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Targeted release Flashcards

1
Q

What are some of the GI conditions that oral medications can target?

A

Irritable bowel disease
Colon cancer
Oesphageal and colon cancer
Non-ulcer dyspepsia
Gastro-oesophageal reflux disease (GORD)
Duodenal and stomach ulcer disease (PUD)

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2
Q

What are some of the challenges with oral drug delivery?

A

Poor oral bioavailability
Swallowing difficulties
Taste of the medication needs masking
Achieving a plasma concentration within the therapeutic window (steady state concentration)

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3
Q

Where does the majority of the drug absorption occur?

A

In the small intestine, therefore is the drug is targeted for local colonic delivery the drug design must be modified to ensure slow drug delivery in the upper gastro-intestinal tract is important.

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4
Q

When is a drug considered to be highly soluble?

A

When the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.

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5
Q

When is a drug considered to be highly permeable?

A

When the extent of absorption in humans is determined to be > 90% of an administered dose.
(Based on mass-balance or in comparison to an intravenous reference dose).

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6
Q

When is a drug considered to be rapidly dissolving?

A

When > 85% of the labeled amount of drug substance dissolves within 30 minutes

(Using USP apparatus I or II in a volume of < 900 ml buffer solutions) .

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7
Q

What are the four classifications of biopharmaceutical classficiation system?

A

Drugs with a:
High permeability and high solubility
High permeability and low solubility
Low permeability and high solubility
Low permeability and low solubility

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8
Q

Give examples of drugs that have high permeability and high solubility?

A

Verapamil
Metoprolol

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9
Q

Give examples of drugs that have high permeability and low solubility?

A

Ketoprofen
Carbamazepine

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10
Q

Give examples of drugs that have low permeability and low solubility?

A

Furosemide
Hydrochlorothiazide

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11
Q

Give examples of drugs that have low permeability and high solubility?

A

Ranitidine
Vancomycin

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12
Q

How can low solubility be overcome, improved or optimised in drug delivery?

A

Use of surfactants
Particle size reduction
Salt formation
pH adjustment

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13
Q

How can low permeability be overcome, improved or optimised in drug delivery?

A

Use of prodrugs
Permeation enhancers
Ion pairing
Will need excipients

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14
Q

What is the role of the duodenum in drug delivery?

A

The duodenum is a hollow tube around 25-38cm in length that connects the stomach to the small intestine. The duodenum regulates the rate of emptying of the stomach via hormonal pathways. The diameter of the pyloric opening varies as according to the nature of the gastric contents.

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15
Q

If a tablet is taken what are some of the factors that gastric emptying is dependent upon?

A

Posture
Volume of fluid taken
Calorific value of food taken before or with the dosing

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16
Q

If a tablet tends to disintergrate and dissolve how does the rate of drug delivery vary?

A

Pulses will appear regularly in the small intestine at a rate determined by the meal.

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17
Q

How does a graph comparing the rate of immediate and extended release vary?

A

Immediate release there are peaks and troughs of the plasma concentration caused by multiple dosing throughout the day whereas extended release involves a gradual increase in a singular dose but then releases the dose slowly.

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18
Q

What is the benefit of extended release?

A

Reduces the need for increased dosing frequently, more convenient, better adherence
Better control of their condition as more of a stable plasma concentration is produced.

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19
Q

What does enteric coated mean?

A

A drug coated in an exicipient that is not soluble in acidic conditions, meaning that it remains insoluble in the stomach. Therefore if gastric emptying is slow and the tablet is enteric coated then it will not be absorbed in the stomach - won’t have relief of symptoms.

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20
Q

When does gastric emptying slow down?

A

After a high fat meal

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21
Q

How is the therapeutic time window extended after a single dose?

A

Because the small intestinal transit time is very short, if focuses on gastric residence and retention in the ascending colon as typically after a meal material is swept forward from the small intestine to clear a path for gastric effluent.

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22
Q

How does disease and gut transit time affect drug absorption?

A

Hospital patients have a slow transit time with intestinal trauma
Disease can significantly affect gastro-intestinal motility which can hence affect the rate of release of the drug into the body.

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23
Q

Define controlled release drug delivery.

A

When there is a formulation constraint on the release of drug from the delivery system.

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24
Q

What are the two types of controlled release?

A

Constant release capsules or tablets
Targeted release capsules or tablets (enteric coated) - cancer treatment

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25
Q

Compare the pharmacokinetic parameters of immediate dose formulations and constant rate formulations?

A

Immediate dose (those with a short T 1/2):
Duration of action is short
AUC is low
Multiple doses per day necessary resulting in uneven blood levels and uneven therapeutic response.

Constant-release formulation:
Reduce the number of doses per day
Improve patient compliance
More consistent blood level of the druf
Improve therapeutic effectiveness

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26
Q

Why may oral controlled release be necessary?

