MR: Vaginal drug delivery Flashcards
What is the general structure of the vagina?
collapsible musculomembranous tube
How is the surface of the vagina? and advantages of this?
highly folded into rugae
- large SA
- rapid drug absorption
What is the disadvantage of the surface of the vagina being highly folded into rugae?
rapid infection by pathogenic organisms
What are the physicochemical properties of vaginal fluid? 3
- aqueous
- pH 3.5-5
- volume + composition can change
What is the blood supply of the vagina from? 2
- internal iliac artery
- uterine artery
What is the advantage of the rich blood supply to the vagina?
can be used to deliver drugs systemically (HRT contraception)
How is the acidic environment of the vaginal fluid maintained?
by conversion of glycogen -> lactic acid by bacteria Lactobacillus acidophilus
What is the advantage of the vaginal fluid being acidic?
Provides resistance from colonisation by various microorganisms
Volume and composition of the vaginal fluid: what 3 things increase with age?
pH,
fibrosity
mucin content
Volume and composition of the vaginal fluid: what 3 things decrease with age?
viscosity
cellularity
albumin content
Give 6 advantages using the vaginal route of admin?
- local admin
- large surface area
- rich blood supply
- avoids hepatic first pass metabolism
- reduced GI side effects
- self insertion and removal
what is uterine first pass effect and is this an ad/disadvantage for vaginal drug delivery?
advantage
potential for uterine targeting: local transport between vagina and uterus
vagina is permeable to a wide range of ocmpounds e.g. X and Y which cant be taken orally as destroyed in stomach low pH?
peptides and proteins
Give 6 disadvantages for vaginal delivery?
- gender specific
- less convenient
- variable permeability
- SR must ensure vaginal environment maintained
- vagina changes with age
- local irritation
absorption across vaginal epithelium is affected by? 2
physiological factors (can’t alter) and physicochemical properties of drugs
What are the 3 routes of drug absorption from the vagina?
- transcellular
- intracellular (through/ between cells)
- receptor-mediated
problem with only relying on receptor mediator transport mechanisms?
The receptors can become saturated meaning limit to amount that can be absorbed
3 physiological factors that may affect drug absorption from vagina?
- thickness of vaginal epithelium
- pH
- volume + composition of v fluid
what does Thickness of vaginal epithelium determine?
how quickly drug absorbed through into bloodstream
pH affect of drug absorption through vagina?
drug ionised… reduce absorption
unionised… help absorption
Will poorly water-soluble drugs have a higher or lower absorption rate if the vaginal fluid is increased? Why or why not?
- higher
- more solvent (aq vaginal fluid) to solubilise drug
Why does vagina pH affect release rate of pH sensitive drugs?
if drug ionised, more soluble so quicker dissolution but slower absorption
What physicochemical properties of the drug affect absorption from the vagina?
- MW (want low)
- lipophilicity (high not too high)
- ionisation (low pH)
- solubility
- partition coefficient
- chemistry (affects all above)
drugs been delivered systemically through vaginal tissue: X bioavailability than oral route and why 2 reasons?
greater as:
- no hepatic first pass effect
- higher intercellular permeablity
With drugs that want a local effect on the vagina, what is undesirable?
absorption
Are low MW drugs likely to have a higher or lower absorption rate? Why?
- higher
- diffuse faster
What questions are considered when formulating vaginal drug delivery systems?
- systemic/local effect?
- need distribution within vagina?
- immediate/sustained release?
- cultural acceptability?
- economic implications
- physicochemical properties of the drug?
what will happen once vaginal ring administered with a really hydrophobic drug in?
drug will sit in ring and wont want to leave + go -> vaginal fluid and tissue
vaginal ring is really hydrophlic. wont dissolve in polymer to be released from drug
what is the name given to the semi solid system in which a liquid phase is constrained within a 3d cross linked matrix?
gel
In which phase is the drug dissolved or suspended in a gel?
liquid
How can vaginal gels behave when applied to the vagina? Why is this useful?
- swell, then spread over vaginal wall
- allow for localised drug delivery + sustained release for longer periods of time
What are the disadvantages of gels?
- messy to apply
- uncomfortable
- leak out
- don’t allow for exact amount of drug to be absorbed (uneven spread)
- difficult to adm dose
- poor px compliance
What are vaginal creams?
semi-solid emulsions of O/W or W/O
miscible w vaginal fluid
what two types of ingredients are creams (semi solid emulsions) made from?
natural and synthetic
3 cons for vaginal creams?
(same as gels)
messy,
leakage
difficult to admin exact dose
What are the advantages of vaginal tablets?
- easy + cheap manufacture
- easy insertion
What types of excipients are used in vaginal tablets?
those used for oral tablets:
- binders
- disintegrants, etc.
in vaginal tabs, what can be varied by changes in formulation/ manufacturing process?
release rate
What excipient helps improve retention time in the vagina?
mucoadhesive polymers
vaginal tabs: what may decrease absorption?
