Drugs delivered as sustained-release injectables
Various drugs are investigated for sustained-release injectable delivery systems for controlled drug delivery as recently
described by these authors (6). These systems include small molecular drugs and protein/peptide drugs. Examples of drugs for
sustained-release injectable delivery systems include: hormone therapy (i.e., human somatropin) (7, 8); protein therapeutics
such as the analog of glucagon-like peptide-1 (9); recombinant human bone morphogenetic protein-2 (10); superoxide dismutase
(11); salmon calcitonin (12, 13); insulin (14–16); gene delivery such as plasmid DNA (17–19); cancer therapeutic agents such
as bleomycin (20), paclitaxel (21), cisplatin (22), a peptide-like antineoplastic agent (23); postoperative pain therapeutic
agents such as ketorolac tromethamine (24); schizophrenia drugs such as aripiprazole (25), olanzapine (26); contraceptive
peptide vaccine (27); drugs to treat alcohol dependence such as naltrexone (28); and immunosuppressive drugs such as rapamycin
Despite a number of parenteral depot studies using a variety of drugs, only drugs in limited therapeutic areas are available
on the market. Antipsychotic drugs and hormones have been used for more than five decades in the field of schizophrenia and
hormone replacement therapy. Since the first launching of microsphere formulation, Lupron Depot (Abbott, Abbott Park, IL)
for the palliative treatment of advanced prostate cancer in 1989, several microsphere formulations and in situ-forming implants have been released on the US market. The therapeutic indications and drugs of commercialized products include:
the palliative treatment of advanced prostate cancer (leuprolide acetate and triptorelin pamoate); the treatment of acromegaly
(octreotide acetate and lanreotide acetate); the long-term treatment of growth failure (somatropin-rDNA origin); the treatment
of schizophrenia (risperidone); and the treatment of alcohol dependence (naltrexone).
Polymers in injectable sustained release
As recently described by these authors (6), a variety of biodegradable polymers for controlled drug delivery intensively studied
over the past several decades include polylactides (PLA), polyglycolides (PGA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone)
(PCL), polyglyconate, polyanhydrides, polyorthoesters, poly(dioxanone), and polyalkylcyanoacrylates. Among the various approaches
to deliver macromolecules parenterally, injectable biodegradable microspheres are the most successful systems (30). Many microsphere
research reports have demonstrated the usefulness of biodegradable polymers such as PLGA microspheres (31–38), PCL microspheres
(39), polyanhydride microspheres (40), polyorthoesters microspheres (41), and polyalkylcyanoacrylate microspheres (42, 43).
The Atrigel technology that is used in Eligard containing leuprolide acetate and PLGA is a once-monthly in situ-forming implant for the palliative treatment of advanced prostate cancer. Many reports have been published on novel biodegradable
in situ-forming polymers such as multiblock poly(ether ester urethane)s consisting of poly-[(R)-3-hydroxybutyrate] (PHB), poly(ethylene glycol) (PEG), and poly(propylene glycol) (PPG) polymer (44), PEG-grafted chitosan
polymer (Chitosan–PEG) (45), methoxy poly(ethylene glycol)–poly(sebacic acid–D,L–lactic acid)–methoxy poly(ethylene glycol)
triblock copolymer (mPEG–poly(SA–LA)–mPEG) (46), PCL–PEG–PCL triblock copolymer (47), and PLGA–PEG–PLGA triblock copolymer
Commercialized polymer-based injectable depot systems have used polymers or copolymers composed of monomers of lactic and
glycolic acid. These polymers have the advantages of being semipermeable, biocompatible, and biodegradable, which makes them
universally acceptable as injectable materials for drug-depot systems (49).
Commercially available injectable sustained-release drugs
The list of commercially available injectable sustained-release drug delivery systems available on the market as pharmaceutical
products is shown in Table II. Parenteral long-acting formulations (oil-based solutions and drug suspensions) have been in
clinical use for many decades in the field of hormone replacement therapy. Sesame oil-based injection containing testosterone
enanthate (i.e, Delatestryl, Endo Pharmaceuticals, Chadds Ford, PA) and castor oil-based injection containing estradiol valerate
(Delestrogen, Monarch Pharmaceuticals, Bristol, TN) were approved by the US Food and Drug Administration in the 1950s, and
drug suspension for injection containing medroxyprogesterone acetate (Depo-Provera, Pfizer) was approved by FDA in September
1960. The administration route of these products is IM injection, and all of these products are still available on the market.
In 2004, long-acting SC injection of medroxyprogesterone acetate (Depo-SubQ Provera 104, Pfizer), which is equally effective
despite an almost 30% reduction in the dose, was approved by FDA. The first long-acting injectable microspheres of recombinant
growth hormone (Nutropin Depot, Genentech) received approval from FDA for pediatric growth hormone deficiency (GHD) in December
1999. Nutropin Depot is designed to be administered by SC injection once or twice monthly.
Table II. Commercially available injectable sustained-release drug-delivery systems.