noninfectious uveitis. PVA membrane.

67
Q

The COLAL colonic delivery system is what?

A

Drug pellets are coated with ethylcellulose and “glassy” amylose. Ranitidine delivered this way.

68
Q

What type of membrane does the RETISERT implant have?

A

PVA.
Stenosis is the narrowing of a blood vessel.
DES limit restenosis following removal of the stent.
Implanted in >6 million people worldwide.
Examples: CYPHER + TAXUS

Dissolving stents are a thing: polylactic acid backbone, polylactic acid/everolimus coating. Stent bioabsorbed in 2 years.

69
Q

TAXUS is an example of:

A

Stenosis is the narrowing of a blood vessel.
DES limit restenosis following removal of the stent.
Implanted in >6 million people worldwide.
Examples: CYPHER + TAXUS

Dissolving stents are a thing: polylactic acid backbone, polylactic acid/everolimus coating. Stent bioabsorbed in 2 years.

70
Q

How does alginate function in swelling and burst delivery devices?

A

Sodium alginate (SAL), a hydrophilic biopolymer obtained from brown seaweeds, has been found to be highly promising in this respect because of its high biological safety.

Ca displaces Na. can link to two molecules of alginate and form cross links,

Drug Delivery (11 decks)

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