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MPharm2 SL22107 > Pharmaceutics > Flashcards

Pharmaceutics Flashcards

1
Q

Why are drugs delivered to the lungs?

A
  • allows direct treatment of respiratory disease
  • provides portal of entry for systemic delivery
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2
Q

What are the 2 advantages for local delivery for inhalation therapy?

A
  • drugs delivered directly to site of action
    • rapid onset
  • lower doses required
    • fewer side effects
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3
Q

What are the 2 advantages for systemic delivery for inhalation therapy?

A
  • extensive blood supply and large SA for rapid absorption into systemic circulation
  • avoids GI tract and first pass metabolism
    • increased bioavailability
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4
Q

What is an aerosol?

A
  • a relatively stable suspension of solid particles or liquid droplets
    • particles must be small: 0.001mcm - 100mcm
    • small particles = low mass = low gravitational force
    • collisions with gas molecules keep particles suspended
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5
Q

What is inertial impaction?

A
  • due to inertial force of a particle in an airstream
  • impaction caused by tendency of particles to continue in a straight line
  • amount of inertial impaction proportional to:
    • aerodynamic diameter (dae)2 x velocity
  • predominantly occurs for large particles when air stream is fast, changing direction or turbulent
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6
Q

What is gravitional sedimentation?

A
  • dependent on terminal settling velocity in respiratory tract is low, so resistance time is high
  • important deposition in bronchioles
  • particle size 1-4 mcm
  • amount of sedimentation is proportional to
    • aerodynamic diameter (dae)2 x resistance time
  • less efficient than inertial impaction
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7
Q

What is brownian motion in aerosols?

A
  • particles bombarded by air molecules
  • important for small particles
  • important for deposition in terminal bronchioles + alveolar regions
  • high resistance time increases diffusiom deposition effect
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8
Q

What is electrostatic deposition?

A
  • charged particles repel, increase in migration towards airwat walls
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9
Q

What are the 3 factors controlling aerosol deposition?

A
  • aerosol properties
    • aerodynamic diameter
    • particle size distribution
  • mode of inhalation
    • flow rate
    • inhaled volume
    • breath holding pause
  • patient related factors
    • anatomical and physiological variations
    • obstructive airway diseases
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10
Q

What are the 6 factors controlling drug delivery to the lung?

A
  • Formulation
  • Device
  • Patient activation
  • Lung deposition
  • Dissolution
  • Absorption
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11
Q

What are pMDIs?

A
  • compact pressurised aerosol containers
  • most commonly used type of inhaler
  • can discharge several hundred accurately metered doses
  • doses rage from 25mcg - 5mg
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12
Q

What are propellants?

A
  • aerosol is formed by propellant
    • gas is compressed to 300-500kPa
    • pressure converts gas to liquid
    • drug is formulated in the liquid
    • when pressure is released, liquid propellant rapidly boils to gas
    • leaving behind an aerosol of drug particles
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13
Q

How is the spray formed by the pMDI?

A
  • patients presses can, opens the channel between metering chamber and atmosphere
  • propellants start to boil in expansion chamber
  • shearing forces produces ligaments
  • propellant droplets form actuation nozzle
  • initial velocity 30m/s
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14
Q

What are suspension based formulations?

A
  • suspensions preferred for most drugs
  • capable of delivering high power loads
  • requires drug to be milled or micronised and practically insoluble in propellant
  • requires vigorous shaking to ensure re-dispersion and formulation homogenity
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15
Q

What are the types of physical instability?

A
  • rapid flocculation: loose agglomerates
  • bulk separation: creaming or sedimentation
  • irreversible aggregation: ostwald ripening, crystal growth and caking
  • crystal structure instability: polymorphic interconversion
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16
Q

What is the role of the excipient?

A
  • primary role: ensure physical stability of suspension
  • must be capable of dispersing and re-dispersing the drug in suspension
  • allows a homogenous distribution of the drug within the suspension
  • minimal segregation during period prior to admin
  • commonly used surfactant in HFA propellants are oleic acid, magnesium, sterate, PEG + PVP
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17
Q

How is a pMDI formulation tested?

A
  • sedimentation rates
  • particle size changes
  • microscopy
  • dose uniformity in aerosol dose
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18
Q

What are solution based formulations?

A
  • can only use if solubility + stability of drug in propellant/co-solvent are adequte
  • need to profile the chemical stability of drug in solution
  • amount of emitted dose directly related to solubility
  • potential for drug to crystallise
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19
Q

What are the 4 problems with solution based formulations?

A
  • co-solvent can cause corrosion of aluminium cannister
  • drugs can be relatively unstable
  • co-solvent lowers internal propellant pressure thus atomisation is less effective
  • modification of chemical structure
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20
Q

What are the 6 advantages of pMDIs?

A
  • many doses
  • compact
  • consistent delivery
  • relatively cheap
  • sealed cannister protects drugs
  • lower capital costs for market entry
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21
Q

What are the 4 disadvantages of pMDIs?

A
  • patient co-ordination and force required to activate
  • tail-off at end of the can
  • force of aerosol spray
  • varying deposition pattern in airways
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22
Q

What are the 4 solutions to pMDI problems?

A
  • dose counters
  • spacers
  • breath-actuated inhalers
  • haleraid
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23
Q

What is the effect of pMDIs on climate change?

A
  • HFA propellants are powerful greenhouse gases
  • 2 puffs a day = 730kg CO2eq per year
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24
Q

What are DPIs?

A
  • inspirational flow driven inhalers
  • drug formulated as dry powder that is sucked into lungs
  • automatically breath actuated
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25
Q

What is aerosolisation?

A
  • prior to inhalation, DPI formulation has no potential to be deposited in the lungs
  • forced inspiratory action provides the energy for fluidisation + entrainment of formulation and de-aggregation of drug
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26
Q

What is FPF?

A

fine particle fraction = % reaching lungs
dependent on:
- inhaler device
- patient expiratory flow
- powder formulation

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27
Q

How does resistance level effect DPIs?

A

resistance /= de-aggregation but is a side effect
internal resistance of device affects speed of airflow through device
higher resistance devices generally perform well at lower flow rates

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28
Q

What are the sizes of particles in powders?

A

1-6mcm

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29
Q

What are the three types of interparticulate forces?

A
  • van der Waals
  • electrostatic
  • capillary
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30
Q

What are van der Waals forces?

A
  • finite attractive forces between all atoms
  • sum of attractions between molecules that are temporarily dipolar
  • short range forces
  • dominant at low humidity in absence of electrostatic forces
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31
Q

What are capillary forces?

A
  • condensation of water vapour between contigous bodies
  • forms a liquid bridge
  • magnitude of forces directly related to relative humidity and hydrophobicity
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32
Q

What are electrostatic forces?

A
  • caused by frictional contact between dissimilar material
  • long range force
  • attractive or repulsive
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33
Q

Which 5 factors influence interparticulate adhesion forces?

A
  • particle sizes
  • particle shape
  • surface roughness
  • surface chemistry
  • humidity
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34
Q

What are the two formulation strategies?

