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Parenteral drug delivery

Dr. Herman J. Woerdenbag

Department of Pharmaceu1cal Technology and Biopharmacy
University of Groningen
The Netherlands
h.j.woerdenbag@rug.nl

2016 H.J.Woerdenbag

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Parenteral administra8on
Drugs administered parenterally are injected via a hollow
needle into the body at various sites and to varying depths
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When parenteral administra8on?

Pa1ent unable to take drug orally
Unconscious pa1ent, refusal
No oral or rectal dosage form of the drug available
Poor absorp1on from the gastrointes1nal tract or other routes of
administra1on
Physicochemical proper1es of the drug (e.g., quaternary ammonium), disease, proteins
Rapid and suciently high concentra1on in the body is necessary
High concentra1on necessary not achieved by tablet or suppository
Con1nuous administra1on necessary for constant blood level
Steady state
Most precise way of administering
Most suitable for narrow therapeu1c window drugs
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Plasma-8me curves
Oral versus intravenous Intravenous, steady state
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Disadvantages parenteral
Produc1on is costly (specic requirements for facili1es)
Infec1on possible: skin and gastrointes1nal tract (natural barriers) circumvented
Unpleasant for pa1ent (needle fear)
Risk of 1ssue damage at site of injec1on (phlebi1s, necrosis)
Mistakes at 1me of administra1on, side eects or hypersensi1vity may cause
considerable damage
Injected air may elicit embolism
Administra1on demands knowledge and skills
Poor stability of drug in solu1on
Drug cannot withstand sterilisa1on
Infusion: obstruc1on and biolm forming, limited mobility pa1ent, applica1on
labour intensive
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Parenteral prepara8ons (1)

PARENTERALIA (Ph. Eur.)

Sterile prepara1ons intended for administra1on by injec1on,

infusion or implanta1on into the human or animal body
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Parenteral prepara8ons (2)

Injec1ons
Infusions
Concentrates for injec1ons or infusions
Powder for injec1ons or infusions
Gels for injec1ons
Implants
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Hygienic manufacture
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Injec8ons (Ph. Eur.)

Sterile solu1ons, emulsions or suspensions
Prepared by dissolving, emulsifying, suspending ac1ve substance(s) and
excipients in water, in a suitable non-aqueous liquid, or in a mixture of
these vehicles
Solu1ons
Clear, prac1cally free from par1cles
Emulsions
No phase separa1on
Suspensions
May have sediment, readily dispersed on shaking
Stable enough to give correct dose
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Infusions (Ph. Eur.)

Sterile, aqueous solu1ons or emulsions with water as the
con1nuous phase

Usually made isotonic with blood

Intended for administra1on in large volume
No preserva1ve
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Concentrates / powder for injec8ons or infusions

Concentrates (Ph. Eur.)
Sterile solu1ons intended for injec1on or infusion ader dilu1on
Diluted to prescribed volume with prescribed liquid before administra1on
Powders (Ph. Eur.)
Solid, sterile substances distributed in their nal containers
When shaken with prescribed volume of prescribed sterile liquid they
rapidly form clear and prac1cally par1cle-free solu1on or uniform
suspension (recons1tu1on)

Ader dilu1on they comply with pharmacopoeial requirements
for injec1ons or infusions
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Gels and implants for injec8on

Gels (Ph. Eur.)
Sterile gels with a viscosity suitable to guarantee a modied
release of the ac1ve substance(s) at the site of injec1on

Implants (Ph. Eur.)

Sterile, solid prepara1ons of a size and shape suitable for
parenteral implanta1on and release of the ac1ve
substance(s) over an extended period of 1me
Each dose is provided in a sterile container
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Parenteral routes
Main Other
Subcutaneous (under the skin, s.c.) Intracutaneous (in the skin)
0.1-2 mL 0.1-0.2 mL
Intramuscular (in a muscle, i.m.) Intra-ar1cular (in a joint)
0.5-10 mL 1-10 mL
Intravenous (in a vein, i.v.) Intracisternal, intrathecal,
1-5000 mL intradural (in cerebral uid)
0.1-10 mL
Intra-arterial (in an artery)
Intracardiac (in the heart)
Intra-ocular (in the eyeball)
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Injec8on or infusion?
Injec1on
Drugs with longer elimina1on half-life
Volume limited (max. 10 ml)

