Routes Of Administration Flashcards
What is the definition of a medicine?
Drug delivery system
What is the definition of a drug?
Active pharmaceutical ingredient (API), therapeutic agent
What is the definition of a formulation?
Recipe for making a medicine, including the ingredients and processes
What is the definition of an excipient?
Ingredient that is not the drug e.g a preservative
What is the definition of a dosage form?
Physical form of the medicine e.g tablet, capsule
What is the definition of pharmaceutics?
Science of medicine design and manufacture
What is the definition of preformulation?
Characteristic of the drug (e.g MW, log P, solubility)
What is the rationale for the formulation design?
Right dose, right place, right time
What is the aim of the formulation and what has to be considered?
Aim is optimal drug delivery to the therapeutic target to maximise therapeutic efficacy and patient safety
Drug properties e.g solubility
Routes of administration e.g local vs systemic, target specificity
Use and patient need e.g elderly
How can a formulation enhance a medicine? How can this be achieved?
Drug delivery and targeting, processability and manufacturing, usability and user acceptability, stability
Achieved using excipients or medical devices
What is Lipinski’s rule of five for orally active drugs? And what does this rule assume?
Molecular weight <500
Log P <5
H-bond donors <5
H-bond acceptors <10
Assumes absorption by passive diffusion
What are the ideal properties for skin absorption?
Molecular weight <500 Da
Log P 1-4
How do you calculate log P?
Log P = log (conc in octanol/conc in water)
Why is log P important?
It determines permeability across biological membranes which effects absorption, and, ultimately efficacy and safety
Affects formulation decisions- solvent choice, dosage form (e.g emulsion vs suspension vs solution)
What is the biopharmaceutics classification system (BCS)?
Framework for grouping drugs by solubility and intestinal permeability based on empirical data
What is the BCS used for?
Predicts Bioavaliability e.g how much of the drug will enter the bloodstream
Establish bioequivalence- will formulations perform the same in patients
Class 1 drugs (most permeable and most soluble) may get a biowaiver- expedites regulatory approval and saves costs
What is solubility?
Maximum amount of substance (solute) that can be dissolved in a given medium (solvent)
Why is solubility important?
-affects drug dissolution and absorption
-determines oral bioavailability (BCS)
-underpins formulation decisions
-many drugs that are poorly water soluble may have increased solubility and absorption in a fatty intestinal environment (e.g after a meal)
-predict formulation stability to be predicted
Why is preformulation important?
Determines the physiochemical properties of the drug- compatibility and stability, ease of formulation (e.g solubility), processability (e.g flow properties)
Informs decisions about the best formulation strategy- suitable dosage form and route of administration.
What does the pka determine? How do you work out pKa?
The extent of ionisation
pKa= -log ([H+][A-]/[HA])
Why is molecular dissociation important?
Affects drug solubility and absorption- ionised form is more soluble, but non-ionised form better absorbed
Varies with body site e.g different parts of GI tract- Accounted for in deciding route of delivery and formulation, may be leveraged e.g enteric coated formulations
Can affect drug formulation instability- ionised drugs may form insoluble precipitates with incompatible counter ions
How is a drug made into a medicine?
Through formulation
What is the purpose of formulation?
To enhance therapeutic efficacy and patient safety through optimal drug delivery, by ensuring that the right dose is delivered at the right place at the right time
What are the advantages of the oral route?
Most common
Simplest, convenient and safe (no infection risk)
Modified release formulations available
High surface area with good absorptive capacity
What are the disadvantages of the oral route?
Slower onset of action
Variable absorption e.g changes with age, food, gender
Hostile environment e.g GI secretions, enzymes, pH
First pass metabolism
Difficult to reverse therapy
GI irritation
What is the average pH of the stomach fasted and fed?
1-2 fasted, 4-5 fed
What is the average pH of the small intestine?
5-7
What is the average pH of the large intestine/colon?
6.5-7
How does fasted vs fed change the environment?
Fed increases pH, increases fluid volume, increase in bile salt
What is the most common type of tablet?
Disintegrating tablet
What are all the different types of tablets?
Disintegrating, Gastro-resistant, modified release, dispersible, lozenges, sublingual and buccal, effervescence.
What are the advantages of tablets?
- Convenient to take and handle.
- Better chemical, physical and microbiological
stability, compared to liquid dosage form – longer
shelf life. - Precise dosing of drug.
