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
What are the properties of an ideal suppository base?
- Solid at room temperature
- Melts at body temp or dissolves in body fluids
- Non-toxic, non-irritant and pharmacologically inert
- Chemically inert and compatible with any medicament
- Easily moulded and removed from mould (contract slightly on cooling)
- Physically and chemically stable during preparation (heat) and on storage
- Good mechanical strength – resistance to handling
What are the 2 types of suppository bases?
- Fatty or oleaginous bases
- Water soluble and water miscible bases
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
Why are surfactants added to fatty bases? What are some examples of these surfactants?
Surfactants may be added to fatty bases to aid the dispersal of medicaments and/or wetting of the dispersed medicament with rectal fluid.
- Act as de-glomerators to avoid medicament caking in the melting base (in vivo).
- Aid spreading of melted base in rectum
- Render fatty bases more hydrophilic – may be preformed emulsions or able to disperse in aqueous fluids
- Surfactants have variable effects on drug absorption from suppositories
- Formation of w/o emulsion is likely to impair release of a water-soluble drug
Surfactants that can form water dispersible suppositories include: polyoxyl 40 stearate, polysorbates (tweens), and sodium lauryl sulfate
Suppocire® - mono-, di- and tri-glyceride esters of fatty acids with polysorbate 65
Fattibase® - triglycerides from palm, palm kernel, and coconut oils with self-emulsifying monostearin and polyoxyl stearate
Discuss the properties of water-soluble and water-miscible bases. Provide some examples
Glyco-gelatin: a mixture of glycerol and water gelled by addition of gelatin (amount of gelatin controls rigidity of gel)
Two types of gelatin available: type A and type B
Type A: from acid hydrolysis –> cationic below pH 7-9
Type B: from alkaline hydrolysis –> anionic above pH 5
Incompatible with oppositely charged ingredients eg Ichthammol (anionic) cannot be used with Type A
> Dissolve slowly in rectal fluids
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
What are some advantages and disadvantages of polyetheylene glycols (macrogols) –> water-soluble/water-miscible base?
Polymers (hardness increases with MW):
MW < 600 are liquids
MW > 1000 wax-like liquids
Advantages
- Can be formed by fusion or compression
- Components adjusted to provide desired properties
- No laxative effect – but may irritate mucosa
- Microbial contamination less likely than glyco-gelatin
- Significant contraction on cooling – no lubricant needed
- MP above body temp; dissolve and disperse slowly – sustained release
- Storage at room temperature
- Forms a high viscosity solution – leakage unlikely
- Good solvent properties
- Forms suppository with smooth appearance
Disadvantages
- Hygroscopic –irritation reduced by dipping in water prior to use
- Potential poor drug release – due to good solvent properties of and viscosity of liquefied base
- Incompatibilities eg bismuth salts, ichthammol, benzocaine, phenol, sulfonamides, aspirin, silver salts, quinine, clioquinol
> sodium barbital, camphor and salicylic acid crystallise out of PEG bases -
>some plastics eg polystyrene, polyethylene –> storage considerations
- Brittleness
Polybase® is a pre-blended suppository base – macrogols and polysorbate 80
Compare fatty bases with water-miscible/water-soluble bases
What are some excipients found in suppositories?
- Viscosity modifying agents eg Colloidal Silicon Dioxide 1-2% may be added to suppository formulation as a suspending agent to prevent sedimentation of drug during pouring
- Hardening agents – raise melting point of base (eg beeswax) or increase gel strength (extra gelatin in glyco-gelatin base).
- Adsorbents – liquid actives adsorbed onto eg starch
- Surfactants/Emulsifying agents eg emulsifying wax, wool fat, wool alcohols, polysorbates
- De-glomerating agents – eg lecithin – reduce the attraction between particles when high concentrations are used – improves the flow of dispersion.
- Antimicrobial preservatives – needed for water-miscible, water-soluble bases (glyco-gelatin) where long shelf life required – usually methyl or propylparaben used
- Antioxidants eg.butylated hydroxyanisole (BHA), alkyl gallates
- Colouring agents
- (Lubricants – for removal of suppository from mould)
