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Medicine Year 3, Sem 1 - Drug Development Process > Oral Biopharmaceutics 2 > Flashcards

Oral Biopharmaceutics 2 Flashcards

1
Q

What is the structure of cyclodextrins (CD’s)?

A

Tube/cage like structure with a hydrophobic interior and hydrophilic exterior

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2
Q

How does the structure of cyclodextrins related to their function?

A

Insoluble hydrophobic drugs can insert themselves into the centre of the ‘tube’
The exterior of the tube is hydrophilic which helps improve their solubility

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3
Q

How are cyclodextrins formed?

A

Supersaturating a CD solution with drug with agitation - for a solution
Kneading a drug/CD/solvent slurry to a paste which is then dried and sieved - for a solid drug

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4
Q

How can the solubility of cyclodextrins be further improved?

A

Add a hydrophilic polymer e.g. HPMC

Improves the solubilising effect of CD’s, so less CD is needed to solubilise the same amount of drug

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5
Q

Why are there few oral-based CD products on the market?

A

Toxicity and stability issues

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6
Q

What are amorphous compounds?

A

Compounds with no crystalline structure

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7
Q

What are the consequences of the structure of amorphous compounds?

A

More unstable and prone to recrystallisation

More soluble as less energy required for dissolution

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8
Q

How are amorphous compounds created?

A

Formulation (of an insoluble) drug with polymers
This can be done by,
1) Spray drying using solvents or replacing with supercritical fluids
2) Hot melt extrusion

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9
Q

Why are polar excipients added to a formulation?

A

To enhance the solubility of a poorly soluble drug

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10
Q

Give some examples of polar excipients.

A

Polyethylene glycol (PEG)
Gelatin
Sugar glasses e.g. inulin
Lipids

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11
Q

How is PEG used to improve solubility?

A

Can be used as a co-solvent in liquid based dosage forms to prevent precipitation of compounds that are poorly soluble
Acts as a wetting agent to enhance dissolution or dispersion
Can be used in combo with other excipients e.g. stearic acid, SLS

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12
Q

What formulations is PEG suitable for use in?

A

Suitable for parenteral and topical application/admin

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13
Q

How is PEG incorporated?

A

Solvent evaporation or freeze drying

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14
Q

How is gelatin used to improve solubility?

A

Gelatin is a naturally derived collagen extract with both +/- charges in its structure
Improves wettability of hydrophobic compounds when used as a granulating agent

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15
Q

How do sugar glasses (e.g. inulin) improve solubility?

A

Inulin is a naturally occurring fructose polymer

Protects the drug from physical and chemical degradation improving solubility

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16
Q

How are sugar glasses formed?

A

Mixing an inulin solution with a drug solution followed by freeze drying creates a sugar glass

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17
Q

What formulations are sugar glasses suitable for use in?

A

Parenteral and pulmonary

GRAS status for oral formulations

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18
Q

Sugar glasses are used in the formulation of which agents?

A

Ciclosporin

Diazepam

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19
Q

How are lipids used to improve solubility?

A

Used in self emulsifying systems e.g. lymphatic delivery

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20
Q

Reduced particle size…

A

Increases surface area: volume ratio and usually improves dissolution properties

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21
Q

Improving dissolution allows the use of what?

A

A wider range of formulation and delivery approaches

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22
Q

How can particle size be reduced?

A

1) Recrystallisation of poorly soluble drugs using liquid solvents and anti-solvents
2) Conventional comminution and spray-drying relying upon mechanical stress to disaggregate the active

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23
Q

What are the problems with each of these approaches for reducing particle size?

A

1) Requires an increasing amount of organic solvents for processing, increasing the complexity of manufacture and expense
2) Puts significant amounts of stress on the drug product and may induce degradation or thermal stress, not suitable for thermo-sensitive or unstable compounds

24
Q

What is the ‘window of absorption’?

