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

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 (29).

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 (48).

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


Table II. Commercially available injectable sustained-release drug-delivery systems.
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.


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