Injectable solution I - Shih

Enteral

Drug administration via the GI tract

Parenteral

Any method of drug administration that does not involve the GI tract

IV, IM, SC

Requirements of parenteral dosage forms

Sterile - free from micro-organisms

Pyrogen free - free from fever inducing agents (LPS from bacteria)

When are parenterals given

When rapid action is needed

When patient is uncooperative, unconscious, or unable to accept or tolerate oral medications

When the drug is ineffective in other methods of administration

Types of parenteral routes

IV

Intraarterial: vasodilators for vasospasm

IM
SC

Intradermal: for allergen testing

Intrathecal: spinal canal for anesthesia

Intracardiac: adrenaline for resuscitation

Intraarticular: joints

Intraperitoneal: peritoneal dialysis

Intravesical: infusion into urinary bladder

IV

Fastest route of administration

Once administered it cannot be retrieved

Possibility of thrombus and embolus formation

Preparations must be isotonic (not suspensions)

Preparations must mix with blood and not precipitate

Small volumes and large volumes - bolus and drip

IM

Less rapid but longer lasting than IV

IM solutions - fast

IM suspension, oleaginous - slow

Point of injection as far as possible form major nerves and blood vessels

SC

Under the skin

For injecting small amounts of medication

1.3-2mL

Intradermal

Very small volume ~0.1mL

Usually done on the anterior forearm

Absorption from this site is slow

Used for immunological diagnostic tests (TB)

Types of injections according to USP

Injection

For injection

Injectable emulsion

Injectable suspension

For injectable suspension

Dispersions

Solutions

For injection

Dry solids that, upon addition of suitable vehicles, yield solutions conforming to the requirements for injections

Injectable emulsions

Liquid preparation of drug substance dissolved or dispersed in a suitable emulsion medium

Injectable suspension

Liquid preparation of solids suspended in suitable liquid medium

For injectable suspension

Dry solid, that upon addition of a suitable vehicle, yields a preparation conforming to the requirements for injectable suspensions

Selecting injection type

Stability - poor → dry, good → solution

Solubility - depending on solubility can make aqueous, oleaginous, emulsion, or suspension

Onset - fast → solution, slow → oleaginous/suspension

Duration - short → solution, long → oleaginous or suspension

Specific requirements for parenteral solution

Solvents or vehicles must meet special purity and safety standards

The use of excipients falls under specific guidelines and is restricted in certain parenteral. Coloring agents are prohibited.

Products are always sterilized, must meet sterility standards, and must not exceed allowable endotoxin limit.

Parenteral must meet standards for particulate matters

Must be prepared in environmentally controlled areas, under strict sterility standards

Parenteral must be packaged in special hermetic containers of specific and high quality

Each container is filled to column in slight excess of labeled volume to be withdrawn

The volume of injection permitted in multiple dose containers is restricted

Specific labeling requirements

Sterile powders are frequently packaged as lyophilized or freeze dried powders for ease of constitution

Active Drug in parenterals

Physical and chemical purity is important

Need special parenteral grade (sterility, pyrogen free, high chemical purity)

Strict conditions to prevent microbial contamination

Small packages to allow usage of the entire pack

Kinds of excipients in parenteral

Solvents in solutions, vehicles in dispersions

Solubilizers

buffers

antioxidants

preservatives

Tonicity contributors

Gases

Purpose of excipients in parenterals

Aid in production of the dosage form

Enhance physical, chemical, and microbial stability

Enhance safety of the product

Requirements for excipients in parenterals

Be non-toxic at the levels used

Not reduce product’s efficacy

Be compatible with other components of the parenteral preparation

Water for parenterals

Must be purified by distillation or reverse osmosis

Must be pyrogen free (<0.25)

Can not be labeled as sterile as it will be sterilized later

Needs to be collected in sterile pyrogen free containers

Limited to plant and manufacturing sites

Intended to be used within 24 hours after collection

Sterile water for parenteral injection

Not used in IV products because it is not isotonic

For reconstituting sterile powders to be used for parenteral administrations

For single dose container not larger than 1 liter

Endotoxin units <0.25

Bacteriostatic water for parenteral injection

Contains bacteriostatic agent

Name and concentration of agent should appear on label

No more than 30mL for multiple dose containers

Toxicity issue

not for use in neonates due to benzyl alcohol use

Sodium Chloride for Parenteral

Solvent

Sterile Isotonic solution (0.9%)

Sterile vehicle for solutions and suspensions for parenteral

No antimicrobial agents

Ringers injection

A sterile solution of NaCl, potassium chloride, and calcium chloride in water for injection

Lactated ringer injection

Has different quantities of the three salts in ringer injection, and it contains sodium lactate. Used as vehicle for electrolyte replenishment

Nonaqueous solvents for parenteral use requirements

Be non-toxic

Be non-irritating

Be non-sensitizing

Not have pharmacologic effect

Not degrade the drug

Have chemical and physical stability

Optimal viscosity for ease of injection

Fluidity over wide range of temperatures

Have sufficient high boiling point, low vapor pressure to allow heat sterilization

Be absorbed by body tissues

Not to be used in IV injections

Examples of nonaqueous solvents

Vegetable oils, glycerin, alcohols

Solubilizers for parenterals

Enhance solubility of the active ingredient

Examples of solubilizers

Ethyl alcohol

Polysorbate 20,40,60,80

Glycerin

Buffer capacity

Measures the ability of buffer solution to resist pH changes on addition an acid or a base. Important because drug properties can significantly be altered by pH changes.

What can cause pH changes

Glass

Dissolved gas

Released material from closures

Reactions within the product

Examples of buffers

Acetate, phosphate, citrate

Antioxidants

Protect the drug from oxidation

Replacing O2 with N2 or CO2

Reducing agents

Preferentially oxidize first

Ascorbic acid, sodium bisulfite

Blocking agents

Block the oxidation chain

Ascorbic acid esters, butyl hydroxy toluene (BHT)

Synergistic agents

Citric acid

Ascorbic acid

Chelating agents

Scavenge catalysts that accelerate oxidation

EDTA sodium

Preservatices

Prevent growth and kill microorganisms

USP requires them to be added to multiple dose containers to prevent growth of microorganisms regardless of method of sterilization employed

Examples of preservatives

Mercury and the cationic surface-active compounds

Chlorobutanol, cresol, phenol

Benzoyl alcohol

Tonicity contributors

Biologic systems are compatible with solutions having similar osmotic pressures, that is an equivalent number of dissolved species. Normal tonicity is 0.9%

Plastic container

Cheap, flexile, non-breakable, light weight

Must not react with the product

Product ingredients must not migrate into the plastic or vice versa

Must withstand sterilization process

Gas permeation is an issue

Examples of plastic containers

PVC bags, PP, HDPE, polyamide

type 1 Glass container

Borosilicate, most resistant

Type 2 glass container

Treated soda lime with sulfure, blocks UV

Type 3 container

Soda lime, most common

Containers for parenterals

Individual drug monographs will indicate which packaging is preferred. Consider size of dose. The size of multiple dose up to 30mL only to limit the number of entries.

Rubber closures

Plastic material

Prevents access of microorganisms into the product

Permit entry and withdrawal product without removing closure

Should not react with product

Caps

Hold stoppers in place

Usually made of aluminum

Ampules

Made of thin, medical grade glass

Used for materials incompatible with rubber or pvc components found in most vials