A

Biological factors:
Pharmacokinetics following oral dosing
Site of action
Toxicity at specific GI sites

Physiochemical factors:
Acid lability

Therapeutic requirement:
Timing
Chronotherapy

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27
Q

What are some examples of oral controlled release formulations?

A

MST continus
Twice daily instead of every 4 hours
Sinemet CR
Twice daily instead of three times a day

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28
Q

What are the four types of controlled release?

A

Monolith devices
Membrane limited systems
Multi-particulate systems
Gastro-retentive systems

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29
Q

Briefly describe what is meant by a Monolith device?

A

A block of material through which a drug is dispersed and released slowly

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30
Q

Do the excipients used in monolith systems tend to be hydrophobic or hydrophilic?

A

Can be either although hydrophilic (PVP, cellulose based) is more common, the drug can be released via a gel layer formed on contact with water (swellable polymers)
Hydrophobic (fatty acids) tends to be used for other drug delivery such as implants

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31
Q

What is meant by membrane limited systems?

A

The coating determines when and where the drug is released and hence absorbed

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32
Q

What is meant by multi-particulate systems?

A

Mini tablets, large granules or pellets are feed into capsules and each individually modified- added different thickness of coating, or each type of pellet loads a different amount of drug.

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33
Q

What is meant by gastro-retentive systems?

A

Forms floating or bioadhesive sticks to the gastro-intestinal lining.

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34
Q

How do the hydrophobic matrix used in monolith systems work?

A

Composed of a fatty acid it will slowly degrade (not swell, as it does not like water). Bile salts used to emulsify fatty foods will erode the matrix and it becomes smaller and smaller, liberating the drug within each layer.

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35
Q

How does swellable matrix occur?

A

Outer layer will absorb the most water forming a jelly layer, the water present will dissolve the drug inside causing it to diffuse out.

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36
Q

What is an example of a hydrophilic monolith matrix excipient?

A

Hydroxypropyl methyl cellulose

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37
Q

What are some benefits of HPMC?

A

Cheap, safe, may be compressed into tablets easily
Variable weight of the drug and degree of viscocity

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38
Q

Are there any time points swelling doesn’t occur?

A

Higher viscocity and molecular weight- have the capability of holding the most water
Swelling always occurs from the outermost layer to the core, so at time zero there would be minimal swelling.

39
Q

How does the Geomatrix technology work?

A

There is a core containing the HPMC with the active drug inside. Either side there barrier layers preventing the core from swelling and hence the drug from diffusing out, which reduces the rate of swelling and hence erosion.

40
Q

Where does drug swelling and erosion occur for Geomatrix systems?

A

Swells in the stomach, 6 hours, 30% release
Erodes in the small intestine for 6 hours, 40% release
Erodes in the colon, resides for 8 hours, last 30% of the drug

41
Q

How does VersaTab work?

A

Controls surface area of the drug, zero-order release (ideal)

42
Q

For best controlled release what should the rate be?

A

Zero order (straight line for release rate against time)

43
Q

What is the cumulative amount of the drug affected by?

A

Surface area (multi-particulate, small / large)
Diffusion co-efficient (lipophilic, hydrophilic)
C0- drug concentration at time zero
Time
Cs- drug solubility in the matrix

44
Q

What does K stand for?

A

It is the proportionality constant (taking into account many of the factors)

45
Q

How can the equation M (t)/M (inf) = K square root t be substituted into an equation?

A

M (t)/M (inf) is the percentage of the drug that has been released by that time. This is plotted on the y axis and this is proportional to the square root of t so t (1/2) is plotted on the x axis.

46
Q

What happens if you switch the square root to n?

A

Square root of time is switched to n. If n is equal to 1/2 then release is by diffusion. If n is equal to one release is controlled by the rate of swelling/ erosion.
If n is in between then it is possible to calculate the relative contribution of each process.

47
Q

How do membrane limited systems work?

A

Membrane is semi-permeable so will let some water in (pores), this part of the film will dissolve first ‘water goes in, drug is partially dissolved and then drugs diffuses out’.

48
Q

Do membrane limited systems swell and erode?

A

They shouldn’t, as four times the dose is loading on to one tablet, potentially causing an overdose (dose dumping).

49
Q

What are some examples of polymers used in membrane limited systems?

A

Ethylcellulose (water insoluble), acrylic co-polymers - pH responsive, and insoluble

50
Q

What is the purpose of adding in plasticizers?

A

They will make the film more flexible, avoids defects on the coating.
They are small molecular weight- will escape first from the film creating pores allowing for water and drug diffusion.

51
Q

What is an example of membrane limited systems and describe the principle of the design?