Infusion
Drugs with shorter elimina1on half-life
Con1nuous blood level
Larger volumes
Limits pa1ents mobility
Toxic and strongly irrita1ng drugs (cytosta1c drugs)
Parenteral nutri1on (TPN)
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Biopharmacy
Rapid ac1on
Drug in solu1on

Prolonged (retarded) ac1on

Intramuscular
Drug as suspension
Drug in implant or gel
Less water-soluble deriva1ve of drug
Drug in microspheres
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Side eects and toxicity (1)

Faster and more intense than ader enteral or cutaneous
administra1on
Rapid interven1on may be necessary
Protein drugs (biopharmaceu1cals)
Immunological reac1ons (hypersensi1vity)
- Aggregates (star1ng point of denatura1on)
- Non-human components

Infec1on
Bacterial
Inser1on channel, surrounding subcutaneous 1ssue, vein wall
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Side eects and toxicity (2)

Phlebi1s
Infamma1on blood vessel, trombophlebi1s (clot)
High or low pH, high buer capacity, high osmo1c value, poor solubility
drug or excipients
Pain
Needle fear
- Local anesthe1c on skin before infusion is brought in
I.m. injec1on with strongly devia1ng pH or osmos1c value
- Add local anesthe1c
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Side eects and toxicity (3)

Extravasa1on
Necrosis
Gangrene
Par1cles
Glass, rubber
- Obstruc1on of capillaries
- Granulomas
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General requirements injec8ons and infusions

As much as possible isotonic with body uids
As much as possible isohydric with body uids
Sterile
Pyrogen free
Par1cle free

Sterilisa1on process places high demands on thermostability

of ac1ve substance
Ader handling injectables sterility should be maintained
Asep1c handling
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Pyrogens and endotoxins

Pyrogens: materials which when injected into a pa1ent will
cause a rise in body temperature (pyrexia)
Bacterial endotoxines: lipopolysaccharides of cell wall of
Gram-nega1ve bacteria causing a pyrogenic response
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Pyrogen free
Ph. Eur.: injected prepara1ons must be pyrogen-free

Use pyrogen-free utensils, materials

Glass, metal: clean with pyrogen-free water, heat
Solu1ons: ultraltra1on
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Substances for injec8on

Small molecules
Molecular weight (MW) to about 800 Dalton

Large molecules
Proteins, monoclonal an1bodies, vaccines, immunoglobulines

Solu1ons
Suspensions
Emulsions
Implants (solid)
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Vehicles
Preference: water as solvent
Replace part of water by a water-miscible solvent
Co-solvents (ethanol, glycerol, propylene glycol, macrogol)
Toxic, painful; i.v.
Lipophilic solvents: plant-derived oil (olive, castor,
sunower), Miglyol
Solu1on in oil i.m.
Emulsion (o/w) i.v.
Advanced delivery (and targe1ng) systems: liposomes,
microspheres, nano- and micro-emulsions, mul1ple
emulsions
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Mul8ple emulsions
Primary emulsion (o/w or w/o) re-emulsied to form w/o/w
or o/w/o mul1ple emulsion
Use suitable emulsiers (high and low HLB value)
Primary emulsion formed under high shear forces (small droplets)
Secondary emulsion at lower shear: avoid rupture of internal droplets
w/o/w systems: lower viscosity than oily or w/o injec1on,
controlled release, enhanced bioavailability, improved
stability
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Water for injec8on

Most parenteral administra1on forms are aqueous
Requirements in Ph. Eur.: Aqua ad injectabilia
Prepared by dis1lla1on or reversed osmosis
Pyrogen-free (endotoxin-free)
Clear, colourless, odourless, tasteless
Bulk (stock)
Storage at temperature 80C
Sterilised in package
WFI
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Excipients (1)
To adjust tonicity
Isotonic with blood
- Sodium chloride 0.9%
- Glucose 5%

To adjust pH
Isohydric with blood, body uids (pH 7.4)
Stability of drug
- Hydrochloric acid, sodium hydroxide, lac1c acid
- Protein: phosphate or glycinate buer
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Excipients (2)
To increase solubility ()
To prevent deteriora1on of API
An1oxidant ()
For freeze-drying (lyophilisa1on), to protect proteins against
denatura1on (lyoprotectants)
To provide an1microbial proper1es ()

