Routes Flashcards
What are the benefits of nasal drug administration? [9]
- Avoidance of 1st pass
- Can be used to administer drugs that are sensitive to intestinal metabolism.
- Can be used for acid-sensitive drugs (e.g. peptides)
- Can be used for polar compounds with poor oral absorption.
- Drops and sprays are easy for young and elderly to use.
- Small, lipophilic drugs can diffuse through nasal epithelium and enter systemic circulation. BA up to 100%.
- Large surface area and highly vascularised
- Rapid delivery possible.
- CNS delivery possible.
What are the disadvantages to nasal drug administration? [4]
- Mucus barrier present, contains enzymes which may degrade drugs.
- Rapid mucociliary clearance - drug ends up being swallowed.
- Poor absorption of drugs >500 Da, so delivery of large molecules is limited to potent drugs.
- Variability and adverse reactions.
How can we improve nasal delivery of drugs? (particularly peptides) [3]
- Alter the mucus layer - surfactants and bile salts decrease mucus viscosity and have been shown to increase the absorption of drugs.
- Increase contact time with the nasal epithelium - delivery to different areas of the nasal epithelium, the use of mucoadhesives.
- Penetration enhancers - reversed micelle formation (bile salts), lipid extraction (surfactants), tight junction modification (EDTA, bile salts).
How can we alter the mucus layer in the nasal cavity to improve drug delivery? [2]
Use surfactants and bile salts to decrease mucus viscosity.
How can we increase the contact time of drugs delivered nasally with the nasal epithelium?
Use mucoadhesives such as Alginate, PLGA, Sephadex, Lactose. Target delivery to certain areas of nasal epithelium.
How can drugs enter the CNS from nasal delivery?
Olfactory epithelium, small SA but effectively an area where the BBB is not present.
Drugs can enter brain directly via paracellular diffusion of axonal transport through olfactory nerves, e.g. dopamine and cocaine.
Why does the presence of mucus present a barrier to nasal drug delivery?
- Acts as physical barrier drugs must cross.
- Can bind drugs - electrostatic interactions or H-bonding.
- Contains enzymes which may actually degrade drugs: neutral endopeptidase, carboxypeptidase N.
Which factors promote the clearance of nasal mucus and thus increases nasally delivered drug clearance? [6]
- Common cold.
- Rhinitis
- Asthma
- Hayfever
- B-Adrenergics
- Cholinergics
What factors inhibit mucus clearance in the nasal cavity? What effect does this have on nasal drug delivery?
- Anaesthetics
- Antihistamines
- Propranolol
- Bile salts.
These factors could cause increased nasal absorption of drug by increasing residence time. Clearance in obstructed nostrils is significantly reduced.
What is TJM?
Tight Junction Modifying peptide which can significantly improve intranasal absorption of human peptides.
How can devices be used to increase nasal absorption?
The ViaNase system disrupts normal airflow via a vortex and maximise nasal deposition of particles leading to increased residence time and minimisation of lung deposition. Also OptiNose Delivery System.
How does the ViaNase system increase nasal absorption of a drug?
The ViaNase system disrupts normal airflow via a vortex and maximise nasal deposition of particles leading to increased residence time and minimisation of lung deposition. Also OptiNose Delivery System.
What are the advantages of pulmonary drug delivery? [6]
- Rapid onset (esp. local)
- Large SA.
- High blood flow.
- High permeability (one cell thick barrier between blood and air)
- Low metabolism of drugs
- Avoidance of first pass metabolism.
What are the disadvantages of pulmonary drug delivery? [4]
- Complex delivery devices are needed.
- Reproducibility - patients cannot into respiring properly.
- Mucus.
- Clearance.
How does the Technosphere device improve pulmonary drug delivery?
- Small particle size.
2. High surface area.
By which routes can drugs be absorbed from pulmonary delivery?
- Transcellular pathway.
2. Paracellular pathway.
What is the transcellular pathway?
Passive diffusion of small, lipophilic drugs through the epithelium down a concentration gradient.
What type of drugs are absorbed via the transcellular pathway?
Small, lipophilic drugs.
What types of drugs are absorbed via the paracellular pathway?
Small, hydrophilic drugs.