A

SODAS technology

It consists of a capsule filled with uniform beads 1-2mm in diameter. These beads are formed of a number of layers of polymers and excipients that form the outer rate controlling membrane. Whilst travelling through the gastro-intestinal tract they dissolve creating holes within their membrane and allowing water in to solubilise the drug and it can be dissolved out in a rate controlled manner.

52
Q

What is osmotic controlled system?

A

Semi-permeable layers with one pore (controlled, fixed diameter)

53
Q

What are the pros of osmotic controlled systems?

A

Compatible with a wide range of drugs
Coating technology is cheap and widely used
Very controlled, precise drug delivery

54
Q

Describe how an osmotic pump works?

A

Contains a water soluble core with the active drug, and a water insoluble semi-permeable coating. When water is present this causes the core to solubilise and suspend the drug with water permeating into the inner core across the outer membrane.
The core materials then undergoes dissolution, suspension and solubilisation. This causes the osmotic pressure to rise and expel the drug.

55
Q

What are the disadvantages of osmotic pump?

A

Precisely drilling is expensive
Intergrity and consistency is essential as it could lead to dose dumping

56
Q

What is an example of osmotic pump?

A

OROS technology

57
Q

What do multi-particulate systems consist of?

A

Lots of individual units of granules often contained within a capsule shell.

58
Q

What are some of the advantages of multi-particulate systems?

A

GI transit more consistent, not just going to be one side of the stomach that the tablet deposition occurs.
Dose dumping less likely
Can manipulate release by mixing units with different film thickenesses
Reduce gastric irritation

59
Q

What are the disadvantages of multi-particulate systems?

A

Higher cost
Technical issues with coating and capsule filling
Small spheres will escape the stomach quickly

60
Q

What is an example of micro-particulate systems?

A

Micropump technology

61
Q

How does the micro-pump technology work?

A

Consists of 5000-10000 micro-particles per capsule/ tablet
200-500 micron particles
Each micro-particle releases drug in the small intestine by osmotic pressure at an adjustable rate over an extended period.

62
Q

How are gastro-retentive dosage useful?

A

Retain concentrated in the stomach for prolonged periods, useful for local conditions (gastric ulcers, dyspepsia)

63
Q

What are the three approaches for gastro-retentive delivery?

A

Effervescent systems that generate gas and float
Bioadhesive
Swelling or extendable

64
Q

What is an example of a floating system?

A

Gavsicon, when it comes into contact with stomach acid it forms alginate acid which is insoluble complexed with calcium and carbon dioxide causing it to float.
Key ingredient: sodium alginate (soluble)

65
Q

What are bioadhesive systems?

A

Materials that adhere to biological membranes (mucal, vaginal delivery). There are certain materials such as alginates, cellulose derivatives, chitosan than link to mucin (composes mucus, nearly 90% water, dehydrates it but hydrates drug making it sticky possibly) and become sticky. Once stuck it becomes a protective layer, increasing the retentive time, slowly releasing the drug.

Could also be thermosetting adhesive gel (radiolabelled molecules within the dosage form)

66
Q

What does swelling and extendable systems involve?

A

It may involve a capsule that is capable of swelling to a size larger than the pylorus or just like the star, a device that unfolds, releasing the material

67
Q

What is the primary function of the colon?

A

To remove water with some enzymatic activity primarily for carbohydrate breakdown normally associated with the presence of anaerobic bacterium.

68
Q

What is the transit time in the colon?

A

Hours to days

69
Q

How does the pH in the ascending colon differ?

A

Ascending colon 6.4
Transverse colon 6.6
Descending colon 7

70
Q

What are floating systems used to treat?

A

Oesophageal reflux

71
Q

What does thermoadhesive setting gel mean?

A

The formulation changes with temperature (for example liquid to an adhesive gel)

72
Q

What would be the rationale for targeting the colon?

A

For the local treatment of diseases affecting the colon such as Crohn’s, inflammatory bowel disease etc.
Induces the systemic absorption of proteins, it is much lower than the smaller intestine and the pH is more neutral

73
Q

What is the target control time for extended release tablets?

A

Normally 12 hours (this may reduce the dosing to just twice a day), 24 hour control time is not achievable to the variability in gastric emptying and transit time within an individual.

74
Q

What does chronopharmacology involve and how does it relate to colon targeting?

A

Chronopharmacology relates to the knowledge of biological rhythms to develop an optimal pharmacotherapeutic plan. Essentially this means knowing when symptoms are likely to flare up, and dosing in advance to ensure that the absorption of the drug from the colon matches the time when symptoms usually start to appear.

75
Q

How is rectal delivery beneficial for targeting the colon and what does it consist of?