A
  • carrier-based systems
  • agglomerated powder systems
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35
Q

What is a carrier-based system?

A
  • blending the drug with carrier
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36
Q

What are the advantages of a carrier-based system?

A
  • allows accurate metering of small quantities of potent drug
  • improves handling and processing
  • FPF can be controlled
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37
Q

What is an agglomerated powder system?

A
  • for high dose drugs, when carrier isn’t possible
  • free-flowing macroscopic agglomerates can be produced via cohesive bond formations
  • efficient de-aggregation of agglomerates can be produced via cohesive bond formation
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38
Q

What are the 5 advantages of DPIs?

A
  • propellant free
  • some have no excipients
  • breath actuated
  • can deliver large doses
  • drug is in dry solid form
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39
Q

What are the 4 disadvantages of DPIs?

A
  • powder de-aggregation dependent on patients ability to inhale
  • more inhalation = more de-aggregation of particles
  • exposure to ambient condtions can reduce stability
  • less efficient delivery
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40
Q

What are the 4 limitations of pMDIs and DPIs?

A
  • require specific technique
  • can’t do very large doses
  • need to stop oxygen to administer
  • can’t use DPIs when ventilated
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41
Q

What are nebulisers?

A
  • drug is contained in sterile aqueous solution
  • uses an external enjoy source to aerosolise
  • areosol is then inhaled tidally
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42
Q

What are pneumatic nebulisers?

A
  • generates aerosol using compressed air which is expelled past the end of a capillary tube
  • shear force of air creates droplets
  • baffle traps oversized droplets
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43
Q

What are the 2 pros of pneumatic nebulisers?

A
  • cheap
  • small particle size
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44
Q

What are the 3 cons of pneumatic nebulisers?

A
  • variable performance
  • portability
  • lower output/doses take time
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45
Q

What are the 4 pros of high performance ultrasonic nebulisers?

A
  • performance is more reproducible
  • small particle size
  • small + quiet
  • lower aerosol inertia
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46
Q

What are the 3 cons of high performance ultrasonic nebulisers?

A
  • expensive
  • poor for suspensions
  • gets hot
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47
Q

What are soft-mist inhalers?

A
  • emerging class of portable inhalers
  • drug dissolved in a non-volatile liquid
  • volumetric dosing
  • aerosolised in a single breath actuation
  • aerosol emitted as sloww moving cloud
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48
Q

What is the respimat SMI?

A
  • drug solution is forced through a micro-nozzle as patient inhales
  • medication stored as a solution
  • avoids problems of moisture absorption and powder aggregation
  • use of solution ensures metered doses
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49
Q

What are the 5 benefits of nasal drug delivery?

A
  • Large absorption area, rich in subcutaneous blood vessels
  • Rapid drug absorption and fast action
  • Not only for local therapy but also systemic delivery
  • Avoids first-pass metabolism
  • Easy to administer
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50
Q

What are the turbinates?

A

Turbinates warm and humidify air as it passes through nasal cavity
Turbinates can swell and contract (allowing/ stopping air form passing through)
In most people one turbinate will swell while other contracts (air through one nostril above the other)- alternates in ‘nasal cycle’
Help detect pathogenicity of inhaled particles
Problems can impair quality of life (e.g., over-swelling or excess mucus)

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51
Q

What are the 5 functions of the nose?

A
  • Breathe: part of the respiratory system
  • Smell: millions of receptors in the nasal epithelium. Warning system but relates to memory and emotions
  • Identity: shape and age
  • Keep debris out: nasal epithelium, mucus and sneezing
  • Condition air: warms and moistens air (turbinates)
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52
Q

What is the ciliated epithelium?

A
  • Pseudo-stratified epithelium with cilia
  • Goblet cells produce mucus
  • Mucus traps dirt/ particulates and cilia move (wavelike) to push them out of nose
    >1,000,000 times more viscous than water
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53
Q

How is mucus produced in the nose?

A
  • Mucus layer: mostly water, some salts, lipids and proteins (e.g. mucins)
  • Mucins are high molecular weight and released by the secretory vesicles (goblet cells)
  • Traps particulates but may also bind to drugs (electrostatically/ hydrogen bonding)
  • Affects how drug behaves (absorption/ prevent diffusion/ cause degradation)
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54
Q

What are the three important factors of nasal drug delivery?

A
  • Drug deposition: where the drug is deposited in the nasal cavity
  • Mucosal absorption: how the drug is absorbed across the mucosa
  • Mucocilliary clearance: the movement of the mucus layer to the nasopharynx
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55
Q

What is mucociliary clearance?

A

Mucus clears every 10-20 mins (towards nasopharynx)
Drug on ciliated regions (posterior of nasal cavity): cleared immediately
Drug on non-ciliated regions (anterior of nasal cavity): move slowly
Larger particles (at nasopharynx): swallowed and lost

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56
Q

What are the 2 requirements of a nasal formulation

A

pH - 5.5-6.5
isotonic

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57
Q

What are the 3 types of nasal formulations?

A

Ointments/ creams
- Long retention time
- Mainly for nasal bacterial infections
- Limited types on market

Aerosols
- Mainly to deliver solid particles

Drops/ sprays
- Widely used
- Sprays: even distribution and can control dose. Avoids postnasal dripping or anterior leakage

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58
Q

What is nasal fentanyl?

A

For breakthrough pain in adults already receiving background opioid therapy for chronic cancer pain
Single dose (50-200 micrograms fentanyl per dose)
Absorbed very rapidly through the nasal mucosa.

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59
Q

What are nasal vaccinations?

A

No needle (good for young children and adolescents)
Live attenuated virus
Small dose into each nostril (0.1mL)
Rapid clearance and inefficient uptake
American Association for Pediatrics: No longer recommends. Reduces chance of getting virus by only 3% compared to no intervention

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60
Q

What is nicotine spray?

A

Nicotine replacement therapy
Each spray: 0.5 mg of nicotine (per nostril), about half of which is absorbed
Rapid absorption compared to other delivery methods

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61
Q

Why are nasal sprays efficient at crossing BBB?

A

Olfactory bulb: Avoids systemic clearance and first pass metabolism. Effectively no BBB. Intracellular or extracellular path
Strategy for tackling migraines in adults

Extracellular (generally faster but has ‘slow’ and ‘fast’ routes). Great for hydrophilic drugs, proteins and peptides

Drug interacts with nerve endings of olfactory receptor neurons and trigeminal neurons

Residence time of drug important for effective absorption!

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62
Q

What needs to be improved in nasal formulations?

A
  • Drug permeability: permeation enhancers, controlled delivery system, colloidal drug carriers
  • Mucocilliary clearance: mucoadhesives (increasing viscosity, adding polymers, using gel formulations)
  • Enzymatic degradation: protective coatings (nanocarriers) but do they reduce efficiency?
  • Toxicity: improved formulations
  • Small volume: increasing concentration could lead to toxicity therefore optimization needed
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63
Q

How can drug permeability of nasal drug delivery be improved?

