Lecture 1 Parenteral Drugs Hafeli

Types of products required to be sterile

Injections: can be ready for injection or a dry solid

that must be reconstituted prior to administration

a) [Drug] Injection – drug in solution in a

suitable vehicle ready for injection

Diazepam Injection

b) [Drug] for Injection – dry solid that after

reconstitution yields a solution

Penicillin G Sodium for Injection

c) [Drug] Injectable Emulsion – drug dissolved or

dispersed in an emulsion

Diazepam Injectable Emulsion

d) [Drug] Injectable Suspension – solid drug

suspended in a liquid

Medroxyprogesterone acetate injectable

suspension

e) [Drug] for Injectable Suspension – dry solid

drug that yields a suspension upon addition of

a liquid

Imipenem/cilastatin sodium for injectable

suspension

Large and small volume parenteral solutions

(intended for IV infusion packed in PVC (glass) or

plastic (non-PVC))

a) Large volume parenterals: volume > 100 mL

b) Small volume parenterals: volume ≤ 100 mL

Essential requirements of parenterals

1) Formulations must be sterile: free of viable

microorganisms to prevent local or systemic

infections

Steam and dry heat

If heat labile: aseptic filtration; gas (ethylene

oxide); radiation

2) Formulations must be pyrogen free

Pyrogens = lipopolysaccharides or endotoxins

of bacterial origin (major component of gram

negative bacteria cell wall)

Causes immune response & fever (45-90 min

post injection latent period)

3) Formulations must be free of particulate matter

> 5-10 um can cause harm (blockage of small

blood vessels, emboli formation, granulomas)

4) Formulations must be isotonic

Tonicity adjusting agents decrease hemolysis

of blood cells & reduce pain and irritation

5) Stable for intended use

6) pH – not vary significantly

Needle size: smaller Gauge number mean larger

needle diameter

Major routes of parenteral administration Route Site Dosage form Max

volume Absorption Complications

Intradermal Superficial dermis skin layer (forearm)

Solutions Suspensions Emulsion

0.1 mL Slow and limited; used for antigen testing

Tissue irritation

Subcutaneous SC skin (thigh, upper arms, lower abd)

2 mL Slow absorption; longer onset than IM

Tissue infection; hardening; abscess formation

Intramuscular Muscle mass (buttocks, thigh, upper arm)

2.5 mL Faster absorption than SC; usually as depot for controlled release; aspirate to check for blood

Muscle contraction; nerve injury; irritation; abscess

Intravenous Into vein (forearm, hand, foot, scalp)

Solutions Emulsions

Variable Rapid response (100% bioavailability)

Hematoma; extravasation; thrombosis; phlebitis; infection

Other routes of parenteral administration Epidural Dura mater

Intra-articular Joint

Intra-arterial Artery

Intracardiac Heart

Intralymphatic Lymphatic vessel/ node

Intraperitoneal Peritoneal cavity

Intraspinal Vertebral column (epidural or intrathecal)

Intrathecal CSF at any level

Intravitreal Vitreous humor of eye

Complications of parenteral administration:

Extravasation: accidentally administer IV solution

into tissue around vein inflammation, pain,

irritation or tissue necrosis

Thrombosis: damaging inside blood vessel clot

(thrombus) thrombophlebitis (inflammation)

dislodge (embolus) embolism

Hematoma: escape of blood from vessel into tissue

Lecture 1 Parenteral Drugs Hafeli

Principles of formulation

Vehicles:

Aqueous vehicles Vehicle Description Sterility Use

Water for injection

Purified by distillation or reverse osmosis

Pyrogen free

Not required to be sterile (used w/in 24h)

Manufacturing of injectables which will be sterilized after preparation

Sterile water for injection (packages ≤ 1L)

Sterilized

Pyrogen free

Solvent for already sterilized & packaged injectables

Bacteriostatic water for injection (packages ≤ 1L)

Sterile

Pyrogen-free

Antimicrobials*

Other substances

Sterile vehicle for preparing solutions or drugs for parenteral administration

Sterile saline for injection

Isotonic saline prepared from water for injection

Sterile

* Adding antimicrobials: can use multi-dose but only in small volumes

(toxicity); NOT in neonates, epidural or intrathecal administration

Non-aqueous vehicle: delivery of hydrophobic/ hydrolytically labile drugs

Always given IM (never IV)

o EXCEPTION: lipiodol = a cottonseed oil based ethiodized oil

mixed with lipophilic anticancer drugs

Must be sterile

May cause allergic reactions

Ex: sesame, corn, peanut, soybean, cottonseed oils

o NEVER mineral oil or paraffin (not absorbed in body)