(SGT)
Hydrophobic and release-reducing materials
non soluble polymers to slow down release
What excipients help enhance absorption of vaginal tablets? How?
- surfactants
- bile salts
absorption enhancers increase solubility of hydrophobic drugs
What are vaginal pessaries? (physical shape)
solid, single-dose ovoid shaped preparations
vaginal pessaries are made of…
API/s dispersed/dissolved in suitable base
base is soluble/dispersible in water/melts at body temperature
(What are examples of excipients added to pessaries?)
- diluents
- adsorbents
- surface-active agents
- lubricants
- antimicrobial preservatives
- colouring agents
shape and use of vaginal rings?
torus-shaped dosage forms suitable for delivering 1+ drugs in sustained fashion (local/ systemic)
What is the major advantage of vaginal rings?
drug release is:
- continuous
- long-term
- at pre-determined rates
all increasing:
- cost-effectiveness
- compliance
- therapeutic efficacy
vaginal rings can be inserted for up to how many months?
12
What are the two materials that IVRs are composed of?
rings
siicone elastomers or EVAc
what are the two main types of vaginal rings available?
matrix and reservoir
Describe the nature of a matrix vaginal ring. e.g. Femring/Nuvaring
drug homogenously dispersed throughout silicone
What is the release rate of matrix rings proportional to? 2
drug loading + surface area of ring
How are matrix rings manufactured? 3
- single step
- injected into mould
- allowed to cure at elevated temperatures
Typical matrix release profile
first order
slowly decreases
Typical matrix release profile
first order
slowly decreases
Typical matrix release profile
first order
down curve time/ release
Describe the nature of a reservoir vaginal ring.
drug in core surrounded by silicone-sheath
How do drug molecules leave reservoir vaginal rings? 2 steps
- first dissociate from crystal lattice + dissolve in silicone elastomer
- then diffuse through sheath -> medium surrounding
What release kinetics do reservoir vaginal rings follow? Why?
zero-order - release rate constant throughout time ring is in place
What does a typical reservoir release profile look like?
release/ time and just straight horizontal line in middle as zero order. constant release
What are the 4 stages of drug leaving a vaginal ring?
- solid drug encapsulated in polymer matrix
- dissolves in polymer matrix in ring
- diffuses out of ring into surrounding fluid then tissue or directly to tissue
- drug diffuses into circulation
in terms of drug release, why is matrix ring first order and reservoir is zero order?
matrix:
Day one burst, get all drug in tissue you need then moved away, degraded. drug decreases
reservoir:
sheath is not saturated at start so no drug in it. Then becomes saturated but can only hold so much drug then stop
when used drug starts to leave medicated sheath and get continuous release, no burst
both matrix and reservoir rings can be controlled release depending on what 2 things?
How thick non medicated sheath is/ how much drug present in core
effect of drug in vaginal ring being soluble in polymer?
will dissolve really quickly and diffuse through :)
…But any drug around surface in contact w epithelium may quickly come out as just sat there and leave pores and voids where vaginal fluid creeps into ring
If ring was reservoir have another medicated sheath around
(image) What 3 factors influence drug release at the drug encapsulation stage? ring
- drug loading
- polymer type
- whether ring is matrix/ reservoir
What 2 factors influences drug release at the drug dissolving stage? ring
- polymer solubility
- crystal lattice E
the 2 types of drug release from ring into body.
Indirect
or direct
What factors influences drug leaving the vaginal ring and entering the fluid/tissue?
- diffusion through: polymer, fluid, tissue
- solubility in: fluid, tissue
- fluid volume
What factor influences the drug reaching the circulation from the epithelium?
epithelial thickness
why is the ideal drug release range 10-70%?
above is drug exhaustion and below is burst
difference between controlled and sustained drug release?
sustained is for period of time
controlled is predict based on surface area and mathmatically predict how much drug will be delivered
what is the cross sectional diameter of vaginal rings (range)?
5-9.5mm
what is the overall diameter range of vaginal rings?
50-75 mm
are vaginal rings sustained or controlled in terms of drug release?
controlled
list all 6 factors that affect the drug release/PK/ absorption from vaginal rings?
drug loading,
polymer type,
ring type,
polymer solubility, f
luid volume
epithelial thickness
what is the indirect mechanism of vaginal rings?
ring -> fluid -> tissue
drug goes through ring, fluid tissue, moves through and diffuses through polymer.
what is indirect mechanism of vaginal rings affected by?
polymer diffusion, fluid vol, fluid solubility (drug, sol in vaginal fluid)
what is the direct mechanism of vaginal rings?
ring -> tissue
why might vitro release rates look much better to those in vivo?
in vitro got what we wanted because formulated for vagina, as drug is water insoluble indirect mechanism so release controlled by solublity in vaginal fluid
