8. Formulation Considerations Flashcards
The respiratory tract
Passageway in the body responsible for respiration:
- Oxygen intake & carbon dioxide expulsion
Divided in upper & lower respiratory tract
- Upper = mouth/nose to larynx
- Lower = trachea to alveoli
Open to the outside world:
- Defences required to protect body from noxious substances
- Defences required to prevent damage to structure
Local aliments
- Nasal congestion or inflammation
- Mouth ulcers
- Oral thrush
- Pharyngitis/laryngitis
Delivering drugs to the upper respiratory tract - systemic delivery
- Nasal to bloodstream
- Nasal to brain via cerebrospinal fluid
- Oromucosal (mouth to bloodstream, non-GI route)
Drug delivery to nasal mucosa - features of the nasal cavity
- Volume of ~30-40 mL
- Surface area of ~160cm2
- Rich blood supply
- Access to the nervous system
+ 5 cm2 olfactory region
+ Area of the nose containing smell receptors
Deposition & retention in the nose
Respiratory tract is like a series of sieves:
- Largest particles are trapped earliest
- To ensure droplets remain in the nose, particle size should ideally be 30-120 µm
- Achieved by design of nasal spray/drop device
Respiratory tract comprises mucosal tissue:
Retention can be achieved by:
- Including excipients that bind to mucosa
- Including excipients that increase formulation viscosity
Both slow the rate of clearance
Absorption through nasal mucosa
Important for drugs acting systemically
Ideal physical properties include:
- Molecular weight & shape:
+ < 500 Da & globular molecules absorb best
- pKa & logP
+ Non-ionised at nasal pH (5.5-6.5, up to 8.3 in rhinitis) absorbed best
+ LogP <5 ideal (but still need some lipophilicity)
- Solubility
+ High solubility in delivery system ideal
+ If in suspension, should rapidly dissolve in mucus
Nasal sprays vs Nasal drops
Nasal sprays:
- Very precise (metered chamber)
- Spray can reliably reach back of nose
- Cannot spray high viscosity liquids
Nasal drops:
- May vary marginally between droplets
- Drop will not reach as far into nasal cavity
- Can apply higher viscosity liquids
Both formulations contain excipients to control osmolarity, viscosity, drug solubility, formulation pH & shelf life
Nasal formulations can reach the CNS - 2 ways
Olfactory bulb
- Part of nose used to detect odours & send to brain
Trigeminal nerves:
- Responsible for facial sensation & motor functions
Drugs can travel through either of these routes to the CNS
E.g. Ketamine-based nasal spray FDA approved for depression
Oromucosal delivery
Buccal route:
- Delivery of drug to the cheek
- Typically used for local aliments (e.g. mouth ulcers or oral thrush)
- Formulation is designed to stick to the mucosa
Sublingual route:
- Delivery of drug under the tongue
- Typically used for systemic aliments (e.g. angina)
- 80-200 µm in thickness, rapid absorption directly into bloodstream
Laryngeal/pharyngeal drug delivery
Difficult to administer drug reservoir on the throat
Antiseptics, anti-inflammatories & analgesics are administered in the following ways:
- Gargles
- Throat sprays
- Lozenges
- Gums
Lozenges & gums
Lozenges:
- To be held in oral cavity
- Slow dissolution allows contents to be gradually swallowed
- Allows soothing effect on throat
Gums:
- To be chewed
- Similar principle to lozenges
- Not typically used for local delivery
Both formulations are used in NRT (systemic)
Lower respiratory tract
Trachea & below
Utilised for gaseous change:
- Alveoli exchange CO2 & O2 between blood & inhaled air
- Large surface area
Highly branched structure:
- Maximises collisions & prevents entry of large objects
Removes unwanted substances via:
- Mucociliary clearance
- Alveolar macrophages
Drug/particle behaviour following inhalation - size determines where particles end up
- Inertial impaction
- Particles > 5 µm in diameter are lodged in large conducting airways - Sedimentation
- Particles sized 0.5-5 µm deposit in bronchioles
- Perfect size for local treatment of respiratory diseases - Diffusion
- Particles <0.5 µm in diameter have difficulty sedimenting
- Will typically be breathed out
Breathing patterns determine where inhaled particles end up
Speed of inhalation influences impaction
- Very fast inhalation - particles as small as 3 µm may be impacted
- Very slow inhalation - particles >10 µm may enter lungs
How long is an inhaled dose held for? - Residence times of particles is important for both sedimentation & diffusion - Deeper deposition may be promoted by: \+ Breathing slowly \+ Breathing deeply \+ Holding breath affect inhalation
Other factors contributing to particle deposition
Patient specific airway anatomy & morphology
- Disease state (asthma, COPD), changes to mucus layer, epithelial thickness, airflow
- Interpatient variation
Device used for inhalation:
- Patient knowledge of appropriate technique
- Devices themselves differ in efficacy
Inhaled drug delivery
- Used for local delivery in asthma, COPD, cystic fibrosis
- Fast onset of action
- Small doses can be administered
- Minimal off target effects
BUT - Patient techniques important
- Device care important
- Mucoirritant drugs not applicable
4 groups of inhalers
- Metered dose inhalers (MDI)
- Dry powder inhalers (DPI)
- Nebulisers
- Soft mist inhalers
Metered dose inhaler
Drug is suspended/dissolved in a propellent
- Volatile surfactant or cosolvent
- Lubricates devices & prevents particle aggression
Canister has 2 chambers:
- Reservoir - contains bulk of formulation
- Metering chamber - contains defined volume that is sprayed out
MDI - Advantages/Disadvantages
Advantages:
- Compact & portable
- Consistent dosing possible
- Can be used independently
- Can be used with spacer
Disadvantages: - Non-breath actuated \+ Large patient variations in technique \+ Issues with hand-breath coordination - Dexterity issues (difficult to grip)
Dry powder inhalers
- Contains defined dose of dry powders
- May be in pellet, capsule, blister or other container
- Drug is either present alone or bound to carrier e.g. lactose
Basic function: - Clicking a trigger dispenses a single dose of a drug - Patient inhales dose of drug - Dry powder inhalers include: \+ Acculaher \+ Tubuhaler
DPI - Advantages/Disadvantages
Advantages:
- Compact & portable
- Does not require coordination of inhalation with activation
- Hand strength not an issue
- No propellent required
Disadvantages: - Requires patient to breathe in \+ Potential issue in children, or patients with low inspiratory flow - May not be appropriate in emergencies - Moisture sensitive
Soft mist inhalers
Propellent-free multi-dose inhalers which force metered dose of drug through unique & precisely engineered nozzle
- Slow speed of actuation
- Longer duration of aerosol cloud
Soft mist inhalers - Advantages/Disadvantages
Advantages:
- Portable & compact
- Easy coordination & actuation
- Considerably smaller dose needed compared with MDI
- No propellents
Disadvantages:
- Max volume is 15 µl, so can only deliver small doses
Summary
ENT:
- Locally acting formulations
- Potential for & application in systemic delivery
- Importance of wettability, mucoadhesion & mucopenetration (nasal formulations)
Respiratory delivery:
- Particle size plays an important role in drug deposition
- Various devices have been developed to control particle size & achieve optimal drug delivery
