Suppositories 1 + 2 Flashcards
How is rectal, vaginal and urethral administration different?
Rectal
- Used for local or systemic effects
- Variety of dosage forms: Suppositories, capsules and tablets, enemas, foams, ointments, gels, etc
Vaginal
- pH 4-4.5
- Vaginal secretions: change with hormonal variations
- Vaginal suppositories, pessaries, tablets, foams used primarily for local effect
- Option for systemic delivery – vagina is well vascularised, avoids first pass effect, has first uterine pass effect
Urethral
- Bougies – different sizes for male and female
- Local effects: antiseptics, anaesthetics, erectile dysfunction
- Water soluble bases used
What are suppositories?
Solid dosage forms intended for insertion into body orifices where they melt, soften or dissolve and exert local or systemic effects
- Rectal, vaginal (pessaries) and urethral (bougies) suppositories available
- Torpedo, bullet-shaped: rectal
- Ovoid: pessaries
- Long, thin and cylindrical: urethral
Why use rectal route?
- Local effect desired
- Avoids acid pH of stomach/enzymes in stomach or intestine
- Drug may be irritating to stomach
- Drug subject to significant first pass metabolism
- Drug has objectionable taste that cannot be masked
- Patient unwilling or unable to swallow
- Patient vomiting
- Dose to high to accommodate in oral dosage form
What are some disadvantages of rectal route?
- Patient aversion
- Slow and sometimes incomplete absorption
- Rectal irritation may develop with long-term use
- Potential for leakage
- Manufacturing, storage and shelf-life issues
What are some local effects and systemic effects of rectal administration?
Local effect
- Local anaesthetic
- Vasoconstriction
- Soothing/anti-inflammatory
- Healing
- Relieve constipation/empty rectal cavity
Systemic effect
- NSAIDs and analgesics (incl. opioid)
- Anti-emetic
- Migraine treatment
- Antipsychotics
Describe the properties and formulation of rectal suppositories
- Solid, single dose preparations with a shape, volume and consistency suitable for rectal administration
- Contain one or more active ingredients in a suitable base
- (Also can have active ingredient in a soft gelatin capsule (eg Panadol children’s suppositories))
- Base is soluble or dispersible in water or melts at body temperature
- Excipients: diluents, adsorbents, surface-active agents, antioxidants, lubricants, antimicrobial preservatives, hardening agents, viscosity modifiers, colouring agents, etc (may be present)
What is the anatomy and physiology of the rectal cavity
- Size: terminal 15-20cm of large intestine; surface area 200-400cm2 (cf. small intestine ≈ 2,000,000 cm2)
- Mucosa: cylindrical epithelial cells; without villi
- Fluid: 2-3mL of inert mucosal fluid; pH 7.2-7.4; buffer capacity low
- Contents: usually empty
- Drug absorption: presence of colonic contents, diarrhoea, colonic obstruction, tissue dehydration will influence rate/degree of drug absorption
- Circulation route important
What influence of bioavailability do rectal veins have?
- Drugs absorbed rectally can bypass the portal circulation
- Drug absorbed via the lower haemorrhoidal veins (inferior and middle rectal veins) enter circulation via the iliac veins and vena cava thus avoid liver on 1st pass
- Superior haemorrhoidal vein transport via portal vein to liver
- Generally accepted 50-70% of drug administered rectally takes direct pathway bypassing the liver.
- Possibility of absorption into lymphatic vessels
What are some physiological factors affecting drug absorption in the rectum?
- Lower suface area than other parts of gi tract –> no villi, few folds
- Limited motility, but enough for spreading of suppository
- Highly vascularised –> varying circulation to liver
- pH is essentially neutral and unbuffered so won’t alter the state of ionization of drugs
- small volume of fluid in which drugs/bases can dissolve (water drawn from tissues)
- Contents of rectum – usually empty, but presence of faecal matter will interfere with absorption, (also diarrhoea –> loss of sup)
- Temperature is 37C (or a little lower) –> bases may melt or dissolve
What are some physicochemical factors affecting bioavailability?
See attached image
What is drug release governed by in suppositories?
Solubility of drug in vehicle
- High solubility in vehicle –> retention in vehicle (esp problematic if fatty base) –> low release
- Undissolved drug sediments is wetted before dissolving
Particle size of drug
- Small particle size = increased dissolution rate, uniformity of content in suppositories, less mechanical irritation, more likely to agglomerate
Spreading capacity
- Good spreading –> maximise area for absorption
Vehicle viscosity at rectal temperature
- The viscosity of liquefied base controls diffusion to the mucosa; sedimentation during preparation and potential leakage
Retention of active principle by vehicle
What is drug absorption governed by in suppositories?
pKA of drug and pH indiuced in rectal fluids
- pKa – governs ionisation at any pH Rectal fluid has no buffer capacity, so drug or formulation will control pH
Presence of buffers
- buffers in formulation will control local pH
Additive effects on membrane permeability
- Surfactants in formulation will have effects on membrane permeability
Partition coefficient of drug
- Log P governs ease of absorption through lipid membrane
> Water solubility required to dissolve in rectal fluids
> Some lipid solubility required for passive absorption through membrane
Also: irritancy of rectum by base –> evacuation. Interaction between base and drug may prevent absorption.