- Relatively cheap to mass produce with consistent
quality.
What are the quality attributes that all tablets must follow?
- Include the correct dose of drug.
- Be consistent in weight, size and appearance.
- Release drug in a controlled and reproducible manner.
- Be biocompatible and not cause harm to patients.
- Be of sufficient mechanical strength.
- Be chemically, physically and microbiologically stable.
- Be a product acceptable to patients.
- Be packed in a safe manner.
- Be resistant to attrition and fracture.
Why disintegrating tablets used? and what are the two types?
Intended to be swallowed and to release the drug in a relatively short time to aid fast and complete drug release once in the digestive fluids.
– Uncoated tablets - often referred to as conventional or plain tablets.
– Coated tablets – have a smooth surface which is often coloured and polished, but the coating does not alter the release profile.
What is the purpose of gastro-resistant tablets and how are they prepared?
- They are delayed-release tablets.
- Intended to resist the gastric fluid and to release the drug in the intestinal fluid.
- Prepared by covering the tablets with a gastro-resistant coating or from granules or particles already covered with a gastro-resistant coating.
What are modified release tablets? What are the three types?
- Coated or uncoated tablets that contain special excipients or are prepared by special procedures, or both, designed to modify the rate, the place or the time at which the drugs are released.
– Prolonged-release – drug is released slowly at a constant rate.
– Delayed-release – drug is released some time after administration.
– Pulsatile-release – drug is released from the formulation in two or more pulses.
What are the 3 types of dispersible tablets?
- Dispersible tablets can be coated or uncoated – intended to be dispersed in water before oral administration, giving a homogeneous dispersion.
- Orodispersible tablets are uncoated tablets – intended to be placed in the mouth where they disperse rapidly before being swallowed.
- Soluble tablets can be uncoated or film-coated – intended to be dissolved in water before administration.
What is the most common technique for tablet manufacturing?
Powder compression
What are the three main stages in tablet formation?
- Die filling
– Powder flows down from a hopper into the die - Tablet formation
– Upper punch comes down into the die compressing
powder into tablet i.e. compression stage
– When required applied force is reached, upper punch
moves upward i.e. decompression stage - Tablet ejection
– Lower punch rises to eject the tablet and a pushing
device removes the tablet from the die.
What are the two main types of tablet press?
Single punch press, rotary press
What are effervescent tablets?
Uncoated tablets intended to be dissolved or dispersed in water before administration
How do effervescent tablets dissolve in water?
Contain a weak acid and a carbonate/bicarbonate which react rapidly in the presence of water to release CO2
How do effervescent tablets provide a faster drug absorption?
High carbonate content results in a buffer solution which temporarily increases the pH of the stomach.
Leads to faster emptying of the stomach content
Allows drugs to enter intestine for faster absorption
Minimises stomach irritation
What are sublingual tablets?
Tablets placed under the tongue
What are buccal tablets?
Placed in the buccal cavity (under the cheek or between the upper lip and gum)
What is the advantage of sublingual or buccal tablets?
Provide rapid drug release for systemic effect without first-pass liver metabolism
What are lozenges and how do they work?
Hard solid, single-dose preparations
Intended to dissolve slowly in the mouth when sucked
What are lozenges usually used for?
Local effect in the oral cavity/throat.
How does the powder compression technique work? (3 main stages)
Die filling- Requires two punches and a die
Tablet formation- Apply force, then bonds are formed between particles during compression which causes a coherent compact to be formed.
Tablet ejection- lower punch rises and ejects tablet via a pushing device which removes tablet from die
What is the single-punch press mainly used for?
Used during formulation development and production for clinical trials
When is the rotary press used?
Large scale production (10,000 tablet/minute)
What properties of a powder mix have to be controlled for a successful tablet formation?
Homogeneity and segregation tendency (under/over mixing), flowability, compression and compaction, friction and adhesive properties.
What are the commonly used excipients?
Filler, disintegrant, binder, anti-adherent, lubricant, glidant.
Why is filler (diluent) used?
To increase the bulk volume of the powered and increase tablet size
What is the most commonly used filler and why is it used?
What is the limitation?
Lactose
Readily dissolved in water, pleasant taste, good compactability, non-hygroscopic.
Lactose intolerance
Why is disintegrant used?
