Oromucosal administration Flashcards
Describe how drugs are absorbed through the oral mucosa
Discuss how drug properties can affect drug transport
Discuss the impact of the type of dosage form on bioavailability
Describe and discuss common pharmaceutical dosage forms used for oro-buccal delivery (local and systemic)
Give examples of mucosal delivery sites (7)?
- oral
- nasal
- intestinal for swallowed dosage forms
- vaginal
- pulmonary
- rectal
- ocular
which oral mucosa is keratinised and purpose?
masticatory - protect against mechanical trauma from chewing
what oral mucosa is targeted for drug admin and why?
lining mucosa: non-keratinised
less barrier to drug absorption compared to keratinised
lining of the oral cavity, what 3 types of stratified squamous epithelium are there?
- mastciatory mucosa
- lining mucosa
- specialised mucosa: taste buds
what 3 main glands produce saliva and how much?
- sublingual
- parotid ++ (close to ears)
- submandibular ++++ (lower jaw)
what is saliva composed of?
an aqueous fluid: water, electrolytes.
glycoproteins (mucin)
enzymes
natural antimicrobials- maintain good health in mouth
where does the digestion process begin?
enzymes in saliva in mouth to begin digestion- amylases
pH of saliva?
fairly neutral in mouth but does have some buffer capacity
3 roles of the oral cavity?
- mastication
- taste
- deglutition
conditions treated by oro-buccal administration for local effect
Dry mouth Infection Irritation Pain Ulceration ...
what 3 things must be considered in terms of oro-buccal formulation?
- Contact with the site of action
- Residence time
- Organoleptic properties:
Sugar content and Acidity .
both can affect buccal/dental health
what are the three types of lozenges?
hard
soft
chewable
moisture content and sugar content of hard lozenges?
low moisture content of 0.5-1.5%
potentially high sugar: 55-65% sucrose
how are hard lozenges prepared?
at high temperature
theyre similar to hard candy
composition of chewable lozenges? 4
- glycerin and gelatin
- API
- colour
- flavour
use of chewable lozenges
paediatric use
-caution may be perceived as candy
not all lozenges are drug free.
give an example of a P lozenge
Flurbiprofen: NSAID and, similar to others drugs in that class, can be irritant to the oral mucosae.
The ‘how to take instructions’ include a recommendation to move the lozenge around in the mouth to avoid prolong contact.
Role of products for mouth ulcers (4)
alleviate discomfort associated with these lesions
reduce inflammation
provide pain relied- local anaethetic
/ speed up healing
how can mouth ulcer treatment be used to prevent infections?
by providing a barrier or through the inclusion of antiseptics.
4 products for mouth ulcers
Mouthwash: saline/antiseptic
Gels
Sprays
Soft lozenges
what can cause dry mouth (xerostomia)? (3)
- ADR to drugs
- medical conditions
- other causes: smoking, mouth breathing, stress…
3 examples of drugs that cause dry mouth?
anticholinergic drugs
diuretics
cancer chemo- or radiotherapy
3 medical conditions that cause dry mouth?
Sjögren syndrome (Links to an external site.)
nerve damage
dehydration
…
complications of dry mouth?
and hows it treated?
increased risk of dental and periodontal conditions,
treated by addressing the underlying cause or using measures that help increase salivation/ artifical saliva substitutes
Artificial saliva substitutes are available as? (4)
what do formulations include? (3)
lozenges, gels, sprays and soft lozenges.
Formulations can include saliva enzymes, mucin or electrolytes.
3 example products used as treatment for infections- affecting diff parts of oropharyngeal region.
hydrogen peroxide
chlorhexidine
antifungals
- nystatin suspension
- miconazole gel
how are cold sores treated in patients not immunocompromised?
with a topical treatment:
Creams - antiviral (e.g. aciclovir) - disinfectants Patches - non-medicated, help with wound healing provide a barrier effect
what 3 sites can drugs released from systemic oro-buccal dosage forms be absorbed from?
- sublingual compartment
- buccal mucosa
- labial mucosa. lining of the lips
4 benefits of Systemic oro-buccal dosage forms?
- quick onset of action
- easy adminstration
- patient adherence
- neutral environment in oral cavity (lower metabolic activity, neutral pH)
why do Systemic oro-buccal dosage forms provide quick onset of action?
directly absorbed into blood circulation, no first pass metabolism
why is patient adherence increased with Systemic oro-buccal dosage forms?
Possibility for sustained release and decrease frequency of administration (mucoadhesive dosage forms)
5 disadvantages of systemic oro-buccal dosage forms
- unsuitable for irritant drugs- damage to mouth mucosa
- limit to dose administered
- require adequate use by patient
- Difficulties in dose splitting for some products
- Impact of saliva
how does saliva negatively impact use of systemic oro-buccal
oral cavity is a low fluid environment
drug wash-out into the saliva
why is there a Limit to dose that can be administered with systemic oro-buccal
Limit to dose that can be administered vs. size of dosage form and patient comfort
- remember the patient might have to keep the dosage form in their mouth for a while!
