Sustained-Release Subcutaneous Formulations

The chronic administration of molecules, which have a short biological half-life and cannot be given orally, presents a difficult challenge to formulators. One strategy which might be considered is the development of a sustained-release intramuscular or subcutaneous injection. Other non-parenteral options could include the inhalation or intranasal route, both of which have their own unique challenges. Sustained-release parenteral formulations might also be required in circumstances where patient compliance is likely to be poor. This consideration has led to the development of some antipsychotics and contraceptives as sustained-release injections. Table 9.6 lists some of the sustained-release parenteral products which are available on the U.S. market and their respective formulations. The typical approaches used in the formulation of sustained-release parenterals are summarised in this section. 

Sustained-release injections, subcutaneous and intramuscular, have been investigated in a variety of different formulations [217,218], Injections of degradable microspheres have efficiently prolonged delivery of numerous drugs [219-222], even antigenic substances and vaccines to produce immunity [223,224]. 

Figure 13.8. Effects of route and sustained release formulation on the time course of human growth hormone concentration in plasma. Shown is the average time course of human growth hormone (hGH) in plasma after intravenous (0.02mg/kg) and subcutaneous (0.1 mg/kg) administration in humans. Arrows indicate weekly subcutaneous dosing of hGH in solution. A single dose of the same protein formulated in polylactide-co-glycolide (PLG) microspheres (0.75 mg/kg) given subcutaneously sustains human growth hormone levels in plasma for at least one month.

Tramadol is available as drops, capsules, and sustained-release formulations for oral use, suppositories for rectal use, and solution for intramuscular, intravenous, and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 h, reach peak concentrations after 4.9 h, and have a bioavailability of 87 to 95% compared with capsules. One 100-mg dose given to healthy volunteers resulted in plasma levels of 375 ng/ml at 1.5 h.55 Tramadol is 20% bound to plasma protein and it is rapidly distributed in the body it is mainly metabolized by O- and A-demethylation forming glucuronides and sulfates that are excreted by the kidney. 

The major use of sesame oil in pharmaceutical formulations is as a solvent in the preparation of sustained-release intramuscular injections of steroids, such as estradiol valerate, hydroxy-progesterone caproate, testosterone enanthate, and nandrolone decanoate, or other oil-soluble drug substances, such as, the decanoates or enanthate esters of fluphenazine. The disappearance of sesame oil from the injection site, following subcutaneous or intramuscular administration to pigs, has been reported to have a half-life of about 23 days. ... 

More recently, Maeda et al. developed a new sustained-release formulation of rhG-CSF [122]. The formulation is a double-layer minipellet (DL-MP) that is designed to maintain a sustained release of rhG-CSF without an initial burst. The DL-MP is composed of a core of collagen matrix and a coating layer with collagen. This formulation of rhG-CSF was then prepared, and its characteristics were determined, in normal rats. After subcutaneous administration, it was found that blood rhG-CSF concentration was maintained for about 1 week. Moreover, after admin-... 

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