Allows tablet to break up into small fragments when in contact with liquid. Promotes rapid drug dissolution thus Bioavaliability.
What is the most commonly used disintegrant and why is it used?
Starch
Swells when in contact with water, this disrupts the tablet and provides a larger surface area during dissolution
How much disintegrant can be added to the formulation?
Up to 10%
Why are binders used?
Ensures granules and tablets can be formed with the required manual strength
What are the two types of binders that can be used?
Soluble binders-starch, sucrose
Dry binders- microcrystalline cellulose
Why is a glidant used?
To improve powder flowability by reducing cohesion between particles
Why is colloidal silica more commonly used as a glidant?
Silica particles are very small, can adhere to the surface of other ingredients, reduce inter-particle friction thus improve flow
Why is lubricant used?
Lowers friction, improves tablet formation and ejection
What is the most commonly used lubricant?
Magnesium stearate
Why is anti-adherent used?
Reduces adhesion between powder and punch faces, prevents particles sticking to punches
What are the advantages of capsules?
• Easy to swallow (smooth, slippery).
• Easy to handle and carry.
• Easy to identify (wide range of colours).
• Mask taste and smells of drugs using odourless and
tasteless shell.
• Minimal excipient needed.
• Minimal pressure is required to compact the materials.
• High drug loading is possible (up to 90%w/w drug fill) as
compared to tablets.
What are the disadvantages of capsules?
• Not suitable for highly soluble substances like
potassium chloride, potassium bromide, ammonium
chloride, etc… can cause sudden release in the
stomach resulting in irritation.
• Not suitable for highly deliquescent materials – may
dry the capsule shell causing brittleness.
• Product cost is mostly more than oral tablets.
What are the two types of capsules?
Hard capsules (two piece)
Soft capsules (one piece)
What raw materials are used in capsules?
Gelatin, colourants, water, plasticisers (soft capsules), optional materials e.g preservatives
What are the two processes for extracting gelatin from animal collagen?
Acid process, alkali process
What are the properties of gelatin?
Non toxic and non irritant
Soluble in biological fluids at body temp
Produces strong flexible film
Still mobile when in a solution of high concentration at 50°C
Changes from solution to gel easily
What are the problems with gelatin?
What could an alternative be?
Gelatin allergy
Not suitable for vegetarians and vegans
Not suitable for certain ethnic groups or religious beliefs
Alternative- semisynthetic polymer Hydroxypropyl methylcellulose (HPMC)
How many sizes are there of hard capsules?
8
What must fillings be for hard capsules?
-Free from large amounts of moisture
-Not react with shell
-Not leak out
-Have good powder flowability
-Not be adhesive
-Be capable of being filled uniformly
What are the three types of filling materials for hard capsules?
Dry solids, semi solids, non aqueous liquids
What are the three types of capsule filling machines?
Hand operated
Semi-automatic
Fully automatic
How many steps does it take to form a soft capsule?
Single step process
What are the advantages of soft capsules?
Improved drug absorption – drug is already in
solution (especially for poorly soluble drugs).
• Convenience, ease of use, no unpleasant taste.
• Enhanced safety: no airborne powders during
manufacture or handling (e.g. cytotoxic drugs).
• Dose uniformity and precision: drugs are in solution
during manufacturing which provides better
homogeneity and flow than powder.
• Product stability: drug is protected by the softgel
shell and liquid vehicles against oxidation, moisture
What are the different types of soft gels?
Oral softgel, chewable, twist-off, suckable, meltable (pessaries)
What is the softgel shell composition?
Gelatin (40%), plasticizers, water, flavours and dye
What are the different types of filling materials for matrices for softgels?
Lipophillic liquids e.g for steroids, hydrophilic liquids, semi-emulsifying systems
What is the definition of a pharmaceutical solution?
Liquid preparations in which the therapeutic agent and excipients are dissolved in a liquid solvent system.
What are the advantages of oral solutions?
•Fast onset of action (drug already dissolved)
•Dose uniformity is assured.
•Volume of liquid dose can be measured accurately to tailor doses.
•Easy to swallow (especially paediatrics and geriatrics).
•Easy to manufacture compared to other dosage forms.
What are the disadvantages of oral solutions?
•Less stable than solid dosage forms:
major signs of instability:
colour change
precipitation
microbial growth
•Many drugs are poorly soluble in water.