A

Drug permeability
(i) the transient opening of tight junction between adjacent cells for improved paracellular diffusion
(ii) perturbation of lipid bilayer integrity and increased membrane fluidity promoting transcellular permeation of drugs

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64
Q

What is the structure of the ear?

A

External ear: from pinna to TM
Middle ear: air-filled cavity with temporal bone of skull around it. Eustachian tube connects to inner ear
Inner ear: cochlear (auditory organ) and vestibular system (organ of balance)
TM not the same thickness in all! (80-100µm; surface area 64.3mm2)

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65
Q

What are the 4 common otic issues solved by direct drug delivery?

A

Acute and chronic otitis media
Ménière’s disease (vertigo)
Sensorineural hearing loss
Tinnitus

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66
Q

What is the tympanic membrane?

A

Outer layer: stratified squamous keratinised epithelium
Middle layer: collagen-rich layer
Inner layer: cuboidal mucosal epithelium
Impenetrable to most things except small, mainly lipophilic molecules
Perforation: middle ear infection hearing loss

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67
Q

What is ear wax?

A

Cerumen: sebum, skin cells, sweat and dirt
Function: protective coating and traps particulates (moving them away from the TM via hair in the auditory canal)
Acidic: not conducive to bacterial growth

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68
Q

What is ear wax impaction?

A

Impaction: narrow auditory canal, overproduction of cerumen or cotton-tipped applicators
Impaction: can lead to tinnitus, vertigo, pain or ear feeling ‘full’
Live insects could cause further issues, inflammation (otitis externa) and infants placing small items into ear

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69
Q

What are tympanic membrane perforations?

A

Types: acute/ chronic (wet/dry)
Acute and wet: heal quickly (usually a few weeks if using topical therapies)

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70
Q

How do TM perforations naturally heal?

A

Epidermis closes first (because of the cell migratory behaviour). Begins almost immediately with flooding of cells and growth factors
Fibrous layer reconstruction (fibroplasia, collagen synthesis, wound contraction, neovascularisation)
Maturation is last phase with long-term remodeling and reorganisation (stronger collagen fibres to restore as much tensile strength as possible)

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71
Q

How are TM perforations healed surgically?

A

Chronic: needs surgery (myringoplasty/ tympanoplasty using grafts)
Problem: perforated eardrum (TM)
Current: autologous graft inserted from behind the ear (‘patch’ may need further surgery)
PhonoGraft: biomaterial initially provides structure but also stimulates self-healing
Inserted though ear canal (less invasive)

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72
Q

What are the components of the middle ear?

A

3 auditory ossicles. Transmit sound from air to fluid-filled part by amplifying vibrations from TM)
Eustachian tube/ auditory tube: drugs administered in middle ear can be cleared
Mostly round window (approx. 70µm thick) used to deliver drugs after injection through TM

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73
Q

What are the components of the inner ear?

A

Cochlear: auditory organ
Vestibular systems: balance
Contains hair cells: sensory receptors for hearing and balance
Mechanoreceptors with cilia at different heights (different frequencies)
Movement generates nerve impulse which is transmitted to the brain
After drugs travel through the round window, distribution depends on inner ear fluids and more barriers! Difficult to get to and small

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74
Q

How are paediatric otic formulations different?

A

Routinely to treat: otitis externa, otitis media, ear wax removal (drops/ sprays)
Small volume as most will be lost out of ear passage
Outer ear not fully formed at birth (changes in physiology with age)
External auditory canal straighter and narrower in infants
Not much difference in formulations

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75
Q

What are the three ways to get drugs across the TM?

A

Noninvasive: diffusion to middle ear
Invasive: injection/device crossing TM
Invasive: drug delivery system on RW allowing diffusion of drugs to inner ear (or other processes such as endocytosis). No stratum corneum in RW compared to TM

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76
Q

How are drug produced for ears?

A

Drug production methods resemble those for transdermal drugs (e.g., hydrogels and nanoparticles)
Chemical permeation enhancers: enhance flux across barriers
Difficult to predict what will happen to drugs after they cross the barrier

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77
Q

How are otic drug applied topically?

A

Direct administration into ear canal
Antibiotics, antifungal drugs, gels and foams (with/ without cotton wool plugs)
High concentration locally than systemic (can easily mix drug treatments)
Rapid and good patient compliance (good for paediatric patients)
Ototoxicity with high concentration

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78
Q

What is ototoxicity?

A

Adverse reaction to drugs affecting inner ear or auditory nerve via cell degeneration
Affects cochlear or vestibular system or both
Over 600 drugs classified as ototoxic: some antibiotics (e.g., aminoglycoside or macrolide), some chemotherapeutic agents, loop diuretics, antimalarials
Tinnitus to permanent hearing loss, vertigo and dizziness

79
Q

What are non-invasive hydrogels?

A

Drugs need to stay on TM for while to be effective (difficult with children)
Hydrogel: liquid solid/gel (e.g., Poloxamer 407)
Provides prolonged release
Need to think about mechanical properties of the hydrogel (degradation? stiffness?)

80
Q

What are chemical permeation enhancers (CPEs)?

A

E.g., surfactants (limonene, sodium dodecyl sulfate)
Increase flux across barriers (not provided by hydrogel system)
Same principles as drugs across skin
Could combine CPEs and hydrogels?

81
Q

What are nano carriers?

A

<1µm diameter therefore able to cross barriers
Can be used in combination with lipid softeners and surfactants
Some method of deposition (microshotgun using water and dispersed using magnets)

82
Q

What are invasive hydrogels?

A

Clearance via Eustachian tube can be avoided
Otiprio (a poloxamer) in chinchillas cure for otitis media in 18h!
Hyaluronic acid is shear thinning (gels after injection): Keyzilen (acute inner ear tinnitus) and Sonsuvi (sudden hearing loss) in Phase 3 trials

83
Q

What are invasive nanoparticles?

A

Surface modification of nanoparticles can enhance penetration properties
pH-sensitive nanoparticles: pH of inflamed tissues 0.2–0.6 units lower than normal
Magnetic nanoparticles for inner ear drug delivery

84
Q

What is otic ultrasound?

A

Ultrasound induced microbubbles to drive drugs through the round window into inner ear
2.8-fold increase in biotin delivery (guinea pigs)

85
Q

What are intra-cochlear pumps/catheters?

A

Mainly tested in animal models to control low diffusion rates
Programmable and implantable delivery devices
Precision control of drug release (10-100 nL min-1)

86
Q

What are colloids?

A

emulsions, microemulsions and creams
- oral suspensions
- topical dosage forms (e.g., lotions)
- injections (IM and SC depot)
- aerosols (nasal and inhalation)

87
Q

What is the theory of colloid stability?

A

For 2 spherical particles of radius “a” at a distance apart “H”
Total potential energy of interaction, Vtotal = VA + VR
VA = attractive potential energy; VR = electrostatic repulsive energy
Attractive forces from van der Waals interactions, VA α -1/H
VR decays exponentially with distance: VR α exp(-κH)

88
Q

What are the opposing forces in particle suspensions?

