Sustained-Release Injectable Drug Delivery - Pharmaceutical Technology

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Sustained-Release Injectable Drug Delivery
A review on the current status of long-acting injectables, including commercially marketed products. This article is part of a special Drug Delivery issue.


Pharmaceutical Technology
pp. s6-s13

In the 1960s, parenteral depot formulations of typical antipsychotic drugs were introduced for clinical use in Europe (50). Although long-acting typical antipsychotic formulations are widely used in Europe, clinicians in the United States have thus far been reluctant to use them despite their potential advantages because of several reasons such as concerns about increased adverse effects compared with oral therapy and the belief that patients do not accept or tolerate depot formulations as well as oral agents (51). Therefore, many oil-based depot formulations containing typical antipsychotic drugs (haloperidol decanoate, flupenthixol decanoate, fluphenazine decanoate, zuclopenthixol decanoate, and pipothiazine palmitate) are available on the market in Europe, Canada and Australia, but only haloperidol decanoate (Haldol Decanoate) and fluphenazine decanoate (Fluphenazine Decanoate injection) formulations are available in the US. In 2003, the long-acting formulation of risperidone (Rispedal Consta, Janssen, division of Ortho-McNeill Janssen Pharmaceutical, Titusville, NJ) became the first depot atypical antipsychotic drug to become available in the US (51). Rispedal Consta is formulated as an aqueous suspension of biodegradable microspheres. Water is added to the vial of microspheres, and the aqueous suspension is injected intramuscularly every 2 weeks (52). FDA approved paliperidone palmitate long-acting injectable suspension (Invega Sustenna, Janssen) for the acute and maintenance treatment of schizophrenia in July 2009 (53–56). Paliperidone palmitate, an atypical antipsychotic agent, is the palmitate ester of paliperidone and is the major active metabolite of risperidone (9-hydroxy-risperidone) (53). Paliperidone palmitate was formulated as an aqueous drug suspension with a specific particle-size distribution that has sustained-release properties and thus facilitates monthly dosing (53). In 2009, a long-acting depot formulation of olanzapine pamoate (Zyprexa Relprevv, Eli Lilly, Indianapolis, IN) was approved by FDA for the US market (57–59). Zyprexa Relprevv is an aqueous drug suspension containing a salt of pamoic acid and olanzapine (olanzapine pamoate monohydrate) for deep IM gluteal injection (60).

Lupron Depot (leuprolide acetate) is the first marketed injectable PLGA microspheres in the US (approved in 1989) (61). Lupron Depot provides fairly constant release of the peptide during 1 month or 3 months in humans after IM injection and show sufficiently reliable efficacy for the treatment of patients with hormone-dependent cancers such as advanced prostate cancer (61). Encouraged by success of Lupron depot, several PLGA microsphere formulations have been investigated, and Trelstar (triptorelin pamoate, Watson Pharmaceuticals, Corona, CA) received approval from FDA for the palliative treatment of advanced prostate cancer in June 2001. Trelstar is designed to be administered by a single IM injection in either the buttocks, and the dosing schedule (one-, three- or six-month) depends on the product strength selected. In January 2002, the first parenteral in situ-forming formulation, Eligard was approved by FDA for the US market. Eligard uses the Atrigel technology, and Atrigel is a polymeric (nongelatin-containing) delivery system consisting of a biodegradable PLGA polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP). Eligard is administered subcutaneously, where it forms a solid drug-delivery depot and is designed to deliver leuprolide acetate at a controlled rate during a one-, three-, four- or six-month therapeutic period.

In April 2006, FDA approved naltrexone extended-release injectable suspension (Vivitrol, Alkermes, Waltham, MA) for the treatment of alcohol dependence. Vivitrol is supplied commercially as a microsphere formulation of naltrexone for suspension, to be administered by intramuscular injection every four weeks.

Sandostatin LAR Depot (Novartis, Basel, Switzerland) received approval from FDA in November 1998 for the treatment of acromegaly, a chronically disfiguring and debilitating hormonal disorder. Sandostatin LAR Depot is a sterile PLGA microspheres formulation of octreotide acetate for IM injection at every four weeks. Although it is not available in the US, a prolonged release PLGA microsphere formulation of lanreotide acetate for injectable suspension (Somatuline LA, Ispen Pharmaceuticals, Kleve, Germany) is available as a commercially available pharmaceutical product on the market in Europe. The indication of Somatuline LA is the same as that of Sandostatin LAR Depot, and Somatuline LA is designed to be administered by IM injection every two weeks.

FDA approved Somatuline Depot for the long-term treatment of acromegaly in August 2007. Somatuline Depot formulation consists of a unique supersaturated concentration of lanreotide acetate (24.6% w/w lanreotide base), and contains only water for injection as an excipient (62). It is thought to form a precipitated drug depot at the injection site due to the interaction of the formulation with physiological fluids because Somatuline Depot can produce a stable gel when mixed with water at a specific temperature and pressure. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot toward the surrounding tissues, followed by the absorption to the bloodstream for a month. The administration route of Somatuline Depot is deep SC injection.


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