•Unpleasant taste and odours are difficult to mask.
•Packaging costs, transportation an storage (some liquids require cold storage to maintain shelf-life).
What properties must oral solutions possess?
Must be stable
Palatable
Appropriate viscosity
Dose in multiples of 5ml for convenience
At a physiological pH (pH 2-9 can be tolerated)
Concentration needs to be well below saturation solubility to avoid drug precipitation
Why is water the most commonly used solvent for oral solutions? Why is purified water used instead of tap water?
Lack of toxicity, low cost
Tap water contains dissolved substances that could interfere with formulation
What excipients are used in oral solutions and why?
Antioxidants- improve stability by minimising oxidation
Flavouring agents- mask unpleasant taste of drug
Colouring agent- correlate with flavouring agents (e.g red for strawberry)
Viscosity enhancers- improve pouring quality
Preservatives- prevent microbial growth
Sweeteners- improve palatability
What properties must remain the same for an oral solution for the duration of its shelf life?
Physical (e.g. colour, viscosity, odour, taste, clarity).
–Chemical (e.g. within limits for API, total impurities).
–Microbiological (e.g. resistant to microbial growth).
–Therapeutic (e.g. maintain efficacy).
–Toxicological (e.g. no significant increase in toxicity).
•No interactions with the container-closure system.
What factors affect chemical degradation?
High temp, pH, oxygen, UV light, catalysis
How can you enhance solution stability?
Formulate at a suitable pH
Use excipients
Include antioxidants to reduce oxidation
Package in containers that reduce light transmission
Purge solution with nitrogen to create nitrogen headspace
What is a cosolvent system?
Where a water miscible or partially miscible organic solvent is mixed with water to form an aqueous solution.
Why are cosolvents used?
Many drugs aren’t water soluble
Used for ionic drugs where solubility can’t be adjusted by pH control
Non polar drugs dissolve in non polar solvents (e.g poorly soluble in water)
Reducing polarity of solvent can increase solubility
What are cyclodextrins? What are the 3 most important ones?
Family of compounds made up of sugar molecules bound together in a ring.
Alpha cyclodextrin (6-members sugar ring), beta-CD (7 membered sugar ring), gamma-CD (8-membered sugar ring).
Why are cyclodextrins used?
To increase aqueous solubility of drug as upon oral administration drug is released from cyclodextrins and free drug is absorbed)
What is the purpose of surfactants? How do they do this?
Reduce surface tension of liquids, have two regions- hydrophobic and hydrophilic, self assemble to form micelles so poorly water soluble drugs can be dissolved in the micelles
What should you consider when switching between oral formulations of the same drug?
Administration times
Bioavaliability differences (may have to adjust dose)
Excipients (allergy)
Modified release formulations
Site of action
Narrow therapeutic index
Some formulations are not interchangeable
What does topical drug delivery mean?
Administered on tissue surface to treat a local condition
Where is the site of therapeutic action when delivering a drug topically? Why is this?
The site of administration.
Minimises systemic absorption to minimise side effects
How does topical differ to transdermal drug delivery?
Transdermal:
Administered on skin surface, acts at a remote site away from site of administration, requires systemic drug absorption
What does percutaneous mean?
Through skin
What is the definition of an ointment?
Drug dissolved in a greasy base
What are the advantages and disadvantages of an ointment?
Occlusive so promotes skin hydration by minimising transepidermal water loss
Can be difficult to spread-patient acceptability could be low
What is a cream?
Semi-solid emulsion
What does (W/O) or (O/W) mean in reference to creams?
Dispersion of water in oil (W/O) or oil in water (O/W)
What are the advantages of creams?
Longer residence time than lotion
I’m able with skin secretions, easily washable
Excellent patient acceptability
Definition of gel
Semi-solid or viscous liquid, often clear or transparent.
What are the three forms that a lotion could be in?
Solution, suspension or emulsion
What are the advantages of a lotion?
High spreadabikity ideal for covering a large area thinly
Suitable administration on hairy skin
What is the definition of a foam?
Dispersion of gas within a liquid
What is a spray and what are the advantages?
Dispersion of liquid droplets in a gas
Rapid and even coverage of a large surface area
What are the advantages of using a patch for topical drug delivery?
Provides occlusion, dose retention and protection of formulation from environmental contamination
What are the pros and cons of the topical route of administration?