A
  1. At short inter-particle distances, attractive forces predominate (primary minimum) and particles tend to agglomerate
  2. As inter-particle distance increases (i.e., sufficient energy added to separate particles) repulsive forces predominate, and particles remain in suspension (maximum)
  3. If inter-particle distance increased further, repulsive force decreases, and particles are weakly attracted (secondary minimum)
89
Q

What is the effect of electrolytes on stability?

A

A: Low electrolyte concentration → total energy curve has large primary maximum but no 2ndary minimum.
B: Moderate electrolyte concentration → a 2ndary minimum and permits stable suspension to form: flocculation occurs in the 2ndary minimum and modest primary maximum sufficient to prevent coagulation in primary minimum.
C: High electrolyte concentration → no primary maximum or 2ndary minimum.

90
Q

What is flocculation?

A

Prevent rigid cohesion by forming loose aggregates
Held together with comparatively weak interparticulate forces
Lattice type structure
- resists complete settling, reduces caking, aids re-dispersion
Effect of electrolyte depends on valence of counterion
- greater the valence, greater its effect on VR
In flocculated systems, repulsive barriers have been reduced and particles form loosely bonded structures (flocs) in 2ndary minimum
particles settle as flocculates not individual particles
Sediment is not closely packed and caking does not occur
Suspension formulation aims for partial or controlled flocculation

91
Q

What is ‘caking’?

A

In deflocculated systems, particles are not associated
However, pressure on individual particles → their close packing at bottom of container
2ndary energy barriers overcome and particles forced together in primary minimum
Irreversibly bound into ‘cake’
Cake avoided with a flocculating agent in formulation
Caking not prevented by reducing particle size or increasing viscosity

92
Q

What is controlled flocculation?

A

Flocculation controlled w/ non-ionic polymers to increase aq. phase viscosity
* Hinders particle movement, may form adsorbed layers on particles too → steric stabilisation and/or inter-particle bridging
* Exs: naturally gums (e.g., tragacanth), cellulose polymers (e.g., sodium carboxymethylcellulose)
* Ideal suspending agent for controlled flocculation:
- is easily and uniformly incorporated in formulation
- readily dissolves/disperses in water w/o need of special techniques
- ensures formation of loosely-packed system that does not cake
- does not affect dissolution rate or absorption rate of drug
- is inert, non-toxic and free from incompatibilities

93
Q

What are HLB systems?

A

Hydrophile Lipophile Balance
A way of measuring a substances solubility within water or oil

Expressed on arbitrary scale from 1 to 20
High HLB => hydrophilic surfactant
Low HLB => oil-soluble surfactants (w/o emulsifiers)

94
Q

What are microemulsions?

A

ME = Thermodynamically stable, homogenous, transparent, isotropic, low-viscosity colloidal mixtures of oil, water and surfactant

95
Q

What are newtonian systems?

A

Systems with constant velocity of zero shear stress

96
Q

What are non-newtonian systems?

A

Non-Newtonian behavior is generally exhibited by liquid and solid heterogeneous dispersions.
Examples: colloidal solutions, emulsions, liquid suspensions, and ointments

97
Q

What is plastic flow?

A

Plastic flow curves do not pass through the origin
Instead, they intersect shearing stress axis at the yield value.
Flow does not begin until a shearing stress corresponding to the yield value is exceeded.
At stresses below yield value, the substance acts as an elastic material.

Substances that exhibit a yield value are classified as solids, whereas substances that begin to flow at the smallest shearing stress and show no yield value are defined as liquids.

Plastic flow is associated with presence of flocculated particles in concentrated suspensions, a continuous structure is set up throughout the system.

The more flocculated the suspension, the higher is the yield value.

A plastic system resembles a Newtonian system at shear stresses above the yield value.

98
Q

What is pseudoplastic flow?

A

Pseudoplastic flow is typically exhibited by polymers in solution.

The rheogram for a pseudoplastic material begins at origin, therefore, there is no yield value
Viscosity of a pseudoplastic material cannot be expressed by any single value. The viscosity of a pseudoplastic substance decreases with increasing rate of shear.
Apparent viscosity at any shear rate = slope of tangent to curve at specified point.

As shearing stress increases, normally disarranged molecules begin to align their long axes in direction of flow.
This orientation reduces internal resistance of material and allows a greater rate of shear at each successive shearing stress.

99
Q

What is dilatant flow?

A

Certain suspensions with a high percentage of dispersed solids exhibit an increase in resistance to flowbwith increasing rates of shear.

Dilatant flow is the opposite of pseudoplastic systems.
Dilatant materials are often termed “shear-thickening systems.”
When stress is removed, a dilatant system returns to its original state of fluidity.
Substances with dilatant flow properties are invariably suspensions containing a high concentration of small, deflocculated particles.
However, such flocculated particulate systems are expected to have plastic flow characteristics.
At rest, particles are closely packed with minimal interparticle volume

Thus, a dilatant suspension can be poured from a bottle because under these conditions it is reasonably fluid.
As shear stress is increased, the bulk of the system expands or dilates; hence the term dilatant.

100
Q

What is thixotropy?

A

Material has a lower consistency at any one rate of shear on down-curve than it had on up-curve.
Indicates a breakdown of structure that does not reform immediately when stress is removed or reduced.
This is known as thixotropy, defined as “an isothermal and comparatively slow recovery, on standing of a material, of a consistency lost through shearing.”
As defined in this way, thixotropy can be applied only to shear-thinning systems.
Thixotropy means ‘to change by touch’.
Thixotropy describes a material which exhibits a reversible time-dependent decrease in apparent viscosity.

101
Q

What are rheograms?

A

Rheogram = plot of shear rate as a function of shear stress.
Rheologic properties of a given material are most completely described by its unique rheogram.
Simplest rheogram is the linear behaviour shown by Newtonian systems.
Plasticity = simplest non-Newtonian behavior; curve is linear only beyond its yield value.
If the curve is nonlinear for all shear rates tested, then system is non-Newtonian and either pseudoplastic (shear thinning) or dilatant (shear thickening).
If the curve shows hysteresis, then system is thixotropic.

102
Q

What are the applications of thixotropic behaviour?

A

Utilised in the application of creams and lotions
Viscosity decreases upon shearing.
Subsequently, a slow increase.
These features can be manipulated to provide better application experience of topical products.

103
Q

How are rheological properties determined?

A

For non-Newtonian systems, essential that viscometer operates at a variety of shear rates to produce a complete rheogram.
For example, multipoint evaluation of pseudoplastic materials allows assessment of viscosity of a suspending agent at rest (negligible shear rate), while being agitated, poured from a bottle, or applied to the skin (moderately high shear rate).
Four common types of viscometer:
capillary – Newtonian materials only
falling-sphere – Newtonian materials only
cup-and-bob – for both Newtonian and non-Newtonian systems
cone-and-plate – for both Newtonian and non-Newtonian systems

104
Q

What are the 3 layers of the skin?

A

Stratum corneum
Epidermis
Dermis

105
Q

What 4 things are topical drugs supposed to do?

