Parenteral products

Parenteral products

Derek G. Chapman

Reasons for parenteral administration

Routes available for parenteral administration

Forms and types of parenteral product

Design of containers for the administration of parenteral products

Formulation and uses of parenteral products

Introduction

In practice, parenteral products are often regarded as dosage forms that are implanted, injected or infused directly into vessels, tissues, tissue spaces or body compartments. Parenteral products are often used for drugs that cannot be given orally. This may be because of patient intolerance, the instability of the drug, or poor absorption of the drug if given by the oral route. From the site of administration the drug is transported to the site of action. With developing technology, parenteral therapy is being used outside the hospital or clinic environment: at a patient’s home or their workplace, allowing self-administration.

Parenteral therapy is used to:

Produce a localized effect

Administer drugs if the oral route cannot be used

Deliver drugs to the unconscious patient

Rapidly correct fluid and electrolyte imbalances

Ensure delivery of the drug to the target tissues.

Parenteral injections are either administered directly into blood for a fast and controlled effect or into tissues outside the blood vessels for a local or systemic effect. An intravenously administered (IV) injection will rapidly increase the concentration of drug in the blood plasma, but this concentration falls due to the reversible transfer of the drug from blood plasma into body tissues, a process known as distribution. An IV infusion administers a large volume of fluid at a slow rate and ensures that the drug enters the general circulation at a constant rate. A steady state is reached when the rate of drug addition equals the rate of drug loss in the blood plasma. When infusion is stopped, elimination of the drug from the body generally follows first-order kinetics.

Following subcutaneous (SC) and intramuscular (IM) injection, there is a delay in the systemic effects of the drug due to the time taken for the drug to first pass through the walls of the capillaries before entering into the blood. This occurs by passive diffusion that is promoted by the concentration gradient across the capillary wall. The drug concentration in the blood plasma rises to a peak level and then falls due to distribution to the tissues followed by metabolism and excretion.

Administration procedures

IV injections and infusions

The vein that is selected for administering the formulation depends on the size of the delivery needle or catheter, the type and volume of fluid to be administered and the rate at which the fluid is to be administered. The fluids are administered into a superficial vein, commonly on the back of the hand or in the internal flexure of the elbow. The intravenous route is widely used to administer parenteral products, but it must not be used to administer water-in-oil emulsions or suspensions.

SC injections

These are injected into the loose connective and adipose tissue immediately beneath the skin in the abdomen, the upper back, the upper arms and the lateral upper hips (Fig. 41.1). Typically, the volume injected does not exceed 1 mL. Following administration, the site of the injection, the body temperature, age of the patient and the degree of massaging of the injection site will all affect the drug distribution.

Figure 41.1 Injection routes. ID, intradermal; SC, subcutaneous; IM, intramuscular.

IM injections

Small-volume aqueous solutions, solutions in oil and suspensions are administered directly into the body of a relaxed muscle, such as the gluteal muscle in the buttock, the deltoid muscle in the shoulder and the vastus lateralis of the thigh (Fig. 41.1).

Other routes of parenteral administration include intradermal, intra-arterial, intracardiac, intraspinal and intra-articular.

Products for parenteral use

Parenteral products include injection, infusion and implantation.

Injections

These are subdivided into small- and large-volume parenteral fluids. Small-volume parenteral fluids are sterile, pyrogen-free injectable products. They are packaged in volumes up to 100 mL. Small-volume parenteral fluids are packed as:

Single-dose ampoules

Multiple-dose vials

Prefilled syringes.

Single-dose ampoules

Most small-volume parenteral fluids are currently packaged as either ampoules or vials. Glass ampoules are thin-walled containers made of Type I borosilicate glass (see Fig. 32.2). Injections packaged in glass ampoules are manufactured by filling the product into the ampoules, which are then heat sealed. To achieve the quality required of these products, the packaged solution must be sterile and practically free of particles. These products are prepared in clean room conditions (see Ch. 40). Opening glass ampoules may contaminate the product with glass particles; this is a hazard to the patient. Modern glass ampoules have weakened necks to reduce the number of particles.

Plastic ampoules are prepared, filled and sealed by a procedure known as blow-fill-seal in which the semi solid plastic is blow moulded and formed into ampoules. These containers are filled with the product and immediately sealed. This system is only used to package simple solutions due to absorption of the drug by the plastic. When the ampoule is opened only a few particles are released into the solution.

Ampoules should have a reliable seal that can be readily leak tested and will not deteriorate during the lifetime of the product. Ampoules do not contain added antimicrobial preservatives. The ampoule must contain a slight excess volume of product. This is necessary to allow the nominal injection volume to be drawn into a syringe.