What is the paracellular pathway for drug absorption?
Involves the passive diffusion of small, hydrophilic drugs down a concentration gradient between the cells of the epithelium. Slower than transcellular route but tight junctions are looser than other mucosal barriers.
Which route is faster for drug absorption, transcellular or paracellular?
Transcellular. Paracellular is slow.
What are the main factors affecting drug absorption via the pulmonary route? [5]
- Mucus
- Surface area
- Blood supply
- Epithelial thickness
- Enzymatic activity
How does the presence of mucus influence drug absorption from the pulmonary route?
Mucus provides a viscous barrier to absorption.
The thickness varies throughout the lungs.
The size of a drug can affect the diffusion through mucus and the mucociliary escalator can result in clearance of trapped drug particles.
How does the epithelial thickness in the lungs affect pulmonary drug delivery?
The thicker the epithelium the harder it will be for drugs to diffuse across/through. Thickness varies throughout the lungs.
How can enzymatic activity in the lungs influence drug absorption? Which enzymes are present?
Enzymes can deactivate drugs: CYP isoenzymes, esterases, peptidases, monoxygenases, transferases.
What is the initial hurdle in nasal drug delivery?
Deposition in the nasal cavity. Liquid drops are spread throughout the cavity, aerosols or powders are distributed according to particle size.
What is Fick’s 1st law?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
What does ‘h’ represent in the equation for maximum flux/Fick’s 1st law in general?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
What does ‘D’ represent n the equation for maximum flux/Fick’s 1st law in general?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
What does ‘K’ represent n the equation for maximum flux/Fick’s 1st law in general?
Jmax = [(Ksc/v * D)/h) * Csatv] Csatv = saturation of drug in vehicle (ug cm-3) D = diffusivity of the drug in membrane. Ksc/v = SC/vehicle partition coefficient. h = diffusion path-length across barrier.
How does mucus influence the terms in Fick’s 1st law equation?
Thickness varies so influences ‘h’ the diffusion path-length across the barrier.
Solubility/diffusivity of drug can change depending on the composition of the mucus so also ‘D’.
Also the partition coefficient K is influenced.
What are the advantages of drug delivery via the buccal and sublingual mucosa? [7]
- Accessible with good blood supply.
- Drains into internal jugular vein so avoidance or 1st pass effect.
- Good permeability of buccal + sublingual epithelia - relatively thin and non-keratinised, looser.
- Extended contact times possible, use of ER/SR formulations possible.
- Saliva can aid the absorption of drugs by rapidly solubilising them.
- Limited metabolism/enzymatic activity.
- Low interpatient variability.
How is the buccal and sublingual epithelia an attractive site for drug absorption?
Good permeability, relatively thin and non-keratinised. Looser with a good opportunity for paracellular uptake of large molecules such as insulin.
How can saliva aid drug absorption via the buccal and sublingual routes?
Can rapidly solubilise drugs.
Why is metabolism of drugs delivered via buccal and sublingual routes less of an issue than enteral delivery of the same drugs?
Low enzymatic activity.
What are the disadvantages associated with buccal and sublingual delivery? [6]
- Excess saliva can rapidly clear drug from mouth into GI tract.
- Mucus acts as a physical barrier.
- Taste of formulations may be objectionable and there may be some irritation.
- Dosage form dislodgement and swallowing due to eating/drinking.
- High MW drugs must be highly potent due to limited uptake.
- High development costs.
Why can developing drugs for enteral delivery be a more attractive prospect than buccal/sublingual administration?
Lower development costs.
How can saliva negatively influence buccal/sublingual drug administration?
Excess saliva can rapidly clear drug from the mouth into the GI tract.
What are 4 examples of mucoadhesives which can be used to enhance nasal drug delivery by increasing contact time?
Aliginates, Lactose, PLGA, Sephadex.
The rate and extent of drug absorption after intravaginal administration may vary depending on: [5]
The rate and extent of drug absorption after intravaginal administration may vary depending on: vaginal physiology, age of the patient, stage in the menstrual cycle, pathological conditions formulation factors.
What current vaginal drug delivery systems exist? [8]
Creams Tablets Gels Suppositories Foams Ointments Tampons Inserts/implants
What are the problems associated with current vaginal drug delivery systems? [3]
Messiness
Leakage
Low residence time
All leading to poor patient compliance and loss of therapeutic efficacy.
