Formulations for Parenteral Administration, University of Portsmouth

General Requirements for Parenteral Formulations

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SINGLE USE ONLY
Formulations for
Parenteral Administration
Drug Development and Formulation
Dr Marta Roldo
marta.roldo@port.ac.uk
General requirementsGeneral requirements for parenteral formulations

• Isotonicity
• Sterility: essential as natural barriers
  (skin, GIT) are bypassed
• Excipients: for isotonicity, solubility,
  stability, shelf life and preservation
• Endotoxins and pyrogens: substances
  released by bacteria, not eliminated by
  sterilisation - their presence must be
  tested
• Particulates: no visible particles, limits
  on subvisible particles set by
  pharmacopoeia, also limits for
  suspensions and emulsions
• Containers: transparent, airtight,
  tamper evident

Small Volume Containers

UNIVERSITYOF
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• Ampoules - single dose small volume
• Glass type I (borosilicate)
• Sealed by fusion, opened at ceramic
  ring
• Fragile, risk of cutting, glass particles
  . Low cost and low interaction

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• Vials - multidose
• Type I glass with resealable rubber
  closure
• Require preservative
• Rubber particles can be producedLarge volume containers
  Infusion bags and bottles

Large Volume Containers

• glass bottles
• collapsible plastic bags
• semirigid plastic bottles
  Plastic materials:
• PVC
• polyolefin plastic
  Problem: adsorption, leaching

AEZ320
1000 ml„
HARTMANN VIAFLO
0860251P
06 2011
Folyfusor
INFUSOR LV
Baxter
REF C1063K
10
ml/h
CE
ml/h
0123
CE
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10
a
b
INFUSOR LV
Baxter
REF C1063K
10
0123

Excipients for Parenteral Formulations

Vehicle Components

-Excipients for parenteral formulations
Vehicle:

1. Solvents
   • Water for injection
   • Saline (0.9% NaCl)
   • Non-aqueous liquid (oil, e.g. arachis oil)
2. Co-solvents
   • Ethanol
   • Glycerol
   • Propylene glycol
3. Solubilisers
   • Cyclodextrins (cyclic oligosaccharides with a
     hydrophobic cavity and a hydrophilic outer
     surface)
   • Polyoxythylene castor oil (Cremophor EL) -
     paclitaxel, diazepam, cisplatin - highly toxic.

OH
O
O
5
OH
5
n
OH
O
5
n
Cremophor EL®
(a)
(b)
OH
6
5
3.
HO
OH OJ
Secondary
face
Primary
face
(c)
HO
OH
-OH
HO
B
Y
(n =7)
(n = 8)
HO-
OH
OH
TCH
HO
HO
5.3 - 4.7 À
6.5 - 6.0 À
8.3 - 7.5 Å
7.9 Å
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Hydrophobic
cavity
a
(n = 6)Excipients for parenteral formulations

Additional Excipients

1. Emulsifying agents: (droplet size <
   3um)
   • Lecithin
   • Sorbitan fatty acid esters
2. Suspending agents
   • methylcellulose
3. Preservative
   • if product intended for multiple use
   • Not suitable for infusions, intraocular and
     intraspinal injections
4. Stabilisers to delay aggregation
5. Antioxidants
   • Packaging under nitrogen gas
   • See table on next slide
     . Antioxidant synergist - chelating agents
   • EDTA
   • Citric acid
     NOTE: if degradation occurs by hydrolysis rather
     than oxidation, water must be removed by freeze-
     drying
6. Buffers
   • pH (3-9) compromise for compatibility and
     stability

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Antioxidant Compounds

Antioxidants

Compound	Concentration	Use
Vitamin C (ascorbic acid)	0.01-0.1% w/v	aqueous products, adjust pH
Vitamin E (a-tocopherol)	0.001-0.05% v/v	oil-based products
Butylated hydroxyanisole (BHA) Butylated hydroxytoluene (BHT)	IM 0.03% w/v IV 0.0002-0.002% w/v
Sodium metabisulfite	0.01-0.1% w/v	also preservative acidic products
Sodium bisufite		neutral pH
Sodium sulfite		alkali parenteral products.

