Routes Of Administration Flashcards
1
Q
What is the definition of a medicine?
A
Drug delivery system
2
Q
What is the definition of a drug?
A
Active pharmaceutical ingredient (API), therapeutic agent
3
Q
What is the definition of a formulation?
A
Recipe for making a medicine, including the ingredients and processes
4
Q
What is the definition of an excipient?
A
Ingredient that is not the drug e.g a preservative
5
Q
What is the definition of a dosage form?
A
Physical form of the medicine e.g tablet, capsule
6
Q
What is the definition of pharmaceutics?
A
Science of medicine design and manufacture
7
Q
What is the definition of preformulation?
A
Characteristic of the drug (e.g MW, log P, solubility)
8
Q
What is the rationale for the formulation design?
A
Right dose, right place, right time
9
Q
What is the aim of the formulation and what has to be considered?
A
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
10
Q
How can a formulation enhance a medicine? How can this be achieved?
A
Drug delivery and targeting, processability and manufacturing, usability and user acceptability, stability
Achieved using excipients or medical devices
11
Q
What is Lipinski’s rule of five for orally active drugs? And what does this rule assume?
A
Molecular weight <500
Log P <5
H-bond donors <5
H-bond acceptors <10
Assumes absorption by passive diffusion
12
Q
What are the ideal properties for skin absorption?
A
Molecular weight <500 Da
Log P 1-4
13
Q
How do you calculate log P?
A
Log P = log (conc in octanol/conc in water)
14
Q
Why is log P important?
A
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)
15
Q
What is the biopharmaceutics classification system (BCS)?
A
Framework for grouping drugs by solubility and intestinal permeability based on empirical data
16
Q
What is the BCS used for?
A
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
17
Q
What is solubility?
A
Maximum amount of substance (solute) that can be dissolved in a given medium (solvent)
18
Q
Why is solubility important?
A
-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
19
Q
Why is preformulation important?
A
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.
20
Q
What does the pka determine? How do you work out pKa?
A
The extent of ionisation
pKa= -log ([H+][A-]/[HA])
21
Q
Why is molecular dissociation important?
A
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
22
Q
How is a drug made into a medicine?
A
Through formulation
23
Q
What is the purpose of formulation?
A
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
24
Q
What are the advantages of the oral route?
A
Most common
Simplest, convenient and safe (no infection risk)
Modified release formulations available
High surface area with good absorptive capacity
25
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
26
What is the average pH of the stomach fasted and fed?
1-2 fasted, 4-5 fed
27
What is the average pH of the small intestine?
5-7
28
What is the average pH of the large intestine/colon?
6.5-7
29
How does fasted vs fed change the environment?
Fed increases pH, increases fluid volume, increase in bile salt
30
What is the most common type of tablet?
Disintegrating tablet
31
What are all the different types of tablets?
Disintegrating, Gastro-resistant, modified release, dispersible, lozenges, sublingual and buccal, effervescence.
32
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.
33
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.
34
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.
35
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.
36
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.
37
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.
38
What is the most common technique for tablet manufacturing?
Powder compression
39
What are the three main stages in tablet formation?
1. Die filling
– Powder flows down from a hopper into the die
2. 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
3. Tablet ejection
– Lower punch rises to eject the tablet and a pushing
device removes the tablet from the die.
40
What are the two main types of tablet press?
Single punch press, rotary press
41
What are effervescent tablets?
Uncoated tablets intended to be dissolved or dispersed in water before administration
42
43
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
44
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
45
What are sublingual tablets?
Tablets placed under the tongue
46
What are buccal tablets?
Placed in the buccal cavity (under the cheek or between the upper lip and gum)
47
What is the advantage of sublingual or buccal tablets?
Provide rapid drug release for systemic effect without first-pass liver metabolism
48
What are lozenges and how do they work?
Hard solid, single-dose preparations
Intended to dissolve slowly in the mouth when sucked
49
What are lozenges usually used for?
Local effect in the oral cavity/throat.
50
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
51
What is the single-punch press mainly used for?
Used during formulation development and production for clinical trials
52
When is the rotary press used?
Large scale production (10,000 tablet/minute)
53
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.
54
What are the commonly used excipients?
Filler, disintegrant, binder, anti-adherent, lubricant, glidant.
55
Why is filler (diluent) used?