How do vaginal secretions influence vaginal drug delivery?
The vaginal discharge is a mixture of multiple secretions that collect in the vagina from peritoneal, follicular tubal, uterine, Bartholin’s and Skene’s glands.
In presence of moisture, solid dosage forms should ideally disperse in the vaginal canal immediately after insertion to avoid inconvenience to the users.
How do vaginal enzymes influence vaginal drug delivery?
The human genital tract has lower enzymatic activity leading to less degradation of protein and peptide drugs in the vagina than the gastrointestinal tract.
How does the vaginal pH influence vaginal drug delivery?
Acidic 3.5-4.5 and is maintained within that range by bacterial conversion of glycogen from exfoliated cells to lactic acid.
The pH changes with age, stage in the menstrual cycle, infections, estrogen levels and variations in the levels of cervical mucus. The control of vaginal pH is a critical factor for the successful vaginal delivery of drugs.
What are the two routes of vaginal drug absorption?
- Intravaginally to the vaginal epithelium
2. Transvaginally through the vaginal mucosa to uterus and systemic circulation.
How can vaginal drug delivery by improved? [3]
Penetration enhancers
Solubility modifiers
Mucoadhesive agents
What are the most preferred penetration enhancers for vaginal delivery? [7]
Surfactants Bile Salts Benzalkonium Chloride Hyaluronic acid Polyethylene glycol Ethoxydiglycol Interesterified stone oil
Water-soluble drugs are good candidates for vaginal drug delivery. How can the aqueous solubility of a non-water-soluble drug be increased?
Solubility modifying agents: citric acid ethylenediamine-tetraacetate, sodium metaphosphate polyvinylpyrroldone, sorbitan tween 80 cyclodextrin
What mucoadhesive agents are available to increase the length of contact time between a formulation and the vaginal mucosal surface?
Polycarbophil Hyaluronic acid Chitosan Sodium carboxymethyl cellulose Carbopol Xanthan gum Sodium alginate
Surfactants
Penetration enhancers
Citric acid
Solubility modifying agent
Tween 80
Solubility modifying agent
Hyaluronic acid
Penetration enhancers + mucoadhesive
Bile Salts
Penetration enhancers
Xantham gum
Mucoadhesive
Interesterified stone oil
Penetration enhancers
Benzalkonium chloride
Penetration enhancers
Cyclodextrin
Solubility modifying agent
Polyethylene glycol
Penetration enhancers
Sorbitan
Solubility modifying agent
Ethoxydiglycol
Penetration enhancers
Sodium metaphosphate
Solubility modifying agent
Chitosan
Mucoadhesive
Carbopol
Mucoadhesive
Sodium alginate
Mucoadhesive
Name three types of vaginal ring systems for sustained release:
Reservoir
Matrix
Pod
In pregnancy how is the vaginal mucosa different?
The cells and thicker and there is more vascularisation.
In the follicular phase what are the cells of the vaginal epithelium like?
Thick
Tight
Cohesive barrier.
Not as favourable to drug transport.
In the luteal phase, what are the cells of the vaginal epithelium like?
Thin
Loose
Porous
More favourable to drug transport.
Drug delivery via the vagina is more effective during what phase?
Luteal phase: Cells are: Thin Loose Porous More favourable to drug transport.
What are the three mechanisms by which particles are deposited in the lungs?
Inertial impaction
Sedimentation
Brownian motion.
TJM
Tight Junction Modifying protein used as a penetration enhancer in the nasal cavity.
What are the three forms of penetration enhancements we can utilise in nasal drug delivery?
Reverse micelle formation
Lipid extraction (surfactants)
TJM, EDTA, bile salts.
Name two enzymes found in nasal mucus that can degrade drugs
Neutral endopeptidase
Carboxypeptidase N
What type of epithelium is the nasal epithelium?
Pseudo-stratified columnar epithelium
Large SA due to microvilli.
What is the major function of the nasal cavity?
Air conditioning,
Smell = minor.
Increased paracellular absorption occurs via the buccal and sublingual routes why?
Lack of TJs