UNIVERSITYOF
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PORTSMOUTH
SINGLE USE ONLY
Formulations for
Parenteral Administration
Drug Development and Formulation
Dr Marta Roldo
marta.roldo@port.ac.uk

Drug Absorption from Injection Site

Drug absorptionDrug absorption from injection site
For a drug to act it must reach its site of action
Drug on site of
injection
Dissolution
Diffusion in the
tissue
Partition into
endothelial
cells membrane
Distribution to
target tissue by
systemic
circulation
Solution
Fast
ABSORPTION: movement of drug from site of
administration to the bloodstream. This occurs
by diffusion of the drug through the tissues
surrounding the injection site followed by
penetration through the walls of blood
capillaries or the lymphatic system.
Suspension
Emulsion
Slow
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• No absorption required for - IV (100%
  bioavailability), Intrathecal /Intra-articular /
  Intravitreal (local action).
• IM, SC, Intradermal need to undergo absorption
  to reach systemic circulation.Drug absorption from injection site

Factors Affecting Absorption

• SC area and muscle - richly supplied with blood capillaries;
• Lymph vessels - extensive in SC tissue and in connective tissue sheaths around muscles
  but only in small number in muscle itself;
• IM/SC: Aqueous solution - absorption comparable to that seen with oral and usually
  complete within 30 minutes;
• Lipid solubility of drug can delay SC absorption;
• Large molecules (peptides, proteins e.g. insulin) and colloidal particles (e.g. iron
  complexes) with MW > 20 kDa are absorbed by lymph vessels rather than capillaries;
• Exercising the muscle or massaging the injection site for SC injections increases
  lymphatic flow and thus systemic uptake.

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Revise your notes on drug
solubility from year 1Drug absorption from iniection site

Oily IM Solutions or Suspensions

Oily IM solutions or suspensions

• Vehicle: metabolisable oils, e.g. arachis or sesame oil
• Drugs: Steroids, hormones, fat soluble vitamins
• Useful for drugs with low aqueous solubility and
  lipidised water soluble drugs e.g.
• Undecanoate, enanthate, propionate, palmitoylate
  esters of soluble drugs
• Viscosity is higher than aqueous solutions, hindered
  diffusion thus formation of a depot
• Drug must partition from oil into aqueous tissue fluid
  prior absorption - Very slow
• Antipsychotics - as oily IM injections every 2-4 weeks
  vs oral OD dosing enhancing adherence and
  compliance.

Testosterone
Propionate
2-3 Days
Testosterone Testosterone
Enanthate
Cypionate
Testosterone
Undecanoate
1-2 Weeks
10 Weeks
Time Between Injections For TRT
O
0
O
C
H
H
H
0
O
Organon
Sustanon '250'
(Testosterone Propionate)
(Testosterone Phenylpropionate)
(Testosterone Isocaproate)
(Testosterone Decanoate)
1 X 1 ml ampoule
1 ml
Testosterone Propionate Ph. Eut.
30mg
Testosterone Phenylpropionate B.P. 60mg
60mg
Testosterone Isocaproate B.P.
100mg
Testosterone Decancate B.P
For Intramuscular Injection
Warning :
To be sold and used on the prescription
a registered medical practitioner
only Keep in a dry place between
2-30 ℃ away from light.
H
H
H
H
H
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POLL OPEN
L.

1. induces vasoconstriction thus reduces the onset time
2. induces vasodilation thus increasing the lidocaine residence
   time and duration of effect.
3. reduces systemic absorption of lidocaine thus increasing the
   maximum safe dose.
4. increases systemic absorption of lidocaine thus increasing the
   maximum safe dose.
5. induces vasodilation thus increasing the lidocaine residence
   time and duration of effect.