A

Rectal delivery is beneficial as it is the most local form of drug delivery specific to the colon. It normally consists of an enema (contains a large quantity of water) if there is less than 50mL of water then it remains within the rectum however around 200mL of water will spread locally to the descending colon.

76
Q

When is rectal delivery for colon targeting not appropriate?

A

When the disease state is in the proximal colon as even with a substantial amount of water used, it is unlikely to reach the proximal colon.

77
Q

Explain the concept of pH controlled systems in regards to colon targeted delivery?

A

A formulated drug may be coated with enteric coating which is pH sensitive meaning that the coating and hence the drug will be dispersible at some pH but will remain insoluble at others.

78
Q

What are some examples of pH controlled systems?

A

Eudragit S and Eugradit R.
Eudragit S is usually sensitive and soluble to higher pHs but remains insoluble at lower ones.
Eudragit R on the other hand is usually sensitive and soluble at lower pHs but do remain insoluble at higher ones.

79
Q

Give example of the use of Eudragit S?

A

Eudragit S can be used to coated sulfasalazine (used to treat Crohns and colitis), as the drug is only soluble at higher pHs, the drug remains insoluble at higher pH environments such as stomach and the proximal small intestine but then will dissolve in the terminal ileum and colon .

80
Q

What is sulfasalazine licensed for?

A

Irritable bowel disease

81
Q

Describe the structure of sulfasalazine.

A

It contains a 5-aminosalicylic acid which is connected by a chemical linker (-N=N-) an Azo bridge to a sulfapyridine molecule.

5-aminosalicylic acid connected by an Azo bridge to a sulfapyridine molecule.

82
Q

Which sub-class of polymers is the Eudragit polymers part of?

A

They are co-polymers of the methacrylic acid and methylmethacrylate

83
Q

How does the colonic bacterium cleave and degrade the structure of sulfasalazine?

A

Due to the drug having limited degradation, absorption in the stomach and small intestine, 85% is present in the colon. The colonic bacterium cleaves the azo bond freeing the 5-ASA and sulfapyridine molecule. Sulfapyridine exerts its effects locally whereas the 5-ASA will then go on to exert its effects locally and will be unabsorbed.

84
Q

What are the other two methods of azo degradation?

A

Instead of two drug like molecules forming you can have a drug-polymer complex form incoporated in a hydrogel system. At specific pHs (when the pH is increased inside the colon) this can induce swelling of the gel, allowing the colonic bacterium to access to the azo bonds which then induces cleavage and release of the drug.

Instead of complexes being formed, the coating of the drug could contain an azo-linked formulation being that the drug in the core and the tablet as a whole will remain intact until reaching the colon where the colonic bacterium degrades the coating, releasing the drug.

85
Q

Aside for utilisation of colonic bacterium what else can be optimised in the colon?

A

As the colon is the site of polysaccride degradation, by incoporating one of these products in to the tablet formulation, colon targetting can be achieved.

86
Q

What are the two methods of colon targeting as according to colon specific polysaccride degradation?

A

Hydrogel system
Polysaccride coat

87
Q

Explain the concept of timed release systems, in application to the structure of a capsule?

A

The capsule contains an soluble gelantin cap and then an impermeable capsule body (ethyl cellulose), no water can go in from outside the capsule. Inside the interstitial fluid this then degrades the gelatin cap exposing the hydrogel cap and causing it to swell and grow in size, once it reaches a critical point, the plug will pop out allowing water to flood in and dissolve the drug (want this to happen around 12 hours when it reaches the colon). Capsule body remains insoluble (unless using a pH responsive body).

88
Q

Describe the Egalet system?

A

It is a two component system, containing a matrix core and then is surrounded by a non-eroding hard shell which is made of polylactic acid and the active pharmaceutical ingredent matrix is exposed at both ends.
Manufactured by co-extrusion (gives a defined shape).

89
Q

How does the Egalet system work?

A

The surface area of the drug molecule does not change as the matrix containing the API is on either end of the capsule, therefore good for giving zero order release.

90
Q

What is a major benefit of Egalet system?

A

Not able to be crushed due to the hard shell and therefore prevents drug-misuse so good for pain relief.
Can precisely control drug release

91
Q

How can controlled release be monitored inside the body?

A

Radiolabelled gamma imaging which involves radiolabelling the dosage form.

92
Q

What is the step by step process of radiolabelling?

A

The first step involves the administration of radiolabelled orange juice and then using a radiolabelled camera to outline the GI tract. Administer the dosage form and monitor the location using the camera- keeping monitoring at different time points.

93
Q

How would you expect the stomach emptying time for a high fat breakfast in comparison to a low fat breakfast?

A

You would expect a high fat breakfast to have a longer/slower stomach emptying time than a low fat breakfast and therefore the time to have an effect will be slower.

Drug delivery (5 decks)

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