A
  • Modulate barrier function
  • Treat disease states in the epidermis and dermis (i.e., dermatology)
  • Alleviate local pain/inflammation in subcutaneous tissues
  • Elicit systemic pharmacological effect
106
Q

What is percutaneous absorption?

A
  • Absorption of drugs from the skin surface into the body
    drug penetrates into the skin
  • Drug cannot be removed by washing
  • Drug is taken up by microcirculation, enters systemic circulation, or is carried to deeper tissues beneath the skin

Percutaneous absorption depends on:
- Physicochemical properties of the drug
- Interactions of drug with vehicle or delivery system and with the skin
- Condition of the skin

107
Q

What is the rate and extent of chemical absorption across skin?

A

In vitro
- Methodology and data analysis
- Permeability coefficient, % dose absorbed

In silico
- Permeability coefficient
- Maximum flux calculation

In vivo
- Pharmacodynamic measurement {vasoconstriction assay}
- Stratum corneum tape-stripping {dermatopharmacokinetics}
- Microdialysis

108
Q

What are the 4 main issues in topical drug formulation?

A
  • Interaction of vehicle with skin (enhancement effects?)
  • Interaction between drug and vehicle
  • No “rules” for matching a formulation to a particular drug
  • What happens to formulation, and components thereof, when it is massaged into skin?
109
Q

What influences choice of formulation?

A

Formulations selected by type of emulsion, lipid content and occlusivity
For chronic skin disease, hydrocarbon-based formulations preferred for their occlusive and protective properties

Water free formulations (PEG-gels, oleogels, fatty ointments) best for psoriasis, chronic eczema, mycosis.

Emulsion gel - Hydrogel containing a dispersed lipid phase
Suspension gels = suspensions of water-insoluble drugs in hydrogels

Gels are not favoured for psoriasis and eczema.
appropriate for anti-allergics, repellents, anti-inflammatories and for acne or rosacea.

Creams (emulsions) = disperse systems; majority of aqueous formulations

w/o emulsions blend easily with SC lipids, improving bioavailability of lipid-soluble drugs and moisturizing skin via slight occlusive effect.
o/w emulsions more cosmetically appealing (less sticky and greasy) as lipids therein are finely dispersed.
w/o lotion: hydrophobic, semi-liquid
w/o cream: hydrophobic, semi-solid
Typically used to treat psoriasis, chronic eczema, mycosis

o/w lotion: hydrophilic, semi-liquid
o/w cream: hydrophilic, semi-solid
Typically used to treat acne and acute and sub-acute eczema

110
Q

What are the 4 types of water free formulations?

A

PEG-gel: polar, 1-phase, semi-solid system, based on polyethylene glycols.

Lipogel: polar, 1-phase, semi-solid system, principally based on triglyceride derivatives.
Oleogel: polar, 1-phase, semi-solid system comprising triglycerides +/or hydrocarbon/silicon oils + inorganic filler.
Fatty ointment: Apolar, 1-phase, semi-solid system, based on hydrocarbon materials, e.g., vaseline, mineral oil.

111
Q

What are the two types of gel formulation?

A

Hydrogel: semi-solid system, typically comprising large organic molecules (e.g., cellulose derivatives, polyacrylic acid and esters) inter-penetrated by water.

Emugel: 2-phase system, consisting of large organic molecules inter-penetrated by water and small fraction of emulsified lipids.

112
Q

What are the two types of w/o formulations?

A

w/o lotion: hydrophobic, semi-liquid, 2-phase system, comprising water and a continuous lipid phase, e.g., triglycerides, waxes, + w/o emulsifiers.

w/o cream: hydrophobic, semi-solid, 2-phase system, comprising water and a continuous lipid phase (as above), + w/o emulsifiers.

113
Q

What are the two types of o/w formulations?

A

o/w lotion: hydrophilic, semi-liquid, 2-phase system, comprising lipids, e.g., triglycerides, waxes, and a continuous aqueous phase + o/w emulsifiers.

o/w cream: hydrophilic, semi-solid, 2-phase system, comprising lipids (as above) and a continuous aqueous phase + o/w emulsifiers.

114
Q

What are the 4 effects of chemical changes to formulations post application?

A
  • Structural matrix of formulation may change due to rubbing or loss of volatile excipient(s)
  • Rubbing may cause emulsifying effects
  • Evaporation may produce a desired cooling effect
  • Evaporation also desirable for repellent/fragrance formulations
115
Q

What are gels for percutaneous delivery of actives?

A

Gel formulations to treat local muscle and joint pain and inflammation.
Significant non-steroidal anti-inflammatory drug (NSAIDs) market.
Results in significantly lower systemic exposure (and avoids any major drug-related side-effects, such as GI disturbance).

116
Q

What is a wound?

A

Any defect or damage in the skin caused by:
Physical, chemical or thermal factors
Damage caused by an infectious disease

117
Q

What are the 6 types of open wounds?

A
  • Incisions
  • Lacerations
  • Abrasion
  • Punctures
  • Penetrations
  • Avulsion
118
Q

What are the 3 types of closed wounds?

A
  • Contusion
  • Hematoma
  • Crashing
119
Q

What are the 3 phases of wound healing?

A
  • Inflammatory phase
  • Proliferative phase
  • Remodelling phase
120
Q

What are the 8 primary wound dressings?

A

Hydrogel dressing
Hydrocolloids
Gauze impregnated
Gauze non-impregnated
Composite dressings
Wound fillers
Alginate dressings
Foam dressings

121
Q

What are the 5 secondary wound dressings?

A

Tape
Elastic bandage
Transparent film dressings
Gauze dressing
Carbon dressing

122
Q

What are petroleum dressings?

A

For clean, healthy wounds with minimal granulation bed
For wounds with no need for debridement, granulation and contraction
Best to use at early stages of wound repair for shallow wounds
Increases wound contraction but delays epithelialization

123
Q

What are hydrogel dressings?

A
  • Contains a solid polymer matrix with propylene glycol.
  • Dependent on wound conditions, it has the ability to absorb wound exudates while maintaining an excellent moisture balance.

Donates moisture
Permits autolytic debridement (removal of dead or infection tissue)
Increases collagenase activity in burns (promoting debridement)
Promotes granulation & epithelialization
Promotes contraction

124
Q

What are hydrocolloid dressings?

A

Early to mid-repair phase of healing
Can also reduce pain in wounds.
Encourages also angiogenesis in acute wounds

Indication:
Wounds with the need for granulation
Minimal to moderate exudates
Advanced wound contraction
Decupital ulcers (pressure ulcers, bed sores), burns, cavity wounds

Action:
Occlusive to semi-occlusive
Highly absorbent
Promotes moist wound healing
Promotes autolysis to debride wounds that are sloughy and necrotic.
Promotes granulation (may cause hypergranulation)
Adhesiveness may reduce contraction

125
Q

What are foam dressings?

A

Non-adherent dressing

Can absorb large amounts of exudates several times their own weight & accumulate the exudate at the back of dressing

Can also be used as secondary dressing

Indication:
Inflammatory or repair phase of healing
Deep wounds with mild to moderate exudates
Decubital ulcers
Can be used at any stage of healing
Best used after granulation, to encourage epithelialization and contraction.