Characteristics of Local Anesthetics

TABLE
Characteristics of local anesthetics3

Local anesthetic	Onset (min)	Duration (min)	Duration with epinephrine (min)	Maximum dose (mg/kg)	Maximum dose with epinephrine (mg/kg)
INJECTABLE LOCAL ANESTHETICS
Bupivacaine	2-10	120-240	240-480	2.5	3
Chloroprocaine	5-6	30-60	N/A	11	14
Etidocaine	3-5	200	240-360	4.5	6.5
Lidocaine	< 1	30-120	60-400	4.5	7
Mepivacaine	3-20	30-120	60-400	6	7
Prilocaine	5-6	30-120	60-400	7	10
Procaine	5	15-90	30-180	10	14
Tetracaine	7	120-240	240-480	2	2
TOPICAL LOCAL ANESTHETICS
EMLA	< 60	60-120	N/A
LMX-4	< 2	30-45	N/A

N/A, not applicable.
Adapted with permission from: Kouba DJ, LoPiccolo MC, Alam M, et al. Guidelines for the use of local anesthesia in office-based dermatologic
surgery. J Am Acad Dermatol. 2016;74:1201-1219.
VASOCONTRICTORS such as adrenaline may be included within the formulation to prolong the drug retention at injection
site and reduce systemic absorption e.g. anaestheticsBenzylpenicillin sodium

Benzylpenicillin Sodium and Benzathine

Chemical Structure and Properties

Chemical structure
O
Na +
O
H
S
H
O
Benzylpenicillin
benzathine
H
H
H H
CH3
CH3
S
HH H
12

	Peak plasma level	15-30 min	48 h
Dosage frequency	Daily in 3-4 separate doses	Single injection lasts for 3- 4 weeks
Excipients	Water for injection	Soya lecithin, Polysorbate 80, Carmellose sodium, Sodium citrate, anhydrous Povidone, Water for injection
	IM only	IM and IV
	Salt increases solubility

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Non-viscous
viscous
Needs dissolution
It's already dissolved
Fast absorption
Slow absorption
Salt increases steric hindrance,
reduces solubilityHydrocortisone Sodium
Succinate

Hydrocortisone Sodium Succinate and Acetate

Chemical Structure and Solubility

Hydrocortisone Acetate
Chemical structure
O
O" Na
O
CHE
HỌC
MOH
HO
H3C
H
H
H
O
Water solubility
Very soluble
Practically insoluble

Peak plasma level	30-60 min	2 days-1 week
Excipients	Sodium hydrogen phosphate buffer, water for injection	Water for injections, Benzyl alcohol, Sodium chloride for injections, Sodium carboxy- methylcellulose, Polysorbate 80 (Tween 80), with NaOH and/or HCI as pH adjusters.

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.OH
HO
HHydrocortisone Sodium
Succinate
Hydrocortisone Acetate
Chemical structure
O
O" Na"
O
CH3
H3C
MOH
HO
H3C
H
川 工
H
O
Water solubility
Very soluble
Practically insoluble

Peak plasma level	30-60 min	2 days-1 week
Excipients	Sodium hydrogen phosphate buffer, water for injection	Water for injections, Benzyl alcohol, Sodium chloride for injections, Sodium carboxy- methylcellulose, Polysorbate 80 (Tween 80), with NaOH and/or HCl as pH adjusters.

Intra-articular injection
IM and IV injection or infusion
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solution
suspension
Needs dissolution
It's already dissolved
Fast absorption
Slow absorption
Esterification with polar group
Esterification with weekly polar group
HO
MIOH
H
H
H
ODrug absorption from injection site

Strategies for Prolonged Drug Effect

SUMMARY - Strategies for prolonged effect and reduced dosing frequency:

• Use IM Suspensions vs solutions: drug needs to dissolve from its solid state before
  absorption from injection site.
• Use "big" counterions to create drug salts with low aqueous solubility causing slow
  dissolution/absorption e.g. Procaine penicillin or benzathine penicillin
• Drug modification by e.g. esterification with non polar moieties: e.g. hydrocortisone
  acetate
• Increase formulation viscosity to reduce rate of diffusion
• VASOCONTRICTORS such as adrenaline may be included within the formulation to
  prolong the drug retention at injection site and reduce systemic absorption e.g.
  anaesthetics

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