Not
If they adversely aect intended medical ac1on
If they cause toxicity or undue local irrita1on
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Increase solubility
Adjust pH
Rela1onship pKa, pH and solubility
Water-soluble salt (hydrochloride of a base, sodium salt of an acid)
Co-solvents
Complex forma1on
Cyclodextrines, polyvinyl pyrrolidone (povidone)
Deriva1sa1on, change molecule
Example: linking a phosphate moiety

Basically similar to oral liquids

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Oxida8on
Oxida1ve degrada1on of a drug is enhanced by heat
(sterilisa1on process)
Remove oxygen during prepara1on by passing through an
inert gas (nitrogen)
Fill ampoules under nitrogen
Disodium ededate: scavenging of metal ions
Ascorbic acid or sodium pyrosulphite: an1oxidants
In some co-solvents less oxygen dissolves than in water
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No microbial contamina8on
Parenteral prepara1ons are prepared using materials and
methods designed to ensure sterility and to avoid the
introduc1on of contaminants and the growth of micro-
organisms (Ph. Eur.)

Manufacture
Package
Storage
Procedures and handling before administra1on
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Preserva8ve in injec8ons
Mul1-dose aqueous injec1ons

Not
Volume to be injected >15 mL
If, for medical reasons, a preserva1ve is not acceptable
- Routes giving access to cerebrospinal uid (intracisternally, epidurally,
intrathecally), intra- or retro-ocularly
Single-dose containers
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Prepara8on steps
Reduce ini1al contamina1on
Materials, utensils, environment
Dissolve ac1ve substance in suitable solvent
Filter
To remove par1cles, to reduce microbial contamina1on
Free from oxygen (if necessary)
Fill out in package
Close
Sterilise
Inspect (par1cles)
Label
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Filling ampoules
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Administra8on of an injec8on
Direct into body (syringe + needle) or via infusion
Slow administra1on
s.c.
i.m.
i.v. (fast dilu1on in blood stream)
Needle thickness
As thin as possible (pa1ent-friendly)
Depends on length (site of injec1on)
Viscosity injec1on uid
Chose syringe that matches to volume to be injected
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Injec8on needles
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Luer-lock connec8on
Universal connec1on
Male part (conus syringe)
Tapered end (standardised)
Around conus ring to lock lips
Female part (needle)
Lips
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Biopharmacy injec8ons
Site of injec1on, depth of injec1on
Physical form of drug injected
Solu1on, suspension, emulsion
Physicochemical proper1es drug
Solubility, charge, aggrega1on
Composi1on of injec1on
Solvent or vehicle, osmo1c value, pH, viscosity, excipients, etc.
Injected volume
Thickness fat layer in rela1on to depth of injec1on
Muscle ac1vity, blood perfusion
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Biopharmacy i.v.
Intravenous
Drug immediately enters circula1on
Fastest way to obtain therapeu1c eect
Bioavailability by deni1on 100%
Dura1on of ac1on depends on dose, infusion 1me,
distribu1on, metabolism, excre1on
Constant infusion (at right dose) yields constant blood level
Dose adjustable with droplet velocity
For drugs with narrow therapeu1c window
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Biopharmacy i.m.
Intramuscular
Injec1on into muscle, through skin and fat layer
Upper arm, buuocks, thigh
Blood perfusion diers
Dierences in absorp1on speed between injec1on sites
Muscle ac1vity inuences blood perfusion and thus
absorp1on
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Biopharmacy s.c.
Subcutaneous
Injec1on in subcutaneous connec1ve 1ssue
Leg, skinfold belly
More painful than intramuscular
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Epidural and intrathecal

Into uid around spinal cord

Pain control
Anesthesia
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Injectables for infusion

Solu1ons or emulsions, never suspensions
Aqueous and electrolyte infusion uids
Maintenance electrolyte balance, hydrata1on
Correc1ng solu1ons
Devia1on in pH, electrolyte composi1on blood
Vehicle for con1nuous administra1on of drugs
Solubility, side eects, con1nuous blood level
Colloidal plasma replacing uid
Supplementa1on of shortage in circula1ng blood volume
Parenteral nutri1on
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Administra8on of infusions
Access to the body
Peripheral (wing needle, canule)
Central (venous catheter in large vein via port system)

Infusion or administra1on system

Infusion bag with infusion line via gravity

Infusion equipment
Syringe pump, drip chamber connected to infusion bag
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I.v. administra8on systems

peripheral

central
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Medica8on by subcutaneous infusion

Applied to severely ill pa1ents
Pain treatment (combined with an1emesis, seda1on)

Consider (physician, pa1ent): convert oral (or rectal)

medica1on to subcutaneous infusion
Try to avoid intravenous administra1on (painful, discomfort)

Ader infusion diusion to blood stream via capillaries and

lymph vessels
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When s.c. infusion?