126
Q

What are alginate dressings?

A

Natural polymers from Brown algae
Composed of either mannuronic or guluronic acid complexes.
Good gel-forming and film-forming properties

Calcium alginate is mainly used in the formation of wound dressing.
Calcium alginate is widely used as hemostatic agent (encourages the clotting cascade within a bleeding wound)

Indication: Burns, shearing/avulsion injuries, cavity wounds
Also encourages wound healing
Best early repair phase of wound healing (after gross contamination & necrotic tissue has been removed)
Best for moderate to highly exuding wounds
Highly absorptive, encourages epithelialization
Promotes autolytic debridement and granulation

127
Q

What are film dressings?

A

Semi-permeable dressings
Play important role both as primary & secondary dressings.
Comfortable dressings
Resistant to shear and tear
Can prevent bacterial colonisation but do not absorb exudate.
Vapour permeable
Allow fluid to evaporate while keeping the wound moist

128
Q

What are the natural polymers used in wound healing?

A

Natural polymers source: animal, microbial & vegetal

Usually are of protein (e.g. fibrinogen, thrombin, collagen, gelatin and albumin) or polysaccharide ( chitosan, chitin, polyN-acetyl glucosamine and cellulose) nature.

Suitable substitutes of the ECM and original cellular environment of the native skin.

Advantages: Biocompatibility, biodegradability and hydrophilicity

Limitations: Batch to batch variability, large heterogeneity, prone to high biodegradability

Successful use of chitosan, collagen and gelatine for wound dressing fabrications.

129
Q

How is collagen used in wound healing?

A

One of the most commonly used natural polymer with a key role in wound dressing
The most abundant protein in the body, major component of skin and musculoskeletal tissues.
Promotes healing by allowing attachment and migration.

Is composed of 3 polypeptide chains with triple helical domains.
Is one of primary initiators of the coagulation process.
Its high thrombogenicity has led to its application as a hemostatic agent.
Frequently used in formulation of different solid wound dressings for blood clotting.
Causes blood clotting through a pathway similar to physiological haemostasis.
Dry collagen material are prepared which physically adsorb blood by trapping blood cells and effectively adhere them to the wound site, providing mechanical strength.
Collagen powder is effective in blood loss reduction in the patients undergoing cardiac operations.

130
Q

How is chitin used in wound healing?

A

The principal structural component of the exoskeleton of invertebrates
Chitin can be converted into soluble derivatives, such as chitosan, carboxymethyl chitin & glycochitin.

Chitin-based biopolymers are versatile materials processed into fibers, sponges, membranes, beads and hydrogels.

Chitosan is prepared from deactelytaion of chitin by enzymatic or alkaline hydrolysis.

131
Q

How is chitosan used in wound healing?

A

One of the most abundantly found natural polymers suitable tor use in wound dressings.

Properties: Bioactive in slightly acidic media, depolymerises to release b-1-4-linked-D-glucosamine which initiates fibroblast proliferation and aids collagen deposition during the wound healing.
At the same time it has hemostatic properties.
- Is also involved in the rapid mobilization of platelet and red blood cells to the injured site during the healing process.
- Also helps in vasoconstriction and activates blood clotting factors, responsible for blood clotting.
In addition to aiding the healing process it is:
biodegradable, biocompatible, non-toxic, bioadhesive, bioactive, non-antigenic and also antimicrobial against a wide range of pathgenic organisms.
It possesses good film-forming properties and is used as hemostatic agent in different forms such as gels, films & scaffolds.

132
Q

How are synthetic polymers used in wound healing?

A

Synthesized & modified in a controlled manner (constant and homogenous physical and chemical properties and stability).
Disadvantage: Biologically inert, so do not offer a therapeutic advantage as seen with natural polymers.
Commonly used synthetic polymers for wound dressings

Advantageous in healing process: Non-toxic, biocompatible, non-immunogenic, hydrophilic and flexible.
PEO & PEG: Can be used to further incorporate mediators such as growth factors to assist the healing process.

133
Q

What is a gel?

A

Gels are viscoelastic solid-like materials comprised of an elastic cross-linked network and a solvent, which is the major component.

The solid-like appearance of a gel is a result of the entrapment and adhesion of the liquid in the large surface area of a solid 3D matrix.

The formation of the solid matrix is a result of cross-linking of the polymeric strands of macromolecules by physical or chemical forces.

134
Q

What are the characteristic features of gels?

A

Large increase in viscosity above gel point

Appearance of rubber-like elasticity

Gel retains shape under low stress, but deforms at higher stress

135
Q

What are hydrogels?

A

Hydrogels retain significant amount of water
( up to 100x their dry weight in H2O)
- but remain water-insoluble
- used in topical drug delivery, wound healing
- soft contact lenses
- Implant coating

136
Q

What are type 1 gels?

A

= irreversible systems
3-D network formed by covalent bonds between macromolecules

Formed by polymerization of monomers of water soluble polymers in presence of x-linker

137
Q

What are type 2 gels?

A

= heat-reversible

Held together by intermolecular bonds (e.g., H-bonds)

Gel on cooling below T = gel point

138
Q

What are cross-linked polymeric systems?

A

If water-soluble polymer chains are covalently x-linked into a 3D structure
gel forms when dry material interacts with water.
Polymer swells but cannot dissolve due to x-links.
Applications include fabrication of expanding implants;
Similar polymer used to fabricate soft contact lenses

139
Q

What are supramolecular gels?

A

Gels of a low molecular mass compound are usually prepared by heating the gelator in an appropriate solvent and cooling the resulting isotropic supersaturated solution to room temperature.

When the hot solution is cooled, the molecules start to condense and 3 situations are possible
(1) A highly ordered aggregation giving rise to crystals i.e., crystallization.
(2) A random aggregation resulting in an amorphous precipitate.
(3) An aggregation process intermediate between these two, yielding a gel

140
Q

What are supramolecular gels used for?

A

(1) Supramolecular organogels used in cosmetics formulations.

(2) Biomedical applications:
Media for tissue engineering

141
Q

What is micellisation?

A

At very low amphiphile concentration, the molecules will be dispersed randomly without any ordering.
At slightly higher concentration, amphiphilic molecules will assemble into micelles or vesicles. This is done with the hydrophobic tail of the amphiphile inside the micelle core.
At higher concentration, the assemblies will become ordered into a roughly hexagonal lattice.

At still higher concentration, a lamellar phase ‘neat soap phase’ may form, wherein extended sheets of amphiphiles are separated by thin layers of water.

142
Q

What is a liposome?