To increase the bulk volume of the powered and increase tablet size
56
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
57
Why is disintegrant used?
Allows tablet to break up into small fragments when in contact with liquid. Promotes rapid drug dissolution thus Bioavaliability.
58
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
59
How much disintegrant can be added to the formulation?
Up to 10%
60
Why are binders used?
Ensures granules and tablets can be formed with the required manual strength
61
What are the two types of binders that can be used?
Soluble binders-starch, sucrose
Dry binders- microcrystalline cellulose
62
Why is a glidant used?
To improve powder flowability by reducing cohesion between particles
63
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
64
Why is lubricant used?
Lowers friction, improves tablet formation and ejection
65
What is the most commonly used lubricant?
Magnesium stearate
66
Why is anti-adherent used?
Reduces adhesion between powder and punch faces, prevents particles sticking to punches
67
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.
68
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.
69
What are the two types of capsules?
Hard capsules (two piece)
Soft capsules (one piece)
70
What raw materials are used in capsules?
Gelatin, colourants, water, plasticisers (soft capsules), optional materials e.g preservatives
71
What are the two processes for extracting gelatin from animal collagen?
Acid process, alkali process
72
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
73
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)
74
How many sizes are there of hard capsules?
8
75
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
76
What are the three types of filling materials for hard capsules?
Dry solids, semi solids, non aqueous liquids
77
What are the three types of capsule filling machines?
Hand operated
Semi-automatic
Fully automatic
78
How many steps does it take to form a soft capsule?
Single step process
79
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
80
What are the different types of soft gels?
Oral softgel, chewable, twist-off, suckable, meltable (pessaries)
81
What is the softgel shell composition?
Gelatin (40%), plasticizers, water, flavours and dye
82
What are the different types of filling materials for matrices for softgels?
Lipophillic liquids e.g for steroids, hydrophilic liquids, semi-emulsifying systems
83
What is the definition of a pharmaceutical solution?
Liquid preparations in which the therapeutic agent and excipients are dissolved in a liquid solvent system.
84
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.
85
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).
86
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
87
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
88
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
89
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.
90
What factors affect chemical degradation?
High temp, pH, oxygen, UV light, catalysis
91
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
92
What is a cosolvent system?
Where a water miscible or partially miscible organic solvent is mixed with water to form an aqueous solution.
93
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
94
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).
95
Why are cyclodextrins used?
To increase aqueous solubility of drug as upon oral administration drug is released from cyclodextrins and free drug is absorbed)
96
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
97
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
98
What does topical drug delivery mean?
Administered on tissue surface to treat a local condition
99
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
100
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
101
What does percutaneous mean?
Through skin
102
What is the definition of an ointment?
Drug dissolved in a greasy base
103
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
104
What is a cream?
Semi-solid emulsion
105
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)
106
What are the advantages of creams?
Longer residence time than lotion
I’m able with skin secretions, easily washable
Excellent patient acceptability
107
Definition of gel
Semi-solid or viscous liquid, often clear or transparent.
108
What are the three forms that a lotion could be in?
Solution, suspension or emulsion
109
What are the advantages of a lotion?
High spreadabikity ideal for covering a large area thinly
Suitable administration on hairy skin
110
What is the definition of a foam?
Dispersion of gas within a liquid
111
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
112
What are the advantages of using a patch for topical drug delivery?
Provides occlusion, dose retention and protection of formulation from environmental contamination
113
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).
114
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.
115
What are the different cellular layers of the skin called?
• Epidermis;
• Dermis;
• Hypodermis.
• Appendageal features.
• Permeability barrier.
116
What is the permeability barrier of the skin called?
Stratum corneum
117
118
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.
119
What is a disperse system?
Two-phase heterogenous system in which an insoluble or immiscible dispersed phase is distributed through a continuous phase.
120
What does the 'brick and mortar' model consist of?
Corneocytes ('bricks')- hydrophilic
Extracellular lipid matrix ('mortar')- lipophilic
121
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
122
How do you work out the permeability coefficient?(Kp)
Kp = K (partition coefficient) x D (diffusion coefficient) / h (diffusion path length)
123
Which dermal route do hydrophilic drugs follow?
Transcellular route
124
Which dermal route/pathway do lipophilic drugs follow?
Paracellular route
125
What is the appendageal pathway (shunt route)?
Through hair follicles and sebaceous glands
126
How can topical drug penetration be assessed?
