This article is part of a special issue on Drug Delivery
(GEORGE DIEBOLD, PHOTODISC, GETTY IMAGES)
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Reproducible sustained delivery of a drug at a target site is one of the main themes in controlled drug-delivery systems.
The most commonly used drug-delivery systems, which can release drugs longer than one week, are parenteral injections and
implants. Certain implant systems can deliver drugs for more than one year, and the longest drug delivery can be achieved
by biodegradable or nonbiodegradable implant systems. Some examples of US Food and Drug Administration approved long-acting
products are listed in Table I.
Table I: Examples of US Food and Drug Admistration-approved long-acting formulations on the market.*
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Long-acting injectable formulations offer many advantages when compared with conventional formulations of the same compounds.
These advantages include the following: a predictable drug-release profile during a defined period of time following each
injection; better patient compliance; ease of application; improved systemic availability by avoidance of first-pass metabolism;
reduced dosing frequency (i.e., fewer injections) without compromising the effectiveness of the treatment; decreased incidence
of side effects; and overall cost reduction of medical care.
This review focuses on the current status and explores long-acting injectables with special attention to marketed products.
Injectable routes, types of long-acting injectables (i.e., oil-based injections, injectable drug suspensions, injectable microspheres,
and injectable in situ systems), drugs and polymers for depot injections, commercially available depot injections, and future injectable sustained-release
drug-delivery systems are also discussed.
Types of injectable routes of administration
It is well recognized that the advantages of parenteral injections are immediate systemic drug availability and rapid onset
of action. Another significant and unique advantage of parenteral injection is a long-term drug delivery by the formation
of a depot or reservoir at the injection site after drug administration. As depicted in Table I, intravenous (IV) injection
can be used for certain prolonged acting drugs due to the drugs' long half-lives in the body after IV administration. The
sustained release of drug from these preparations is a result of the long-acting property of drug and its residence in the
bloodstream or the bone.
In general, there are two routes by which long-acting parenteral injections are most frequently administered: intramuscular
(IM) and subcutaneous (SC). To determine the injectable route of administration for long-term delivery formulations, many
factors should be considered such as safety profile, ease of administration, patient's limited mobility, area for target injection
sites, quality of life and cost of therapy (1). In many cases, SC is the preferred route for administering a drug by injection
because of greater area for target injection sites, use of shorter needles, ease of self-administration, less discomfort and
inconvenience for patients, and better safety profile (1). Various insulin products are given SC, and this route of administration
presumably continues to represent the primary route of delivery for protein-based drugs. However, the volumes of SC injection
are usually limited to no more than 1–2 mL, and only nonirritant substances can be injected by a SC route because irritants
can cause pain, necrosis, and sloughing at the site of injection. On the other hand, greater injection volumes (2–5 mL) can
be given by the IM route. Mild irritants, oils, and suspensions can be injected by IM route in the large skeletal muscles
(i.e., deltoid, triceps, gluteus maximus, and rectus femoris) because these muscles are less richly supplied with sensory
nerves and are more vascular. Therefore, a few SC injections for long-term release can be found on the market (i.e., Depo-SubQ
Provera 104, Pfizer (New York); Nutropin Depot, Genentech (South San Francisco, CA), and Eligard, sanofi-aventis (Paris),
and many long-acting IM injections are available on the market (oil-based injections, injectable drug suspensions, and injectable
microspheres).