A

The transit time through the small intestine

25
How do particles in the micro vs. nano range compare in terms of absorption?
When the drug is in the form of nanoparticles, there is a much greater s.a: vol, increasing solubility allowing all of the drug to be absorbed in the 'window of absorption' The reverse is true for larger micro size particles, only part of the drug is dissolved and some is excreted unchanged
26
What are some of the benefits of nanoparticle formulations on drug delivery? (3)
Greater bioavailability Less variability with food Dose proportionality
27
How can nanoparticulation be performed?
Micro-milling - may operate to sub-micron sizes with physical and thermal stresses Piston gap methods - create drug nanoparticles through hydrodynamic cavitation Supercritical fluids - create nanoparticles by control of solubility under pressure and temp. in solvents such as CO₂
28
What is the problem with micro-milling?
Not suitable for thermosensitive or unstable drugs
29
Can traditional methods of comminution, such as grinding and milling, reduce the particle size sufficiently for insoluble drugs?
No
30
Why are supercritical fluids (SCF's) used in manufacture?
To produce different sizes and shapes of drug particles
31
What is a SCF?
E.g. CO₂, H₂O Fluids at a temp. and pressure above their thermodynamic critical points meaning they assume the properties of both a liquid and a gas
32
Explain the graph in relation to SCF's.
Temp. on X-axis and pressure on Y-axis As you increase temperature and pressure, you will reach the triple point, where the substance behaves like all 3 states of matter If you continue increasing the temperature and pressure, you will reach the critical point Temperatures and pressures above this point are in the supercritical region and produce a so-called 'supercritical fluid'
33
What makes SCF's useful?
Small changes in temp. and pressure can have a big impact on SCF's and this gives you much greater control over their properties
34
SCF's can... (solid/liquid)
Diffuse through solids like a gas and dissolve materials like a liquid
35
How are SCF's used for nanoparticle engineering?
SCF-solubilised drug particles can be recrystallised to obtain greatly reduced particle sizes, often 5-2000nm in diameter
36
What allows the recrystallisation of drug particles in a highly controlled manner?
The fact that small changes in temp. and pressure alter the properties of the SCF
37
At near critical temp, SCF's are highly what? What properties does this impact?
Compressible | Allows moderate changes in temp. and pressure to greatly alter their density, mass transport and solvating power
38
Manipulation of the pressure of SCF's improves ______ and reduces __________.
Diffusivity | Viscosity and surface tension
39
What form are a lot of liquid dosage forms in?
Soft or hard-shelled caps containing an emulsion of the drug and emulsifiers
40
What do emulsifiers do?
Improve drug solubilisation and prevent drugs from precipitating out of the micro-emulsion
41
Give 2 examples of emulsifiers.
Tweens (polysorbates) and labrafil (polyoxyethylated oleic glycerides)
42
What do co-solvents do?
Increase the amount of drug dissolved into the lipid base of the emulsion
43
Give 3 examples of co-solvents.
Ethanol, PEG, propylene glycol
44
How are solid self-emulsifying systems formed?
Solid products are suspension dried to obtain stable drug particles in powder form e.g. Eurand's nanolipispheres Then these drug particles in powder form are used to create a stable colloidal microemulsion suspension of sub-micron drug particles in a solid lipid matrix which turns into liquid in vivo
45
What are SEDDS?
Self-emulsifying drug delivery systems
46
What are SMEDDS?
Self micro-emulsifying drug delivery systems
47
What are SNEDDS?
Self nano-emulsifying drug delivery systems
48
How are self-emulsifying lipid based formulations prepared?
Involves incorporation of the drug into an oil-surfactant mixture, which is then loaded into hard or soft gelatin capsules
49
What does presence of lipid in the duodenum stimulate?
Stimulates secretion of biliary lipids, generating colloidal micelles, mixed micelles, vesicles and emulsion droplets allowing dissolution
50
How much lipid is needed to stimulate the duodenum?
<2g, ~2 caps or food, not very much
51
What is an important step for lipid formulations?
Digestion of lipids | Important for bioavailability enhancement as lipids must be digested for the drug to be released from the system
52
The interaction of TG's and surfactants from the formulation with the wall of the GIT promotes...
Solubilisation and absorption
53
How are drugs absorbed from lipid based formulations?
``` Drug co-administration with lipids influences their path of absorption - lymphatic route High lipophilicity (logP of 5 or higher) facilitates absorption into the intestinal lymphatics and then systemic circulation avoiding first pass ```
54
As you increase lipophilicity...
You increase the amount absorbed into lymphatics (% dose)
55
How do lipids enter lymphatic circulation?
1) Micelles break down and feed a pool of dissolved TG's 2) Dissolved TG's and FA's enter the enterocyte by diffusion 3) Triacylglycerol (synthesised in the ER) and fat soluble substances are packed into lipoproteins called chylomicrons 4) Chylomicrons enter circulation via the lacteals

Medicine Year 3, Sem 1 - Drug Development Process (8 decks)

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