Diffusion cell and tape-stripping
127
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
128
Where does absorption occur in the nose?
across turbinates and septum
129
Which cells secrete mucus in the nose?
Goblet cells on the mucous membrane
130
How are lipophilic drugs absorbed nasally?
Transported by passive diffusion (down conc gradient), by receptor mediated and vesicular transport mechanisms
131
How are polar drugs absorbed nasally?
Pass through epithelium via gaps between cells (tight junctions) so limited to drug molecular size >1000 Da
132
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.
133
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.
134
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.
135
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.
136
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.
137
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.
138
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.
139
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.
140
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.
141
What is otitis externa?
Inflammation of the external ear canal, often referred to as "swimmer's ear".
142
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.
143
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.
144
What is paracellular transport?
The transfer of substances across an epithelium by passing through the intercellular space between the cells.
145
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.
146
What does parenteral mean?
Drug administration other than via the GI tract e.g the skin
147
What are all the different drug administration injections?
Intravenous
Intrathecal, epidural and intraspinal
Intra-arterial and intracardiac
Intradermal
Subcutaneous
Intramuscular
Intra-articular
Intraocular
148
Can you administer water-in-oil emulsions/suspensions via IV?
No because the oil phase/suspended drugs can block blood vessels
149
What could happen if you administer a hypertonic or extreme pH drug solution via IV?
Cause inflammation and pain at injection site
150
What are subcutaneous injections also known as?
Hypodermic injections
151
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.
152
What volume can a subcutaneous injection be up to?
Volume up to 1ml
153
When are intra-arterial injections used?
Only used when IV access cannot be established e.g. pre-mature babies
154
Why is the intra-arterial route less common than the IV route?
More invasive and less accessible than via the veins
155
When is the intracardiac route used?
Only in life-threatening emergencies to produce a rapid, local effect in the heart
156
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
157
What is the maximum volume that an intradermal injection can be?
0.2ml
158
How fast is absorption of an intradermal injection?
Absorption is slow as not well-perfused by blood
159
Where are intramuscular injections usually administered?
Tissue of a relaxed muscle in buttock, shoulder or thigh
160
Is absorption of intramuscular or subcutaneous faster?
Subcutaneous
161
Can aqueous or oily solutions/suspensions be administered via an intramuscular injection?
Yes as long as volume less than 4ml
162
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
163
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
164
Where is an epidural injection administered?
Given into the epidural space between the dura mater and the vertebrae
165
What must all intraspinal injections be? and what can they not include?
Must be isotonic aqueous solutions and cannot include preservatives
166
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
167
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)
168
What is the maximum volume for an intracameral injection? What is it usually administered for?
0.1ml-1ml
Antibiotics or local anaesthetics
169
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
170
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.
171
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
172
Why are excipients used?
-Adjust isotonicity
-Adjust pH
-Increase drug solubility
-Increase drug stability
-Increase shelf life
173
What are the two most commonly used vehicles for injections?
Water for injections
Saline for injections
174
What can be added to injections to make them more soluble?
Solubilising agents or co-solvents
175
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
176
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
177
Why are suspending agents used?
Used in suspensions to ensure drug can be readily re-suspended by shaking prior to use
178
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.
179
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
180
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
181
What must parental injections which are solutions be?
Must be clear, free from visible particles
182
What must parental injections which are suspensions be?
Readily re-suspended on shaking, ensure uniform dose to allow withdrawal
183
What must emulsions injections which are solutions be?
Must not show signs of creaming or cracking
184
What must aqueous injections for multiple dosing contain?
An antimicrobial preservative
185
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
186
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
187
What are the general requirements for containers for injections?
Must be sufficiently transparent
Made from glass/plastic
Effectively sealed to prevent contamination
Be airtight
188
What requirements must glass ampoule containers follow?
Typically 1-10ml in volume
Single use
Typically type 1 glass
189
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
190
What type of excipient is used to change the osmolality of an injectable formulation?
Tonicity agents
191
What is the osmolarity of blood?
275-295 mOsm/kg
192
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
193
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
194
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
195
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
196
What are the three stages particles go through in the airways? Which is considered the rate-limiting step?
Deposition
Dissolution (rate limiting step)
Absorption
197
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
198
How does optimal aerosol deposition occur?
