PARENTERAL PREPARATIONS

Definition:

The word ‘parenteral’ came from the Greek work ‘para enteron’ that means ‘beside the intestine’. So parenteral products mean the dosage forms those deliver drugs through a route other than oral route.

Types of injections

Injections may be classified according to the route of administration, which is given in the tabular form under Routes of Administration.

Intradermal injection

They are made into the skin between the inner layer or dermis, and the outer layer, or epidermis. The skin of the front of the left forearm is usually selected. Other details are given in the table. The drug is injected into the dermis of skin raising a bleb (e.g. BCG vaccine, sensitivity testing of drugs) or scarring / multiple puncture of the epidermis through a drop of the drug (small pox vaccine) is done.

This route is employed for testing of allergen, such as pollens, dust or microorganisms (tuberculin or histoplasmin).

Absorption is very small from this site because very small number of blood capillaries are present. The site should not be massaged.

Body sites of injection: Usually on the outer surface of the left forearm.

Subcutaneous (or Hypodermic) injection

These injections are made under the skin, into the subcutaneous tissue. The drug is deposited in the loose subcutaneous tissue which is richly supplied by nerves (so irritant drugs cannot be injected) but is less vascular (so absorption is slower).

Care must be taken to ensure that the needle is not in a blood vessel. This is checked by lightly pulling back the syringe plunger (a method known as aspiration) before making an injection. If the needle has pierced into a vessel then blood will appear in the syringe and in that situation the injection should not be made.

Sometimes dextrose and electrolyte solutions are given subcutaneously in amounts from 250 to 1000mL. This technique is called hypodermoclysis. This method is used when veins are not available in a patient or are difficult to use for further medication. In this case the hyalouronidase is co-administered with the large volume injection (LVP) that helps in hydrolysis of hyalouronic acid (the cell-cementing material that binds the cells of the tissues), increases the absorption of the liquid and decrease tissue distension.

Body sites of injection: Usually on the most portions of arms, legs and abdomen.

Advantages:

1.       Self injection is possible because deep penetration is not required.

2.       oily solutions or aqueous suspensions can form a depot which will release drug slowly for a prolonged period.

Disadvantages:

1.       Since skin is richly supplied by nerve-endings hence irritant drugs cannot be injected.

2.       Drugs administered in this route produce slower onset of action than i.m. or i.v. route.

3.       This route should be avoided in shock patients.

e.g. Insulin injection.

Intramuscular injection

                The drug is injected in one of the large skeletal muscles that lie below the subcutaneous layer.

Body sites of injection:  Deltoid (upper arm), gluteal (buttock), vastus lateralis (lateral thigh) msucles.

It is important to aspirate before injection to ensure that the needle does not enter into a vein.

Advantages:

1.       Muscle is less richly supplied with sensory nerves, hence mild irritants can be injected.

2.       Muscle is more vascular hence absorption is faster (onset of action 15 to 30mins) than subcutaneous route.

3.       It is less painful.

4.       Depot preparations can be injected by this route and the action of the drug may be prolonged.

Disadvantages:

1.       Since deep penetration is needed hence self-medication is not possible.

2.       Large volume cannot be given.

e.g. Low volume injections - Vitamin A, hydrocortisone acetate, tetanus toxoid, antibiotic etc.

Intravenous injection

                The drug is injected as a bolus (venipuncture) or infused slowly over hours (venoclysis) in one of the superficial veins (generally medial basilic vein).

Rug must be administered through this route slowly because irritation or an excessive drug concentration at sensitive organs such as the heart and brain  (drug shock) may occur.

The duration of action of a drug depends on the pharamcokinetic parameters (rate of distribution and elimination)

Advantages:

(i)                   The drug directly reaches the blood stream and effect is produced immediately, hence, this route can be used in emergencies.

(ii)                 The inside of the veins is insensitive (because no nerve endings are there) and drug gets diluted with blood quickly, therefore, even highly irritant drugs can be injected intravenously.

(iii)                Large volumes can be infused (e.g. normal saline).

(iv)               It is useful in unconscious patients.

(v)                 Desired blood concentration can be achieved.

Disadvantages:

(i)                   Drugs that precipitate in the blood cannot be administered. Only aqueous solution can be administered.

(ii)                 If the needle puncture the vessel (i.e. extra vasation) then thrombophlebitis of the injected vein and necrosis of the adjoining tissues may occur.

(iii)                No drug can be given in depot form - so the action is not prolonged compared to other parenteral administrations.

(iv)               Untoward reactions if occur are immediate.

(v)                 Once administered, withdrawal of the drug is not possible.

Inta-arterial injection

The intra-arterial route involves injecting a drug directly into an artery. It is important that the artery not be missed, since serious nerve damage may occur to the nerves lying close to the arteries.

Dose given through this route must be minimum and given gradually, since, once injected, the drug effect cannot be neutralized.

This route of injection is used to administer radiopaque contrast media for viewing an organ, such as the heart or kidney, or to perfuse an antineoplastic agent at the highest possible concentration to the target organ.

Intrathecal injection

The intrathecal route is employed to administer a drug directly into the cerebrospinal fluid at any level of the cerebrospinal axis. This route is used when it is not possible to achieve sufficiently high plasma levels to accomplish adequate diffusion and penetration into the cerebrospinal fluid. Intrathecal, intraspinal, and intracisternal routes must be formulated at physiologic pH, must be isotonic and must not contain any preservatives in order to minimize nerve damage.

Local anaesthetic drugs are injected through this routes.