3 types of barriers to drug absorption?
physiological barriers
physico-chemical barriers
formulation barriers
how is the small intestine
a) beneficial
b) limiting?
a) largest SA for absorption
b) enzymatic activity and the risk of first pass metabolism can be problematic for some drugs.
how is drug absorption impacted in mouth?
the fluid volume is small, but there is also a quick turnover of the saliva and this can have an impact on drug absorption.
order these in terms of enzymatic activity:
buccal stomach small I large I rectum
stomach and SI
large I and buccal
rectum
highest to lowest
order these in terms of pH:
buccal stomach small I large I rectum
smallest to highest
stomach
small I
large I
rectum and buccal
order these in terms of fluid volume:
buccal stomach small I large I rectum
buccal
stomach
large I
small I
rectum none
order these in terms of surface area:
buccal stomach small I large I rectum
buccal rectum stomach large I ... small I
what are the 3 main types of mucosa in oral cavity?
Masticatory
Lining
Specialised
what is the role of each type of mucosae in oral cavity
masticatory: mechanics of chewing. heavily keratinised
lining: non-keratinised. oro-mucosal drug absorption
specialised: taste buds to detect true taste
where is each type of mucosae in oral cavity found?
mastciatory: hard palate and gums
lining: lips,cheeks, sublingual area, soft palate
specialised: tongue
why is lining mucosamost suited to oro-mucosal drug absorption?
low levels of keratinisation.
what three parameters (physico-chemical properties) are important in absorption in oral cavity?
Ionisation state: at buccal pH 6.2-7.4
Log P: balance between lipophilicity and hydrophilicity
Molecular weight
why may oro-mucosal formulation be preferred?
preferred to maximise the bioavailability of a drug that is subject to extensive first-pass metabolism
6 Examples of drug formulated for oro-mucosal administration
Drug name Molecular weight (Da) log P
Midazolam 325.8 4.3
Prochlorperazine 373.9 4.9
Fentanyl 528.6 2.3
GTN 227 1.6
Buprenorphine 467.6 4.98
Nicotine 162.2 1.17
2 types of drug transport through oral mucosa
transcellular
paracellular
how do transcellular and paracellular pathways differ?
trans: drug crosses cell membrane and travels THROUGH CELL
para: drug moves/ diffuses IN BETWEEN cells
what is paracellular pathway of drug absorption through oral mucosa suitable for?
fairly hydrophilic and small drug molecules. fit in between intracellular space
how can drug absorption be enhanced in paracellular pathway?
use of permeation enhancers: create more space between cells for bigger molecules to diffuse/travel through
what does drug absorption depend on?
the oro-buccal dosage form and drug released
where is drug absorbed from oro-buccal?
- mouth and avoid first pass metab
- mix with saliva and swallowed. go through GI tract and intestinal mucosa. subject to first pass metab and stability issues- degradation at low pH
what type of kinetic profile would you get for drugs which fraction absorbed in intestine also bioavailable?
2 peak: biphasic.
[blood]/time graph
1st peak: fraction absorbed in mouth,
2nd peak: SI. may be lower depending on how extensively metab. later on as time to travel through GI
how may drug given in this route be inactivated?
mix with saliva and be swallowed
This can lead to inactivation of the drug
what will drug activity and second peak in plasma conc vx time curve depend on? absorption
properties of the drug and its bioavailability when going through the GIT
what can Dosage forms be designed to provide
Immediate drug release
Controlled drug release
always: goal = deliver drug in a bioavailable form.
3 Formulation considerations
contact
residence time
disintegration
why are we concerned about Contact of formulation?
Is the drug in direct contact with its site of absorption in the oral cavity?
why are we concerned about residence time of formulation?
How long is the drug in direct contact with its site of absorption in the oral cavity?
why are we concerned about disintegration of formulation?
how quickly dosage form disintegrates to release the drug
- depend on the proposed use of the dosage form:
immediate vs controlled release
how are oro-mucosal preparations Similar to other dosage forms? formulation considerations
will need to meet BP requirements
what is the requirement of oro-buccal solution?
example?
must stay in contact with the lining mucosa (e.g. cheek) and is administered using the applicator provided
midazolam
Oro-mucosal dosage forms: example II
Medicated chewing gum
3 benefits
Oral care
No water required
Stress relief
Oro-mucosal dosage forms: example II
Medicated chewing gum
4 limitations and example
Organoleptics properties
Variable release
Production costs
Similar issues as non-medicated gum
Example: nicotine
why is no liquid intake required with dosage form iii: Oro-dispersible formulations?
