Formulations Flashcards
Rectal drug delivery?
Most useful when the oral route is not available. This could
be due to nausea, trauma, oesophageal stricture (where the patient can’t swallow), post-operative (effect of anaesthetic) or uncooperative (children, psychiatric patients, elderly – dementia, unconscious).It is also used where drugs are not stable in the upper GIT, due to acid hydrolysis by enzymatic degradation, extensive first-pass metabolism or causing unwanted GI side effects.It can be used to treat local conditions e.g. astringents to treat haemorrhoids, steroids to treat colitis, glycerine to treat laxatives.
Issues with rectal delivery?
There is a strong aversion to rectal drug delivery in the UK, because there of patient acceptability and issues with absorption; absorption is slow & incomplete, with variations in the absorbed dose inter-subject (between patients) and intra-subject (between doses).
Anatomy and physiology of the rectum?
The rectum is the last 1.5-2cm of the GI tract and is anatomically part of the colon. The rectum is divided into two parts: the ampulla is the main body of the rectum (80% of the volume) and the anal canal.The rectum is a hollow organ, which is usually empty as faecal matter is stored further up in the colon. It has a flat surface, with 3 major folds. There are also 3 veins that drain from the rectum:
VEIN
- Middle haemorrhoidal vein
Superior haemorrhoidal vein
o This vein drains to hepatic portal vein – drugs that are absorbed into the superior HV
may undergo first-pass metabolism - Inferior haemorrhoidal vein
The anal canal is squamous stratified epithelium and is primarily protective in nature
it is not good for absorption. The ampulla has similar epithelium to the rest of the GIT. It has simple columnar epithelium (80%), one cell layer, no villi but goblet cells to produce mucus so primarily absorptive in nature; it is good for absorption.
There is 300cm of rectal wall
– not a huge surface area to facilitate absorption, but the epithelium of the ampulla is very thin, aiding absorption. The rectum secretes mucus (~3 mL) with a pH of 7.5, however it does not have a buffer capacity. As a result, a very acidic formulation will alter the pH of the rectum until clearance.
There is a high rate of motility, sufficient to spread most viscous molten bases over entire area.
What are Rectal formulations?
Solids – suppositories
These are the most common formulation for rectal delivery. Suppositories are shaped specifically so the pointed (but blunt) end is inserted and the tapered end is held during insertion. They are made by incorporating the fine powder of drug into melted base (usually triglyceride wax). The size of the mold is defined by volume of (usually fatty base) to give the final required weight. A ‘displacement’ calculation must be performed to find the volume of base displaced by added ingredient(s).
There are water-soluble bases available,
however these are used for constipation (glycerin mixtures) only, because there is insufficient fluid in the rectum for dissolution so fluid may be drawn from the mucosa causing irritation.
Fat-soluble bases are more commonly used
Theobroma oil was previously used but is no longer employed due to polymorphic forms, poor mold-releasing properties, has low softening temperature, is chemically unstable and expensive. Now, adeps solidus (Witepsol) is used; it is a semi-synthetic mixture of triglycerides, meaning that its stability can be modified for optimum release.
Drug release from suppositories
Suppositories tend to melt at 30oC, melting, spreading the drug which may dissolve in the rectal fluid. The drug can have a local affect or may diffuse across the rectal wall (transcellularly). If it is absorbed via the middle or inferior veins, it is systemically circulated. They must be water soluble to be available for absorption and lipid soluble to allow partitioning into the membrane. They should be small particles (50-100μg) to favour dissolution but prevent agglomeration.
Advice to patients on administering suppositories
If necessary, empty bowels (and wash hands). Remove wrapping from suppository and either in a squatting position or lying down with one leg straight and the other bent, firmly push the suppository into the rectum far enough that it won’t slip out (and wash hands). Close legs and sit still for a few minutes, avoiding emptying bowels for at least one hour.
Formulation issues relating to the base
- Viscosity
o The higher the viscosity, the slower the rate of sedimentation so the suppository will
be more homogenous Melting point of base
o Bases should melt at 30-35oC * Compatible
o Must be non-toxic
o Allows for wetting and release
Displacement value
The displacement value can be defined as the volume of drug that displaces 1 gram of suppository base; e.g. lidocaine has a DV of 0.5; 0.5g of lidocaine displaces 1g of base.
The suppositories will be made using a 4g mold and each suppository will contain 10mg Lidocaine. You need to supply 55 suppositories. Given that the displacement value of Lidocaine in the oily base is 0.5, calculate how much base and active ingredient are required if a surplus of 5 suppositories are to be made.
Liquids - enemas
Liquids include solutions/ suspensions; they are usually aqueous but can be oily .
* High volume (~100 mL) – this volume is too large for the rectum, but the aim is to
administer to the upper colon, to treat local conditions such as inflammatory bowel
disease.
* Micro-enema (~3-5 mL) – this is ideal volume for rectal delivery. It is very useful for
treating status epilepticus with diazepam where oral route is not available of when injection is not desirable.
Enemas
are constituted of the active ingredient, vehicle and aids to solubility and stability. They do not usually contain preservatives because the GIT harbours many microorganisms anyway.