• Advantages:
• Avoid gastrointestinal drug degradation and hepatic first-pass metabolism.
• Non-invasive, thus well accepted by patients.
• Better drug targeting, thus minimal systemic side effects.
• Easy dose withdrawal in case of adverse reactions.
• Convenient: portable and self-administrable.
• Disadvantages:
• Low skin permeability: only a small selection of drugs deliverable, and even then
their uptake is slow.
• Skin irritation.
• Difficult to determine dose accurately (e.g., creams, gels, ointments).
Factors affecting dermal drug transport
• Drug properties:
• Lipophilicity (ideally log P: 1–4).
• Molecular weight (ideally MW < 500 Da).
• Potts & Guy (1992) predicted Kp from log P and MW.
• Anatomical site:
• Barrier thickness.
• Hair follicle density
• Age:
• Thickness, hydration, lipid content and microvascular clearance decline with
age.
• Corneocytes enlarge with age.
• Disease:
• Broken skin: higher permeability—‘Do not use on broken skin’.
• Scaly skin (peeling): impaired permeability barrier, but also often dehydrated,
which reduces permeability.
• Thickened skin reduces permeability due to increased diffusional path length.
What are the different cellular layers of the skin called?
• Epidermis;
• Dermis;
• Hypodermis.
• Appendageal features.
• Permeability barrier.
What is the permeability barrier of the skin called?
Stratum corneum
What is a pharmaceutical suspension?
A pharmaceutical suspension is a liquid disperse system consisting of particles distributed within a liquid vehicle. Appear cloudy not clear.
What is a disperse system?
Two-phase heterogenous system in which an insoluble or immiscible dispersed phase is distributed through a continuous phase.
What does the ‘brick and mortar’ model consist of?
Corneocytes (‘bricks’)- hydrophilic
Extracellular lipid matrix (‘mortar’)- lipophilic
What are the dermal drug transport mechanisms?
Partitioning- from one medium into another (solubility driven)
Diffusion- within the same medium down a conc gradient
Skin permeability- function of the partitioning coefficient and the diffusion coefficient
How do you work out the permeability coefficient?(Kp)
Kp = K (partition coefficient) x D (diffusion coefficient) / h (diffusion path length)
Which dermal route do hydrophilic drugs follow?
Transcellular route
Which dermal route/pathway do lipophilic drugs follow?
Paracellular route
What is the appendageal pathway (shunt route)?
Through hair follicles and sebaceous glands
How can topical drug penetration be assessed?
Diffusion cell and tape-stripping
What are the advantages of the nasal route?
- Easy to administer.
- Non-invasive, painless.
- Avoids first-pass effect
- Low enzymatic activity
- Direct route to brain is possible
- Potential to elicit a rapid onset of action.
- Newer formulations potentially allow for peptide delivery.
- Could achieve better systemic bioavailability than the oral
route:
– Oral Imigran® (Sumatriptan) – dose 25 / 50 or 100 mg
– Nasal Imigran® – dose 5 or 20 mg
– Subcutaneous Imigran® – dose 4 or 8 mg
Where does absorption occur in the nose?
across turbinates and septum
Which cells secrete mucus in the nose?
Goblet cells on the mucous membrane
How are lipophilic drugs absorbed nasally?
Transported by passive diffusion (down conc gradient), by receptor mediated and vesicular transport mechanisms
How are polar drugs absorbed nasally?
Pass through epithelium via gaps between cells (tight junctions) so limited to drug molecular size >1000 Da
Describe how the nose-brain pathway offers a potential advantage for drug delivery.
The olfactory mucosa in the nose is in direct contact with the brain and cerebral spinal fluid, allowing drugs to bypass the blood-brain barrier. This offers a potential route for targeted and rapid delivery to the CNS.
What is mucociliary clearance, and how does it affect drug delivery?
Mucociliary clearance is the process by which cilia on epithelial cells move mucus toward the nasopharynx, clearing foreign substances including drugs. This limits the time available for drug absorption, ideally to within 12-15 minutes.
What are two reasons why intranasal drug delivery might be preferred in an emergency situation?
Intranasal delivery can provide a rapid onset of action and potentially achieve better systemic bioavailability than the oral route. This is particularly beneficial in emergency situations requiring immediate therapeutic effects.
Explain the relationship between drug solubility and its suitability for nasal administration.