Quick dissolution
but some formulations not meant for oro-mucosal absorption = expected to swallow the drug after the film or tablet has dissolved
6 advantages of Oro-dispersible formulations
- Convenience
- Immediate release
- Easyadministration
- Can be suitable for patient with difficulty swallowing
- Less obtrusive than buccal tablets
- Improved bioavailability
oro-dispersible forms have improved bioavailability provided what?
provided buccal absorption is maximised (i.e. contact with site of action)
4 disadvantages of oro-dispersible formulations?
- Difficult to split dose
- Very hygroscopic: handle with care
- Organoleptic properties to consider
- A fraction of the drug may be swallowed
2 examples of oro-dispersible forms and how different?
nicotine and ondansetron films
one applied to roof of mouth, one to tip of tongue.
both allowed to fully dissolve
Oro-mucosal dosage forms: example IV
Compressed lozenges how are they produced?
Produced through compression of a powder blend and very different to hard lozenges (local action)
2 properties of compressed lozenges
high mechanical strength and low porosity.
common excipient in Compressed lozenges and how administered?
Often formulated using dextrates as diluent and without disintegrant.
NOT chewed or swallowed whole.
associated with high inter- and intra-individual variability.
Examples: fentanyl, nicotine
most common materials used for mucoadhesion
polymers (long chains of repeating units).
anionic/cationic/ neutral
in terms of mucoadhesion, how will CATIONIC material work?
through electrostatic interactions with the negatively-charged mucus layer
in terms of mucoadhesion, how will ANIONIC and NEUTRAL material work?
through hydrophobic and/or hydrogen bond formation
ideal properties of mucoadhesive material ? (6)
- biocompatible: non-toxic, non-irritant
- form strong bonds
- produce quick adhesion
- have no incompatibilities
- have good stability
- be cost-effective
Mucoadhesive tablets
Advantages (3)
- slow dissolution
- improved contact with site of absorption
- increased residence time
Mucoadhesive tablets
Disadvantages (3)
- Discomfort
- Can be irritant
- Can detach from mucosa: risk if then adheres to a different mucosal surface
Buccal tablets can be…
Buccal tablets can be uni- or multidirectional.
how do uni and multidirectional buccal tablets difefr?
uni: drug released in one direction, to oral cavity only
multi: drug released anywhere from tablet. fraction absorbed in o.c, majority mixed with saliva and swallowed.
Example: prochlorperazine
what happens after drug release and absorption of multidirectional tabs?
depending on drug properties and stability.
degradation in GI tract and first pass metab extensiveness- decides if 2nd absorption peak/not
what is added to unidirectional tabs to ensure drug released in one direction and implication?
coated polymer = ensures max absorption in oral cavity thus bioavailability
not released in mouth and swallowed in saliva
Sublingual administration (under tongue) Advantages
- Rapid onset of action
- Easy administration
- Extensive drug absorption
- Thin lining mucosa
- Can be used in emergencies
- Fast dissolution of dosage form
- No need for water intake
Sublingual administration (under tongue) Disadvantages
- hard to use in unconscious patients
- Smoking may reduce drug absorption
- Size limit to ensure patient comfort
why may sublingual administration not be used for sustained drug release?
Can interfere with eating/drinking.
examples of sublingual formulation
and examples of drugs
spray
oil solution
- peppermint/ coconut
Examples: glyceryl trinitrate, nicotine and prochlorperazine
Why is the hard palate less suitable for oro-buccal drug absorption?
The hard palate is heavily keratinised.
What is the main source of fluid in the oral cavity? What roles do it play?
Saliva is the main source of fluid
What type of non-specific interactions are involved in mucoadhesion? (3)
Electrostatic
Hydrophobic
Hydrogen bonding
What drug properties are important for oro-buccal absorption?
Molecular weight, log P and ionisation state
What makes fentanyl a suitable candidate for oro-mucosal administration?
logP: 2.3
MW: 529Da
Low oral bioav.
consider how likely the drug is to mix with saliva and be swallowed = biggest impact on final bioavailability. SmPC
Want good balance between unionised:ionised fraction (LogP) lipophilic enough to pass but soluble enough to dissolve (must be in solution to dissolve). Good for Oro-mucosal
what has lowest bioavailability?
Buccal tabs
Sublingual
Lozenges
- Lowest BA: compressed lozenges.
- release fentanyl in all directions, some may be swallowed, = lower the overall bioavailability.
- likely to be some intra-
and inter-patient variability as well, depending on technique - Possible to have 2 peaks- one for absorption in the mouth and a delayed response from absorption in the intestine.
whats the impact of swallowing the fentanyl tabs/ lozenges whole on tmax and cmax?
Fentanyl subject to extensive hepatic and intestinal first-pass elimination.
Swallowing Effentora/Actiq would:
- increase tmax (will take longer to reach peak plasma concentration)
- decrease Cmax (peak will be lower as limited bioavailability).