Multiple-dose vials

These are composed of a thick-walled glass container that is sealed with a rubber closure. The closure is kept in position by an aluminium seal (see Fig. 32.4), then covered with a plastic cap. The cap is removed before a needle, attached to a syringe, is inserted through the rubber closure to withdraw a dose of product. The contents of the vial may be removed in several portions.

There are disadvantages with the use of glass vials. Fragments of the closure may be released into the product when the needle is inserted through the closure. There is also the risk of interaction between the product and the closure. Repeated withdrawal of injection solution from these containers increases the risk of microbial contamination of the product. These products must, therefore, contain an antimicrobial preservative unless the medicine itself has antimicrobial activity. An example of such a multidose product is insulin.

Prefilled syringes

With these devices, the injection solution is aseptically filled into sterile syringes. The packed solution has a high level of sterility assurance and does not contain an antimicrobial preservative. The final product is available for immediate use. Prefilled syringes are becoming increasingly common.

Administration of small-volume parenteral products

Hypodermic syringes and needles are extensively used for administering small volumes of parenteral formulations to the patient. These syringes have been sterilized by ethylene oxide gas or by gamma irradiation following packaging. Various sizes of hypodermic syringes are available. They are composed of a barrel, having a graduated scale, together with a plunger and a headpiece, known as a piston (Fig. 41.2). These components are often made of polypropylene.

Figure 41.2 Hypodermic syringe for single use.

Formulation of parenteral products

Vehicles for injections

The vehicle provides the highest proportion of the formulation and should not be toxic nor have any therapeutic activity.

Water for Injections

Water for Injections is the most extensively used vehicle in parenteral formulations, Water for Injections must be free of pyrogens and have a high level of chemical purity. The BP considers that Water for Injections can only be prepared by distillation.

Sterilized water for injections

This is prepared by packing a volume of Water for Injections in sealed containers. These containers are then moist-heat sterilized which yields a sterile product that remains free of pyrogens.

Pyrogens

Pyrogens are fever-producing substances. Water is the greatest source of pyrogens in parenteral products. Pyrogens can be removed in the preparation of water for injections by distillation. Water that is free from pyrogens is termed apyrogenic.

Microbial pyrogens arise from components of Gram-negative and Gram-positive bacteria, fungi and viruses. Non-microbial pyrogens are for example some steroids and plasma components.

Parenteral products must be prepared in conditions that reduce microbial contamination because bacteria contaminating aqueous solutions can release pyrogens. Contaminated solutions will become more pyrogenic with the passage of time. Therefore, these products must be sterilized shortly after preparation.

Dry heat at 250°C for 30 min is the most common method of inactivating pyrogens.

Non-aqueous solvents

Water-miscible co-solvents, such as glycerin and propylene glycol, are used as vehicles in small-volume parenteral fluids. They are used to increase the solubility of drugs and to stabilize drugs degraded by hydrolysis.

Metabolizable oils are used to dissolve drugs that are insoluble in water. For example, steroids, hormones and vitamins are dissolved in vegetable oils. These formulations are administered by intramuscular injection.

Additives

Various additives, such as antimicrobial agents, antioxidants, buffers, chelating agents and tonicity-adjusting agents, are included in injection formulations. Their purpose is to produce a safe and elegant product. Both the types and amounts of additives to be included in formulations are given in the appropriate monograph in the BP.

Antimicrobial agents

Antimicrobial agents are added to inhibit the growth of microbial organisms that may accidentally contaminate the product during use, for example, multiple-dose vials. The antimicrobial agents must be stable and effective in the parenteral formulation. Rubber closures have been shown to take up antimicrobial preservatives from the injection solution. Preservative uptake is more significant with natural and neoprene rubber and much less significant with butyl rubber closures.

Antioxidants

Many drugs in aqueous solutions are easily degraded by oxidation. Small-volume parenteral products of these drugs often contain an antioxidant. Bisulfites and metabisulfites are commonly used antioxidants in aqueous injections. Antioxidants must be carefully selected for use in injections to avoid interaction with the drug. Injections may, in addition to antioxidants, also contain chelating agents such as EDTA or citric acid, which remove trace elements.

Buffers

The ideal pH of parenteral products is pH7.4. If the pH is above pH9, tissue necrosis may result, while below pH3, pain and phlebitis can occur.

Buffers are included in injections to maintain the pH of the packaged product. Changes in pH can arise through interaction between the product and the container. Acetate, citrate and phosphate buffers are commonly used in parenteral products.

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Tags: Pharmaceutical Practice

Jun 24, 2016 | Posted by admin in PHARMACY | Comments Off

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