A
  • Liposomes are vesicular structures based on lipid bilayers encapsulating an aqueous core.
  • The lipid molecules are usually phospholipids
  • Such moieties spontaneously orientate in water to give the most thermodynamically stable conformation, in which the hydrophilic head-group faces out into the aqueous environment and the lipid chains orientate inwards avoiding the water phase.
  • This gives rise to bilayer structures.
  • Liposomes can serve as carriers for both water-soluble and lipid-soluble drugs.
  • The rigidity and permeability of the bilayer strongly depend on the type and quality of lipids used.
  • The alkyl-chain length and degree of unsaturation play a major role.
  • The presence of cholesterol also tends to rigidify the bilayers.
  • Such systems are more stable and can retain the entrapped drug for relatively longer periods
143
Q

What 3 things is liposome stability dependent on?

A

Lipid composition
Storage condition
- Light
- Oxygen
- Temperature

Stabilizers
- Cholesterol
- Alpha-tocopherol
- Inert atmosphere

144
Q

Why are liposomes attractive drug carriers?

A
  • bio-compatible/biodegradable.
  • biologically inert; weakly immunogenic ; Low intrinsic toxicity.
  • substantially alters tissue distribution of carrier-associated agents
145
Q

What are the 4 classifications of liposomes?

A
  • Conventional liposomes, which are neutral or negatively charged, are generally used for passive targeting to the cells of the MPS (mononuclear phagocyte systems).
  • Sterically stabilised liposomes with hydrophilic coatings used to obtain prolonged circulation times.
  • Immunoliposomes, either conventional or sterically stabilized, are used for active-targeting purposes.
  • Cationic liposomes, positively charged, are used for the delivery of genetic material.
146
Q

What are conventional liposomes?

A
  • Liposomes that are typically composed of only phospholipids (neutral or negative) and/or cholesterol.
  • Protect encapsulated molecules from degradation
  • Can passively target tissues or organs that have a discontinuous endothelium
    On intravenous administration, are rapidly taken up by the phagocytic cells of the MPS localizing predominantly in the liver and spleen, and removed from blood circulation
    Used when targeting to the MPS is the therapeutical goal:
147
Q

What are long-circulating liposomes?

A

Made by attaching the hydrophilic polymer, polyethylene glycol to the liposomes bilayers.

The highly hydrated PEG group create a steric barrier against interactions with molecular and cellular components in the biological environment.

148
Q

What are immunoliposomes?

A

Immunoliposomes have specific antibodies or antibody fragments on their surface to enhance target site binding.

The primary focus of their use has been in the targeted delivery of anticancer agents.

Long-circulating immunoliposomes can also be prepared.
The antibody can be coupled directly to the liposomal surface, however the PEG chains may provide steric hindrance to antigen binding.

149
Q

What are cationic liposomes?

A

The cationic lipid components of the liposomes interact with, and neutralize, negatively charged DNA, thereby condensing the DNA into a more compact structure.

Depending on the preparation method used, the complex may not be a simple aggregate, but an intricate structure in which the condensed DNA is surrounded by a lipid bilayer.

150
Q

How can liposome formulations be toxic?

A

Most liposome formulations are very well-tolerated

Cationic liposomes may activate complements and induce adverse effects via IV route.

PEGylated liposomes may induce a transient reaction upon injection in a subset of patients.

151
Q

What are nanoparticles?

A
  • Solid colloidal particles ranging in size from 1-1000nm
  • Consist of macromolecular materials
  • Can be used as drug carriers in which the active drug is adsorbed or attached’
152
Q

What is nanomedicine?

A
  • Increased drug penetration and stability
  • Too small to be detected by immune system
  • Deliver the drug in the target organ using lower doses so as to reduce side effects
153
Q

What are vesicle based lipsome carriers for topical drugs?

A
  • Lipid bilayer structures made of phospholipids (and cholesterol)
  • Hydrophilic drugs are entrapped in the aqueous layer of the liposomes, while hydrophobic drugs are incorporated in the lipid bilayers
154
Q

What are the 2 advantages of liposomal carriers for topical drugs?

A
  • Biocompatibility, low toxicity
  • Targeted delivery of drugs to the site of action
155
Q

What are the 2 disadvantages of liposomal carriers for topical drugs?

A
  • Limited penetrating ability
  • Chemically and physically unstable
156
Q

What are the 2 vesicle based transferome carriers for topical drugs?

A
  • Ultra-deformable liposomes, composed of phospholipids and additional surfactant /emulsifier
  • Edge activators: Destabilize the lipid bilayers of the stratum corneum and increase in deformability by lowering interfacial tension of lipid bilayers
157
Q

What are the 2 advantages of transferome carriers for topical drugs?

A

By squeezing themselves along the intracellular sealing lipid of the SC, the drug penetrating ability increases.
Localized at higher concentration

158
Q

What is the 1 disadvantages of transferome carriers for topical drugs?

A

Edge activators must be highly pure to avoid skin irritation & toxicity

159
Q

What are classical ethosomes?

A

Soft lipid vesicles composed of phospholipids, water and ethanol in relatively high concentrations (up to 45% W/W).

160
Q

What are the advantages of ethosomes?

A
  • More effective transdermal delivery than classical liposomes
  • They are smaller and have higher entrapment efficiency
  • Interferes with lipid bilayers of the SC due to fluidizing effect of alcohol
  • Shows better skin permeation and stability than classical liposomes
  • Alcohol also enhances the deformability of the vesicles
161
Q

What are the disadvantages of ethosomes?

A
  • Skin irritation due to high concentration of alcohol
162
Q

What are binary ethosomes?

A
  • Ethosomes developed by adding another type of alcohol to the classical ethosomes. The most commonly used alcohols in binary ethosomes are propylene glycol (PG) and isopropyl alcohol (IPA).
163
Q

What are transethosomes?

A
  • Transethosomes are the new generation of ethosomal
    systems
  • Contains the basic components of classical ethosomes and an additional compound, such as a penetration enhancer or an surfactant in their formula.
  • Developed in an attempt to combine the advantages of classical ethosomes and transfersomes in one formula to produce transethosomes.
164
Q

Why is celecoxib a good example of the benefits of suspensions?

A
  • NSAID COX-2 inhibitor
  • Prevent skin cancer development and increase the effectiveness of anticancer drug
  • Ex vivo permeation studies through excised human skin
  • All formulations improved the drug penetrating ability with respect to an aqueous suspension
  • Larger amount of CXB penetrated into the excised human skin when transfersomes and ethosomes were used
165
Q

What are solid-lipid nanoparticles?

A

1st generation of LNs
Increased adhesiveness to surfaces
Controlled occlusion effect
Increased skin hydration

166
Q

What are the three types of Solid Lipid Nanoparticles?

A
  • Homogenous matrix model (release form)
  • Drug-enriched shell model (fast compound delivery)
  • Drug-enriched shell core (slow controlled release)
167
Q

What are the 2 disadvantages of solid lipid nanoparticles?

A
  • decreased loading capacity
  • expulsion of drug during storage
168
Q

What are nanostructured lipid carriers?

A

2nd generation of lipid nanoparticles
Overcome the limits of SLN
Different matrix structure

169
Q

What are the three types of nanostructured lipid carriers?

A
  • Imperfect type (blend of different solids + liquids)
  • amorphous type (lipid solid matrix)
  • multiple type (drug solubility in liquid lipids higher than in solids)
170
Q

What are the 6 advantages of lipid nanoparticle carriers?