Maintenance of solubility:

Cosolvent: solubilize

drugs for injection as

aqueous solutions

precipitation if diluted

ethanol, glycerol,

propylene glycol, PEG

Surfactants: non-ionic

used to produce micellar

solutions

Polysorbates,

Cremopher EL,

pluronics

precipitation if diluted

below critical micelle

concentration

Maintenance of sterility:

preservatives are required for

multidose products

(sometimes single dose)

benzalkonium chloride,

benzoyl alcohol, parabens,

chlorobutanol,

chlorocresol, phenol,

thiomersal

Buffers, pH adjustment:

optimize solubility of drugs

(pH 4-8)

Common buffers: citric

acid/citrate; acetic

acid/acetate; phosphates;

benzoic acid/benzoate

Antioxidants/chelators:

ascorbic acid;

bisulfites/metabisulfites;

EDTA; citric acid

For hydrolytically labile

products, freeze drying

may be an option

If mixing formulations, pH

changes precipitation

Lyphophilization

Advantages Disadvantages

Removal of water at low temp.

Drug may not be stable

Ease of reconstitution Damage by the stresses

Compatible w/ aseptic operations

Not all solutes can be freeze-dried to acceptable cake

Relatively high surface area (rapid, complete reconstitution)

Cost may be issue

Temp. difference b/w chamber &

condenser + pressure differential

b/w solution in vial & vacuum

pump drives ice out of vial into

condenser

Characteristics:

Intact cake

Sufficient strength

Uniform color

Sufficiently dry & porous

Sterile

Pyrogen & particulate

free

Chemically stable (dry &

reconstituted)

Ease of administration: adjust isotonicity (not a must): NaCl & dextrose

Lecture 1 Parenteral Drugs Hafeli

Principles of formulation of parenteral suspensions

Particle size < 5 um and total solid content b/w

0.5 -5% w/v

Flow characteristics:

o Syringeability: ability to draw the susp. Into

syringe from vial w/o clogging or foaming

o Injectability: flow properties during

injection (force required for injection &

evenness of flow)

Wetting agent to prevent aggregation

(polysorbates, lecithin, pluronics)

Flocculating agent and/or suspending agent (Na

carboxymethylcellulose, methylcellulose,

polyvinylpyrrolidone, high MW PEG (3350/4000)

Nanocrystal Technology

GRAS stabilizers (generally regarded as safe)

Surface area bigger by making particles smaller

dissolve and are soluble at much higher levels

Controlled release parenterals

Oily solutions

Aqueous suspensions

Oily suspensions

Methods of Intravenous administration

IV injection (IV direct, push, bolus)

Injected using syringe directly into vein or

into port of an injection set

Max 2 mL over 1-5 min

Not all drugs (toxicity)

100% bioavailability

Often followed by a flush

Butterfly needle & heparin lock: needle

attached to tubing (2-3 inch) w/ a re-

sealable rubber port

Upon completion, the needle remains in

pt but tubing flushed w/ saline and

small amount of heparin added to

prevent clotting

Another injection can be made at a later

time

IV infusion or bolus

Continuous intravenous infusion: large volumes infused

over long period of time constant blood levels of drug

First diluted in large volume of

infusion fluid & administered at

constant rate

Exact flow rate: infusion pump

(portable; implanted; non- portable)

Non exact: drip chamber (# of drops/min + clamp to

adjust rate)

Intermittent IV infusion: administered at spaced time

intervals; diluted in mini-bag infused over 15-60 min

Piggyback administration:

Piggyback bag (2o) is hung higher than primary

bag and flows first due to hydrostatic pressure

Once secondary bag (w/ drug) done, primary bag

automatically starts to flow w/o interruption

Check valve prevents backflow of 2o solution

Central line devices – Vascular Access Devices (VAD): administration of meds & fluids; blood tests (mixed

venous oxygen saturation); measurement of CV parameters (CVP); access to other procedures; hemodialysis

1. Hickman line (central venous) catheter: surgically inserted into large central vein leading directly to heart

(jugular, subclavian, femoral) – tunnel made under skin from an exit site to insertion site; catheter sutured

2. Hickman subclavian port: similar to above but does not hang external to body (port implanted under skin)