A drug must be in solution to be absorbed nasally, but only a limited volume can be administered. Drugs with low aqueous solubility and/or requiring high doses pose challenges for formulation and effective delivery.
How can drug lipophilicity/hydrophilicity influence its absorption from the nasal cavity?
Lipophilic drugs are absorbed quickly via the transcellular route with bioavailability comparable to IV administration. Hydrophilic drugs are absorbed through the paracellular route, offering a much smaller area for absorption, thus limiting their effectiveness.
Explain the effect of molecular size on the rate and extent of drug absorption in the nasal cavity.
The rate and extent of absorption are inversely proportional to the molecular weight of the drug. Drugs under 1 kDa are absorbed efficiently. Particles 10-50 microns in size adhere best to the mucosa, while smaller particles may reach the lungs and larger ones are expelled.
Why might pre-warming oil-based ear drops be necessary?
Pre-warming oil-based ear drops can reduce viscosity, enhancing their spread and distribution within the ear canal for increased efficacy.
Describe the mechanism of action of cerumenolytics.
Cerumenolytics work by softening ear wax and lubricating the ear canal, facilitating its removal. They may also disintegrate the wax, further easing its elimination.
What are Turbinates?
Bony structures located in the nasal cavity that create turbulence in inhaled air, helping to warm, humidify, and filter the air. They are also covered in mucus, which traps foreign particles and helps to prevent infection. The turbinates play an important role in drug absorption from the nasal cavity.
What is otitis externa?
Inflammation of the external ear canal, often referred to as “swimmer’s ear”.
What is bioavailability?
The proportion of a drug that enters the circulation when introduced into the body and so is able to have an active effect.
What is the first pass effect?
The initial metabolism in the liver of a drug absorbed from the gastrointestinal tract before the drug reaches systemic circulation through the bloodstream.
What is paracellular transport?
The transfer of substances across an epithelium by passing through the intercellular space between the cells.
What is transcellular transport?
The transfer of substances across an epithelium by passing through the cell, entering on one side and exiting on the other.
What does parenteral mean?
Drug administration other than via the GI tract e.g the skin
What are all the different drug administration injections?
Intravenous
Intrathecal, epidural and intraspinal
Intra-arterial and intracardiac
Intradermal
Subcutaneous
Intramuscular
Intra-articular
Intraocular
Can you administer water-in-oil emulsions/suspensions via IV?
No because the oil phase/suspended drugs can block blood vessels
What could happen if you administer a hypertonic or extreme pH drug solution via IV?
Cause inflammation and pain at injection site
What are subcutaneous injections also known as?
Hypodermic injections
Where are subcutaneous injections usually administered and why?
Inject into loose connective/adipose tissues below the dermal skin layer. Typically abdomen or upper legs/arms.
Highly vascular site so absorption is rapid and predictable.
What volume can a subcutaneous injection be up to?
Volume up to 1ml
When are intra-arterial injections used?
Only used when IV access cannot be established e.g. pre-mature babies
Why is the intra-arterial route less common than the IV route?
More invasive and less accessible than via the veins
When is the intracardiac route used?
Only in life-threatening emergencies to produce a rapid, local effect in the heart
Where are intradermal injections administered and when are they used?
Inject into skin between the epidermis and dermis
Used for immunological diagnostic tests and vaccinations e.g. BCG
What is the maximum volume that an intradermal injection can be?
0.2ml
How fast is absorption of an intradermal injection?
Absorption is slow as not well-perfused by blood
Where are intramuscular injections usually administered?
Tissue of a relaxed muscle in buttock, shoulder or thigh
Is absorption of intramuscular or subcutaneous faster?
Subcutaneous
Can aqueous or oily solutions/suspensions be administered via an intramuscular injection?
Yes as long as volume less than 4ml
Where is an intrathecal injection administered and why?
Directly into the cerebrospinal fluid (CSF) in the subarachnoid space/spinal canal
Allows drugs to bypass the blood brain barrier and 100% absorption into the CSF
What is the maximum volume for an intrathecal injection? What are some examples of intrathecal drugs?
up to 10ml
anticancer drugs or antibiotics for meningitis
Where is an epidural injection administered?
Given into the epidural space between the dura mater and the vertebrae
What must all intraspinal injections be? and what can they not include?
Must be isotonic aqueous solutions and cannot include preservatives
Where are intra-articular injections administered and what are they for?