Specialized Large-Volume Parenteral and Sterile solutions

Large volume parenterals are designed to provide fluid (water), calories (dextrose solutions), electrolytes (saline solutions), or combinations of these materials.

Hyperalimentation solution (Total Parenteral Nutrition)

Parenteral hyperalimentation involves administration of large amount of nutrients (e.g. carbohydrates, amino acids, lipids and vitamins) to maintain a patient who is unable to take food orally for several weeks at caloric intake levels of 4000kcal/day or more. The formulation when administered through a peripheral vein intravenously at a slower rate the body does not get enough nutrition, so this type of LVP is given as hypertonic solution and given through subclavian vein so the liquid gets diluted very quickly with the blood. This formulation generally consists commonly a mixture of dextrose, amino acids and lipids (usually soybean oil, sunflower oil or mixture of two) containing added electrolytes, trace metals and vitamins.

Nutrition is supplied in this method to comatose patients, patients undergoing oesophageal obstruction, GI disease (including GI cancer), ulcerative colitis, etc.

Cardioplegic solutions

Cardioplegic solutions are large-volume parenteral solutions used in heart surgery to help prevent ischemic injury to the myocardium during the time the blood supply to the heart is clamped off and during reperfusion, as well as to maintain bloodless operating field and to make the myocardium flaccid.

This solutions are typically electrolyte solutions where the electrolyte composition is intended to maintain diastolic arrest.

These solutions are administered in cold condition in order to cool the myocardium and minimize metabolic activity.

These solutions are slightly alkaline and hypertonic in order to minimize acidosis and to minimize reperfusion injury resulting from tissue edema.

Peritoneal dialysis solutions

The sterile peritoneal dilysis solutions are infused continuously into the abdominal cavity, bathing the peritoneum, and are then continuously withdrawn.

The purpose of peritoneal dialysis is to remove toxic substances from the body and accelerates the excretion rate of the drug from the body in case of acute renal insufficiency.

These types of formulations contains

(a)     glucose and ionic content similar to extraceular fluid. In some cases hypertonic glucose solutions are prepared to draw excess fluid from the patient.

(b)     An antibiotic is often added to this solutions as a prophylactic measure.

Irrigating solutions

Irrigating solutions are intended to irrigate, flush, and aid in cleansing body cavities and wounds.

Normal saline may be used as irrigating solution.

Irrigating solutions are sterile and pyrogen free because while it is used to wash the wounds small amount of solution infuses inside the wound.

Formulation factors

The formulation of injections involves careful consideration of the following factors:

1.       The route of administration

2.       The volume of injection

3.       The vehicle in which the medicament is to be dissolved or suspended.

4.       The osmotic pressure of the solution.

5.       The need for a preservative.

6.       The pH of the solution.

7.       The stability of the drug.

1. Routes of administration

Routes	Usual volume	Needle Used Length / Dia	Formulation constraints	Types of medication administered
Subcutaneous	0.5-2ml	5/8in 23gauge	Must be isotonic	Insulins, vaccines
Intramuscular	0.5-2ml	1.5in, 22gauge	Can be oils, suspensions, emulsion. Preferably isotonic.	Nearly all types of drugs.
Intravenous                 Small volume                 Large volume                 (infusion)	1-1000ml 101 and above	Veinpunture 1.5in,20-22gauge Venoclysis 1.5in, 18-19gauge	Solutions, emulsions and liposomes Solutions and some emulsions (TPN)	Nearly all types of drugs Nearly all types of drugs
Intra-arterial (Directly into an artery)	2-20ml	20-22gauge	Solutions and some emulsions	Radiopaque media, antineoplastics, antibiotics.
Intrathecal (into spinal canal)	1-4ml	24-28gauge	Must be isotonic	Local anaesthetics, analgesics, neurolytic agents.
Intraepidural (into epidural space near spinal cord)	6-30ml	5in,16-18gauge	Must be isotonic	Local anaesthetics, narcotics, a2-agonists, steroids.
Intracisternal (directly into caudal region of the brain between the cerebellum and medula oblongata)			Must be isotonic

Routes	Usual volume	Needle Used Length / Dia	Formulation constraints	Types of medication administered
Intra-articular (directly into a joint)	2-20ml	1.5-2in, 18-22 gauge	Must be isotonic	Morphine, local anaesthetics, steroids, NSAIDs, antibiotics.
Intracardial (directly into the heart)	0.2-1	5 in 22gauge		Cardiotonic drugs (epinephrine), calcium.
Intrapleural (directly nito the pleural cavity of the lung)	2-30ml	2-5 in 16-22 gauge		Local anaesthetics, narcotics, chemotherapeutic agents
Intradermal	0.05ml	½ - 5/8 in, 25-26 gauge	Should be isotonic	Diagnostic agents for investigation of immunity and allergy to any agent.

 

2. Volume of injection

Usually the volume of an injection depends on the route of administration. Only the intravenous route is really suitable for large volume parenterals (LVP).  In subcutaneuous route generally 0.5-2ml volume may be injected. Some times veins of a patient are unavailable. In those cases instead of intravenous infusion large volume parenterals (250 to 1000ml) may be injected subcutaneously. This technique is called hypodermoclysis. In most of this case the injection is given along with hyalouronidase an enzyme that hydrolyses the hyalouronic acid, the viscous cell-cementing agent. It helps in rapid absorption of the injection and reduces tissue distension. The hydrolysis is reversible and the acid is reformed in about 20minutes after completion of the injection.

The volume must be convenient to administer. Less than 20ml is suitable for injection with a syringe and more than 250ml injections are given as infusion.

3. Vehicle