A
  • Low toxicity
  • Small particle size
  • Increase skin hydration -> occlusive effect
  • Enhance the stability of liable compounds
  • Physical sunscreen on their own
  • Reduce skin irritation
171
Q

What are niosomes?

A

Bilayered structures made of non-ionic surfactant and cholesterol

172
Q

What are the 2 advantages of niosomes?

A
  • Able to entrap wide range of chemicals (both hydrophilic and hydrophobic)
  • Less toxic than carriers with ionic surfactant
173
Q

What are the disadvantages of niosomes?

A
  • Limited shelf-life
  • Time-consuming & specialised required for the preparation process
174
Q

What are nano-emulsions?

A

Isotropic dispersed systems of 2 immiscible liquids: o/w or w/o nanoemulsions

175
Q

What are the advantages of nano-emulsions?

A
  • Both hydrophilic and hydrophobic drugs can be applied
  • Solubilisation/extraction of SC lipids, thereby decreasing resistance for drug transport
  • Greater and extended cellular penetration
  • Raised efficacy due to increasing surface-to-volume ratios
  • Non-toxic and non-irritant
  • Kinetically stable
176
Q

What are the disadvantages of nano-emulsions

A

Stability problems

177
Q

What is contained with the anterior segment of the eye?

A
  • Sclera
  • Iris
  • Cornea
  • Pupil
  • Lens
  • Cilliary body + muscle
  • Conjunctiva
178
Q

What is contained with the posterior segment of the eye?

A
  • Retina
  • Optic nerve
  • Macula
  • Retinal blood supply
  • Vitreous body
179
Q

What are typical diseases of the anterior segment?

A

Dry eye
Blepharitis: inflamed eyelids. Eyelid cleansing treatments
Conjunctivitis
Uveitis: inflamed uvea tract. Steroid treatment or surgery
Keratoconus (KCN): gradual thinning of cornea (contact lenses/ corneal cross-linking or keratoplasty)

180
Q

What are cataracts?

A

Portion of lens hardens and becomes cloudy
Annoying to painful (with a range of blurred vision and sensitivity to glare in between)
Causes: age, eye injury, previous surgery, certain medications
No known treatments other than surgery
Surgery: replacement of lens with a plastic lens (usually monofocal)
1: phacoemulsification: ultrasound tip to break down cataract
2: removal of debris
3: lens implantation into capsule

181
Q

What are the typical posterior eye diseases?

A

Age-related macular degeneration (AMD): degeneration of central part of retina (macula) causing loss of focus. Irreversible. No cure but can manage symptoms (e.g., reducing abnormal vessel growth)
Central Serous Retinopathy (CSR): disorder of the outer blood-retinal barrier. Fluid build-up under retina. Laser-based therapies

182
Q

What are the 3 types of glaucoma?

A

Primary open angle glaucoma: slow build-up of fluid caused by blockages
Acute angle closure glaucoma: sudden fluid build-up caused by blockages
Secondary glaucoma: existing underlying eye condition (e.g., uveitis)

183
Q

What makes up the conjunctiva of the eye?

A

Palpebral conjunctiva: inner surface of upper and lower eyelids
Bulbar conjunctiva: surface of the globe
Fonix (forniceal): region connecting palpebral and bulbar areas

184
Q

What makes up the cornea of the eye?

A

Epithelium: lipid-rich epithelium next to conjunctiva. 1 week turnover for cells
Stroma: thickest layer composed of collagen matrix and keratinocytes. Collagen fibril bundle spacing contributes to cornea being clear
Endothelium: single cell layer also lipid-rich to maintain hydration as it faces the inner part of eye

185
Q

What is lacrimal fluid composed of?

A

Tears: distribute nutrient across surface of eye, maintain hydration and remove debris
Blinking: 15-20 blinks per min (clearing approx. 1 µL/min)
Composition: water, lipids, lysozyme, lipocalin, glucose, and sodium
pH 7.4 (good buffering properties which could affect drug formulations)
Isotonic with blood (0.9% w/v NaCl; important to note for ocular formulations)

186
Q

What is required of ocular formulations?

A

Sterility
Chemically stable: preservatives as most eyedrops are multidose
pH ideal: buffering potential of lacrimal fluid vs stability of formulation

Viscosity match: (a) easily filtered during manufacture, (b) easily sterilised (by filtration), and (c) compatible w/ other excipients (e.g., preservatives)

Salt match: affects solubility but high concentration causes irritation

Comfort/ no irritation: stinging/ irritation caused by formulation which affects tear production/ clearance

Low MW and small particle size: <10 µm

Amphipathic: cornea structure is lipid-aqueous-lipid

187
Q

What are ocular ointments?

A

Mixture of semisolid and solid hydrocarbon (paraffin) with a melting point of ocular physiological temperature (34°C)
Helps to sustain drug release and improves bioavailability
Viscosity of formulation an issue
Greasiness/blurred vision caused by thicker formulation (better overnight)
Prolonged exposure and repeated blinking can lead to irritation/ inflammation
Systemic complications with chronic administration

188
Q

What is peri-ocular delivery?

A

Periocular: around the eyeball (but within the orbit)
Transscleral pathway; systemic circulation through the choroid; or through the tear film, cornea, aqueous humor, and the vitreous humor
Still various barriers to contend with
Drainage an issue in some strategies

189
Q

What intravitreal delivery?

A

Intravitreal: into vitreous (direct administration)
Distribution is non-uniform
Particle size matters (small easily distributed, large not so much)
Chemistry and MW of formulation matters
(vitreous component interaction)

190
Q

What is Iluvien?

A

Fluocinolone acetonide (corticosteroid) implant for Chronic Diabetic Macular Oedema (DMO)
Reduce VEGF (a protein that increases vascular permeability and causes oedema)
Intravitreal injection
3.5mm implant sits in vitreous fluid and can release drug for up to 36 months

191
Q

What is Lucentis?

A

Treatment for chronic diabetic macular oedema (DMO) and neovascular (wet) age- related macular degeneration (AMD)
1 mL contains 10 mg ranibizumab
Intravitreal injection
Reduces abnormal blood vessel growth (anti-VEGF)

192
Q

What is Dextenza?

A

For inflammation following surgery (e.g., cataract) or persistent itching associated with allergic conjunctivitis
Active ingredient: dexamethasone
Hydrogel-based implant acts as a plug into tear duct
Degrades over time

193
Q

What are nanocarriers?

A

Typically, under 100 nm
Research for both anterior segment and posterior segment
Advantages: decrease irritation, improve dispersion and improve tissue compatibility
Nanomicelles: most common. Surfactant or polymer-based but generally amphiphilic
Liposomes: lipid-based vesicles with a phospholipid bilayer and an aqueous core
Dendrimers: branched/ star-shaped. End of branches can carry cargo (drugs)
Nanoparticles: generally, protein/ lipid/ another natural matrix component-based. Drug-loaded spheres (throughout) or capsules (inside)

MPharm2 SL22107 (4 decks)

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