Given into the synovial fluid of joints cavities.
For anti-inflammatory drugs to treat arthritic conditions or sports injuries
Where are intraocular injections administered and what are the two sub-classifications?
Administered into the eyes
Intracameral injections (anterior chamber in front of lens) and intravitreal injections (vitreous chamber)
What is the maximum volume for an intracameral injection? What is it usually administered for?
0.1ml-1ml
Antibiotics or local anaesthetics
What is the maximum volume for an intravitreal injection? What is it usually administered for?
Max vol- 0.1 ml minimise risk of damage to retina
Treat ocular disease e.g endophthalmitis
What are the advantages of the parenteral route?
- Most routes allow rapid onset of action.
- Avoids first pass hepatic metabolism thus improves
bioavailability. - Allows higher concentration of drug in the systemic
circulations or local site. - Suitable for unconscious patients, or unable to administer
orally. - Delayed onset of action is possible through intramuscular
injection. - Infusion of drugs for prolonged period is possible to maintain
steady-state plasma level.
What are the disadvantages of the parenteral route?
-Usually requires healthcare professional to administer
-Potential risks during administration e.g. air embolism, haemolysis
-Needle-stick injuries
-Needle phobia and poor patient acceptability
-Formulation and manufacturing costs are higher as require sterile and highly controlled pyrogen-free environment
-Shelf life usually shorter than oral forms
-Extra cost- usually requires refrigerated storage
Why are excipients used?
-Adjust isotonicity
-Adjust pH
-Increase drug solubility
-Increase drug stability
-Increase shelf life
What are the two most commonly used vehicles for injections?
Water for injections
Saline for injections
What can be added to injections to make them more soluble?
Solubilising agents or co-solvents
Why are antioxidants used in injections? and how is it added?
Reduce drug degradation by oxidation thus extend product shelf life
Nitrogen gas bubbled through the drug solutions to displace oxygen in the formulation
What is the acceptable pH range for injectable products? What can happen if it is outside this range?
pH 3-9
Too corrosive so can cause tissue damage
Why are suspending agents used?
Used in suspensions to ensure drug can be readily re-suspended by shaking prior to use
What are the pharmacopeial requirements for parenteral preparations in regards to sterility?
- All parenteral preparations must be sterile.
- Drug formulations are directly injected into the blood or
body tissue bypassing the body’s natural defence
mechanisms.
What are endotoxins and pyrogens?
Endotoxins- lipopolysaccharides found in the outer membrane of gram-negative bacteria
Pyrogens- substances that cause fever, typically produced by viruses or bacteria
What does the pharmacopeia say about particulates?
Except suspensions for IM, SC or intra-articular routes, all other products must be free of visible particles and only very low numbers of sub-visible particles.
Because suspended particles will travel through the venous system to lung could result in pulmonary embolism
What must parental injections which are solutions be?
Must be clear, free from visible particles
What must parental injections which are suspensions be?
Readily re-suspended on shaking, ensure uniform dose to allow withdrawal
What must emulsions injections which are solutions be?
Must not show signs of creaming or cracking
What must aqueous injections for multiple dosing contain?
An antimicrobial preservative
When can a preservative not be used?
What are unpreserved injections formulated in?
dose volume >15ml
injecting into eye or spine
formulated in single-dose containers
What are the requirements for parenteral infusions?
Sterile aqueous solutions or emulsions
Water as continuous phase
Isotonic
Typical volume 100-1000ml
Do not contain preservatives
What are the general requirements for containers for injections?
Must be sufficiently transparent
Made from glass/plastic
Effectively sealed to prevent contamination
Be airtight
What requirements must glass ampoule containers follow?
Typically 1-10ml in volume
Single use
Typically type 1 glass
What requirements must vial containers follow?
Type 1 glass with reusable synthetic rubber closure- held in place by aluminium cover seal with flip off cap
5-100ml
What type of excipient is used to change the osmolality of an injectable formulation?
Tonicity agents
What is the osmolarity of blood?
275-295 mOsm/kg
Why is the lung a good area for absorption?
-Large surface area
-Highly vascular surface promoting rapid absorption and onset of action
-Air-blood barrier is thinner compared to intestines and other mucosal routes, allowing better drug permeability
Why is inhaled drug delivery commonly used for local action?