Occurs with slow, deep inhalations to total lung capacity, followed by breath-holding prior to exhalation
199
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
200
What are the three particle deposition mechanisms?
-Inertial impaction
-Gravitational sedimentation
-Brownian diffusion
201
What are the three main categories of devices for inhaled drug delivery?
pMDIs, DPIs and nebulisers
202
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
203
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
204
What size of particles is gravitational sedimentation important for?
1-5μm diameter.
205
What is the predominant mechanism for particles 0.5-1μm?
Brownian diffusion
206
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
207
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)
208
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
209
What is required for drug absorption to occur?
Dissolution must be faster than clearance
210
What is the absorption rate of hydrophobic materials dependent on? (Inhaled)
Dependent on their oil/water partition coefficients (LogP)
211
How are hydrophilic compounds absorbed when administered through the inhaled route?
Poorly absorbed through membrane pores at rates inversely proportional to molecular size
212
What is the predominant deposition mechanism for particles >10μm?
Inertial impaction
213
Drug deposited in the ciliated conducting airways are normally cleared by mucociliary clearance within how many hours?
24
214
What is the optimum particle size for effective inhaled drug deposition?
Optimum particle size= 1-5 μm
215
How is a drug absorbed rectally for systemic action?
Absorbed by passive diffusion through mucous membranes of the rectum.
216
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.
217
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
218
How does absorption rectally differ from the oral route?
Generally lower absorption than oral route -> smaller surface area available
219
What happens after absorption via the rectal route?
Following absorption, drug enters the haemorrhoidal veins
Blood in the inferior and middle haemorrhoidal veinsdrain into the systemic circulation directly
Blood from the superior haemorrhoidal vein enters the portal vein, which flows into the liver-> first pass metabolism occurs.
220
What are the physiological factors than affect rectal absorption?
Quantity of rectal fluid
Properties of rectal mucus- pH 7-8
Contents of the rectum- enema given before administration to prevent this being an issue
Motility of the rectal wall- influence rate of dissolution
Circulation route
221
What are all the rectal dosage forms?
– Suppositories,
– Foams,
– Solutions,
– Suspensions,
– Emulsions,
– Rectal capsules,
– Rectal tablets,
– Tampons
222
What are some examples of rectal semisolids and why are they used?
Rectal creams, ointments and gels
Used topically to treat local conditions e.g pain and inflammation
223
What are the two types of suppository bases?
Lipophilic drugs-> water-soluble bases
Hydrophilic drugs-> Glyceride-type fatty base suppositories
224
What are the issues with using hydrophilic bases in suppositories?
-Due to the small amount of liquid present in rectum, hydrophilic base could draw water from the rectal epithelium (could result in dehydration and pain)
-Many drugs incompatible with hydrophilic bases
-Drug release could be slow because of its interaction with the base- drug could remain in base
225
What are the excipients used for drugs administered rectally?
Surface-active agents- enhance wetting properties of base with rectal fluid-> enhances drug release
Hygroscopicity reducing agents- reduce uptake of water from atmosphere
Melting point controlling agents
Diluents, Adsorbents, Lubricants, Preservatives, Colouring
226
What is the general rule when formulating a drug for rectal administration?
First choice should be a readily water-soluble drug dispersed in a fatty base.
W/O emulsion-type suppositories not recommended
227
What is the pH of the vagina and what does it depend on?
Slightly acidic 4-5
Depends on amount and duration of lumen secretion
228
Explain anatomy of vaginal wall.
Vaginal wall-> highly vascular with relatively large surface area
3 layers- epithelial layer, muscular coat and the tunica adventia
229
What are the advantages of vaginal administration?
-Can be used for local effects, allowing a smaller dose to be used
-Permits use of prolonged dosing, with extended release
-Avoids fluctuations resulting from daily intake
-Alleviate inconvenience caused by pain
-Large permeation area, rich vascularization, relatively low enzymatic activity
-Non-invasive
230
What are the disadvantages of the vaginal route?
-Gender specific
-Systemic treatment not widely popular
-Menstruation cycle and hormonal variations affect systemic absorption
-Vaginal fluid volume variations affect local drug absorption
-Acidic pH may enhance degradation of some drugs
-Often require special applicators
231
What are the three types of intravaginal drug absorption?
-Transcellular- via conc dependent diffusion through cells
-Paracellular- mediated by tight junctions
-Vesicular or receptor mediated transport
232
What are the two main steps of intravaginal drug absorption?