What are some formulation factors that have to be taken into consideration for suppositories?
- Lipid-water partition coefficient of drug vs nature of base: principle of opposite characteristics
- Melting point or solubility of base
- Particle size: if not soluble in the base the smaller the particle size, the greater the rate of dissolution and absorption. Less mechanical irritation (also less sedimentation during preparation)
- Suspended drug will sediment through molten base to the mucosa where it requires wetting with rectal fluid prior to dissolution
- Properties of the base:
> irritancy of rectal mucosa –> potential evacuation
> interaction with drug to affect absorption
- Viscosity of liquefied base (affects preparation and release of drug):
> leakage may occur with low viscosity
> rate of spreading of base around rectum
> transport of dissolved drug in liquefied base
> sedimentation during preparation
How does the drug:base characteristics affect the release rate of drugs?
- Oil-soluble drug: oily base = SLOW RELEASE; poor escaping tendency
- Water-soluble drug: oily base = RAPID RELEASE
- Oil-soluble drug: water-miscible base = MODERATE RELEASE
- Water-misible drug: water-miscible base = MODERATE RELEASE, based on diffusion
How is suppository bases based on solubility
See attached image
Discuss the properties of fatty (oleaginous bases). Provide some examples
Theobroma Oil (cocoa butter)
- Limited use – largely superseded by synthetic fatty bases
- Triglycerides of oleopalmitostearin and oleodistearin
- Melting range 30-36oC
- Bland and soothing on rectal mucosa
- Polymorphism: overheating may result in formation of γ crystals (mp 15oC) or α crystals (mp 20oC) – won’t set. Will eventually (days) revert to stable β crystals (mp 34-35oC).
- Poor water absorption
- Expensive
- Melting point reduced by a number of medications – need to add waxes to formulation to increase mp.
Synthetic fatty/oleaginous bases
- Less prone to oxidation than TO (hydrogenated removing double bonds)
- Often capable of absorbing more water than TO - hydroxyl numbers relate to amount of mono- and di-glycerides present –> high number = increased capacity to absorb water
- Better contraction on cooling than TO
Examples of synthetic fatty bases: witepsol, fattibase, wecobee
Witepsol (triglyceride of saturated vegetable fatty acids with monoglycerides)
- Solidifying point unaffected by overheating
- Melting range: 33.5-35.5oC
- Difference between melting and solidifying only 1.5-2oC – solidify quickly in the mould
- Contracts a little on cooling – lubricant not needed theoretically – in practice use Soap Liniment
- Ranges available with different MP and hardness
- Greater capacity to absorb water than TO
- Disadvantage: brittle if cooled too quickly
See rest of synthetic fatty bases in images
What are some advantages and disadvantages of glyco-gelatin base?
Advantages
- can incorporate wide range of medicaments
- suitable for vaginal delivery (after heat treatment)
- Can be stored at room temperature
Disadvantages
- physiological effect: laxative due to osmotic effect (cf glycerol suppositories) = may not be desirable –> limited usefulness
- Hygroscopic: dehydration effect on mucosa and irritation – moisten with water prior to insertion
- Hygroscopic: must protect from atmospheric moisture on storage
- Microbial contamination likely: preservative required for long-term storage
- Long preparation time, mould lubrication required –> oily lubricant
Compare fatty bases with water-miscible/water-soluble bases
How are calculations performed in suppositories
Suppositories are filled by volume, not weight. Mould needs to be calibrated for each base.
- If a specific dose of drug is required in each unit (as opposed to a % formula), then the amount of base displaced by the drug and excipients must be determined.
- Displacement values for various drugs in fatty bases (based on Theobroma Oil) are reported in official references eg APF and PCx 11
- PEG and Glyco-gelatin bases are 1.2x as dense as fatty bases and this conversion factor can be used to determine the displacement in those bases.
See attached image for displacement principles
What is the displacement value? How to calculate it?
Displacement Value (DV) or Density Factor is the amount of ingredient that displaces 1g of fatty base or 1.2g of PEG or Glyco-gelatin base.
- DV: the quantity (g) of medicament that displaces 1g of the base.
- Eg hydrocortisone acetate (DV 1.5): 1.5g HC displaces 1g T.O. base (or 1.2g of Macrogol or glyco-gelatin base)
- 5 g displaces 1 g
- 8g displaces xg
x= 0.8/1.5
see attached image for another example (Always calculate for 3 extra suppositories)
How to administer suppositories rectally?
See attached image