-Results in a rapid onset of action
-Smaller doses can be used thus reducing side effects
What are the advantages of the inhaled route?
-Smaller doses (reduces systemic side effects and drug costs)
-Rapid absorption leads to fast onset of action
-Avoids harsh GI environments thus minimises chemical and enzymatic drug degradation
-Avoids GI upset
-Avoids hepatic first-pass metabolism
What are the disadvantages of the inhaled route?
-Requires complex delivery devices- high costs
-Aerosol devices can be difficult to use
-Reproducibility of dose delivery is low due to various factors e.g. incorrect use of device, lung capacity, breathing pattern.
-Drug absorption may be limited by mucus layer
-Mucociliary clearance reduces the retention time of drugs within the lungs so not suitable for long-acting formulations
-Oropharyngeal deposition may give rise to local side effects
What are the three stages particles go through in the airways? Which is considered the rate-limiting step?
Deposition
Dissolution (rate limiting step)
Absorption
What are the patient factors that affect particle deposition?
Lung physiology e.g lung capacity
Breathing patterns
Co-ordination of aerosol generation with inspiration
Breath holding
How does optimal aerosol deposition occur?
Occurs with slow, deep inhalations to total lung capacity, followed by breath-holding prior to exhalation
What are the physiochemical factors that affect particle deposition?
-The aerodynamic size of the drug particle (size and density), most important factor
-Shape and physical stability of particles
What are the three particle deposition mechanisms?
-Inertial impaction
-Gravitational sedimentation
-Brownian diffusion
What are the three main categories of devices for inhaled drug delivery?
pMDIs, DPIs and nebulisers
What is inertial impaction? When is it the dominant deposition?
Particles within the airstream having high momentum will impact on the airway’s walls rather than following the change in air flow.
Dominant for particles >5μm in the upper airways
What is gravitational sedimentation dependent on and where does it occur?
Dependent on particle size, density and residence time in the airways (stokes’ law)
Occurs in small airways and alveoli, where velocity is lower
What size of particles is gravitational sedimentation important for?
1-5μm diameter.
What is the predominant mechanism for particles 0.5-1μm?
Brownian diffusion
What is Brownian motion and where does is commonly occur?
Particles <1μm are bombarded with random gas molecules, which results in particle collision with the airway walls
Occurs in regions where the airflow is very low e.g. alveoli
How does particle size effect deposition?
Upper size and lower size limit for effective drug deposition in the lung.
Larger particles >5μm mostly deposit in upper airway by inertial impaction
Particles 1-5 μm mostly deposit in the lower airways by gravitational sedimentation.
* Particles <1 μm mostly deposit in the lower airways by Brownian motion. (But likely will be exhaled)
What does dissolution consist of? (Inhaled drug delivery)
-Aerosolised drug powder must first dissolve in mucus layer before absorption
-Once in solution drug will diffuse through mucus layer and enter aqueous environment of the epithelial lining liquid
What is required for drug absorption to occur?
Dissolution must be faster than clearance
What is the absorption rate of hydrophobic materials dependent on? (Inhaled)
Dependent on their oil/water partition coefficients (LogP)
How are hydrophilic compounds absorbed when administered through the inhaled route?
Poorly absorbed through membrane pores at rates inversely proportional to molecular size
What is the predominant deposition mechanism for particles >10μm?
Inertial impaction
Drug deposited in the ciliated conducting airways are normally cleared by mucociliary clearance within how many hours?
24
What is the optimum particle size for effective inhaled drug deposition?
Optimum particle size= 1-5 μm
How is a drug absorbed rectally for systemic action?
Absorbed through mucous membranes of the rectum.
What are the advantages of the rectal route and when can it be used?
-Avoids first-pass metabolism
Used when:
) The patient is unable to swallow.
2) The drug is inactivated in the stomach acid.
3) The drug undergoes high first-pass metabolism.
4) The drug possesses limited absorption in the upper GI tract.
5) The drug may cause irritation to the gastric mucosa.
6) The drug requires high doses and cannot be easily formulated as oral dosage
form.
What are the disadvantages of the rectal route?
-Patient acceptability can be low
-Specialist advice on administration is required
-May result in local side effects
-Generally slower drug absorption than oral route
-Manufacture of suppositories is more difficult than for other common dosage forms
-Upwards movement of dosage may increase first-pass metabolism