1. drug dissolution in vaginal lumen
2. membrane penetration
233
What are the physiological factors which affect vaginal absorption?
-Volume, viscosity and pH of vaginal fluid
-Stage of menstrual cycle
-Age
-Sexual activity
234
What are the drug related factors which affect vaginal absorption?
-Drug solubility, ionization behaviour
-Molecular weight
-Release characteristics
-Dosage form
235
What are some important characteristics for drugs for vaginal administration?
-Long acting, easy to apply with infrequent dosing
-Free from local irritation
-Colourless, odourless and resistant to leakage
-Should not affect sexual activity
-Should not cause staining or discolouring of undergarments
236
How are suppositories manufactured?
Moulding method:
Base heated above melting point, drug dissolved in liquid
Molten product poured into moulds, cooled then removed for final packing.
237
What are vaginal rings (implants)?
Solid formulations that provide a controlled release of drug over a period of time
Rings are flexible, circular system containing the drug trapped in a polymer network
238
What are the two major mechanisms for drug-release for vaginal administration?
-Melting- designed to melt at body temp to release drug, molten mass disperses in available space
-Disintegration- solid dosage forms release drug by dissolution/disintegration, followed by dispersion of contents in vaginal fluids
Semi-solid dosage form releases drugs by diffusion or dispersion of contents from formulation to vaginal fluids
239
What is one of the major problems encountered when formulating a drug for vaginal administration?
Low retention time due to self cleansing action of vaginal tract
240
What are some ways to improve vaginal absorption?
Mucoadhesive agents- Permit close contact with vaginal mucosal surface
Nanotechnology- Reduces required dosage and side effects, improves resulting activity
Penetration enhancers
Solubility modifiers- Solubilizing agents/ co-solvents
241
What are the advantages of using mucoadhesive polymers to improve vaginal absorption?
Flexibility- Controls interpenetration between polymers and mucosal/epithelial surface
Hydrophilicity- Polymers=hydrophilic so form strong bonds with mucosal membranes
Hydrogen bond- Hydrogen bonds between OH and COOH of polymer and mucosal surface facilitates muco-adhesion, sustained release of drug by diffusion within the polymer.
High molecular weight- provide more available binding sites, slows down drug
diffusion.
242
What is the pH of normal tears and when is it lowest?
7.3-7.7
Lowest on awakening
243
How does contact lenses or diseases of the eye affect tears?
-Tears are more acidic in contact-lens wearers
-Tears are more alkaline in case of diseases
244
What is the normal human tear volume?
The normal human tear volume is 5-9 μL
245
What are the three types of ocular drug delivery routes?
Cornea- main route for topical administration
Periocular delivery- Bypass conjunctival and corneal epithelium
Intravitreal delivery- Directly reach the back of the eye
246
What are the challenges for ocular drug delivery?
* The lachrymal (tear) system continually washes the eye.
* Blinking also promotes fluid clearance.
* Overall effect is effective clearance of eye drops within 4 to 23 minutes.
* Maximum dose volume 20-30 μL.
247
What must ocular preparations be?
-Isotonic
-Close to neutral pH
-Stable
-Sterile
-Particle free
-Contain preservatives if multi-dose container
-Relatively easy for patient to administer on own
-Can provide rapid onset of action
-Avoid hepatic metabolism
248
Why should all ophthalmic preparations be sterile? How can you ensure this?
-Ocular infections may lead to vision loss
-Preservatives must be included in multi-dose containers:
Inhibit microbial growth
cannot be used in intraocular products- single use
249
What occurs if an ocular drug is hypotonic or hypertonic?
Hypotonic- causes oedema
Hypertonic- dehydration
250
What is an acceptable pH range for an ocular solution?
pH 3.5-9
251
What happens if an ocular solution is too viscous or not viscous enough?
Too viscous causes irritation and blurring
Not viscous enough- won't stay in eye
252
What form are most ophthalmic presentations?
Solutions
253
What are ion-exchange resins? and how are they used for ocular administration?
Drug ionically bond to an ion-exchange resin to form insoluble complex
Drug is released from the complex through exchange of the drug ions with ions in tears
The resin particle size is one of the factors that controls the rate of drug release
254
Where are intravitreal injections administered and what volume can be administered?
Vitreous cavity
Volume between 20 and 100μL can be injected.