Limita1ons with oral administra1on
Nausea, vomi1ng
Swallowing problems
Severe weakness or disturbance of consciousness
Limita1ons with rectal administra1on
Diarrhoea
Personal objec1ons pa1ent
Bowel obstruc1on
Wish of pa1ent / family
An1cipa1on on terminal phase
If pain is a major problem
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Pros and cons

Mobility and freedom for the pa1ent
No long hospitalisa1on, care can be given at home
Constant blood levels
Bolus administra1on possible in case of breakthrough pain
No daily repeated injec1ons

Irrita1on around needle inser1on site

Not suitable in edematous pa1ent, in skin on or surrounding
tumour, skinfolds, skin on or surrounding joints
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Considera8ons
Site of injec1on should have good lympha1c drainage
Site of injec1on should not hinder pa1ent
Upper arm, infraclavicular region
Not: upper belly, upper leg

Beware of
Allergic reac1on to needle
- Weekly change or more frequent
Chemical reac1on with subcutaneous 1ssue
Infec1ons
pH and tonicity injected solu1on
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Products / devices
Medica1on casseue (with pump)
Syringe pump
Elastomer infusion pump

Filling these systems is done extemporaneously, tailor-made

for the pa1ent
Product protec1on, asep1c handling
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Medica8on casseYe
50-100-250 mL, single use
Infusion speed adjustable with CADD pump
Mostly 1 mL/h (max 5 mL/h)
For con1nuous or intermiuent infusion
Subcutaneous, intravenous, epidural, intrathecal
Filling (extemporaneous) not easy
CADD: computerised
ambulatory delivery device
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Syringe pump
Infusion speed adjustable
History available, recording
Warnings (almost empty, low bauery)
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Elastomeric pump
Infusion by posi1ve pressure of elastomer on content
No current or baueries necessary, no pump
Adjustable infusion speed (via a membrane), but less precise
Suspension height, viscosity, temperature
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Pallia8ve medica8on
Morphine analgesic
Metoclopramide an1-eme1c
Haloperidol an1-eme1c, neurolep1c
Dexamethasone an1-eme1c
Midazolam seda1ve

Morphine + haloperidol pain and nausea

Morphine + midazolam seda1on
Morphine + dexamethasone increased cerebral pressure
Morphine + metoclopramide + dexamethasone increased cerebral pressure
Morphine + midazolam + haloperidol + butylscopolamine pain, bowel obstruc1on and seda1on
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Pay aYen8on to
Stability
pH, temperature, exposure to light, oxida1on, API concentra1ons
- Haloperidol may crystallise when combined with other drugs
- Morphine is sensi1ve to oxida1on
- Metoclopramide is unstable at higher pH

Excipients
Incompa1bili1es
Midazolam injec1on may not be mixed with alkaline solu1on
Tonicity of the combined product
Physiological: 290 mOsmol/L
Drugs that may elicit a hypersensi1vity reac1on
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Opioid rota8on
Calcula8ons
Transdermal to oral
Oral (/rectal) to s.c.
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To be cri8cally considered
Shelf-life when stored and storage condi1ons
Stability when connected to pa1ent
Room temperature, body temperature, protec1on against light
Labeling
Concentra1on of drug substances included
Infusion speed
Dosage per 24 h
Booster or bolus
Shelf-life before and ader connec1on to pa1ent
Composi1on per 100 mL (or applicable volume)
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Auto-injectors
Medical device designed to deliver single dose of a drug
Insulin, epinephrine, atropine
Spring-loaded syringes
Self administra1on (thigh, buuocks)
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Needle-free injec8ons
Recent development
Gun (jet injector) which res drug (solu1on, powder) through
external layers of the skin under high pressure
Less pain, bruises?
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Final remarks
Most parenteral dosage forms are quite simply cons1tuted
from a pharmaceu1cal viewpoint
Solu1ons with as liule excipients as possible

High requirements set to chemical stability API because of

sterilisa1on process

Biotech products (proteins) and nanomedicines require

special auen1on
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Acknowledgement
Drs. Carolina Visser, Department of Pharmaceu1cal
Technology and Biopharmacy, University of Groningen, for
her contribu1on to the topic medica1on by subcutaneous
infusion