Long-acting injectables (LAI), typically administered through subcutaneous or intramuscular routes, form a drug depot at the injection site, enabling sustained release of the medication. These formulations are capable of releasing drugs continuously over days to months, offering advantages such as reduced dosing frequency, simplified administration regimens, fewer adverse reactions, and minimal pharmacokinetic fluctuations. Long-acting injectables find widespread use in the fields of antipsychotic, antiviral, and addiction treatments.
Figure 1. Fundamentals of the development and application of long-acting injectables [2]
Compared to oral formulations, long-acting injectables offer the advantages of stable blood drug concentrations and an extended effective duration lasting several weeks to months, thereby reducing the dosing frequency.
Common Types of Long-Acting Injectables
The key to achieving sustained drug release in LAIs lies in slowing down the release of the drug at the administration site through specific means. Currently, there are two common types of long-acting injectable formulations: carrier-controlled release and drug self-controlled release.
Drug Self-Controlled
Self-controlled release LAIs rely on the inherent properties of the drug to achieve controlled release. Drug molecules possess specific chemical structures and characteristics that allow for controlled release through factors such as their solubility, degradation rate, or complex chemical reactions.
In the drug self-controlled release formulation, drug molecules are designed to release at a slow rate, thereby achieving a prolonged therapeutic effect. This can be accomplished through the regulation of the drug molecule's physicochemical properties, crystalline form, structural modifications, and other means.
1. Ester prodrugs
Esterification is one of the commonly used methods for forming lipophilic prodrugs. Typically, this method involves the esterification of the hydroxyl group in drug molecules with fatty acids, aiming to adjust the drug's solubility, distribution coefficient, and melting point, among other physicochemical properties. After release, most ester prodrugs can be effectively cleaved into the parent drug in the body by esterases. The process of esterase cleavage further enhances the slow release and absorption of the drug.
Representative examples of this technology include the first generation of typical long-acting antipsychotic drugs such as Lyogen Depot (fluphenazine decanoate), Fluanxol Depot (flupentixol decanoate), Clopixol Depot (zuclopenthixol decanoate), etc.
2. Microcrystal Technology
Microcrystals refer to small crystalline particles with dimensions typically ranging from a few micrometers to a few hundred micrometers. The release of drugs from crystals is primarily determined by the dissolution kinetics in the local tissue fluid and the surface area of drug crystals. Microcrystal technology, by controlling the surface area of microcrystals, and altering properties such as adsorption capacity and surface activity, enables the controlled release of drugs. Common methods for manufacturing microcrystals include solvent-antisolvent precipitation, media milling, and high-pressure homogenization.
Poorly water-soluble drugs, after undergoing microcrystal technology to be processed into micrometer or nanometer particles, can further be formulated with appropriate excipients into suspensions to achieve a prolonged and sustained-release effect. Representative drugs include Invega Sustenna (1-month paliperidone palmitate extended-release injectable suspension), Invega Trinza (3-month paliperidone palmitate injection), as well as Kenalog (triamcinolone acetonide injection suspension) and Bicillin L-A (suspension of benzathine penicillin G).
Carrier-Controlled
In carrier-controlled LAIs, the drug is embedded or encapsulated in a carrier such as polymers, microspheres and gels, etc. The characteristics and degradation rate of this carrier influence the rate of drug release. Over time, the carrier gradually degrades, leading to the slow release of the drug into surrounding tissues. This approach allows for more precise control of the drug release rate.
1. Implants
There are mainly two types of implants, preformed implants and in-situ formed implants.
Preformed implants refer to cylindrical solid structures with a length of 1-3 cm and a diameter of 1-3 mm, which are injected subcutaneously through surgery or a large syringe. Preformed implants can further be classified into biodegradable and non-biodegradable types:
- ▶ Non-biodegradable implants typically require surgical removal at the end of the treatment.
- ▶ Biodegradable implants gradually degrade into metabolizable organic monomers (such as PLGA degrading into lactic acid and glycolic acid) after implantation.
Regardless of whether they are degradable or not, patients using preformed implants cannot avoid wound injuries during the usage [5].
Zoladex®, a long-acting subcutaneous (s.c.) implantable formulation of goserelin acetate, was developed by AstraZeneca UK Limited and approved by FDA in 1989 for the treatment of hormone receptor-positive patients with premenopausal and peri-menopausal breast cancer, prostate cancer, endometriosis, and other conditions.
Leuprone® HEXAL® (leuprorelin acetate implant) is an implant in the form of a rod, where leuprorelin is uniformly dispersed in a matrix of PLGA (poly(lactic-co-glycolic acid)) and polylactic acid after being converted into its acetate form. This implant enables sustained release for a period of 1-3 months and is used for the treatment of advanced hormone-dependent prostate cancer.
Viadur® (leuprolide acetate implant) is a small, rod-shaped device that is surgically implanted under the skin. The implant slowly releases leuprolide acetate into the body over up to 12 months, providing a continuous and controlled release of the medication and decreasing serum testosterone in advanced prostate cancer patients.
In situ forming implants are injectable liquid formulations that form solid or semisolid depots following injection. These depots provide a controlled release of the drug over an extended period. Compared to preformed implants, in-situ formed implants have lower invasiveness.
SUSTOL® (granisetron) extended-release injection is a serotonin-3 (5-HT3) receptor antagonist that utilizes Heron's Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for ≥5 days, covering both the acute and delayed phases of chemotherapy-induced nausea and vomiting (CINV).
2. Microcapsule/Microsphere Technology
Microspheres and microcapsules are established as unique carrier systems for many pharmaceuticals and can be tailored to adhere to targeted tissue systems. For the preparation of microspheres, the drug can be dispersed, dissolved or emulsified in the matrix-forming material. For microcapsules, the core material may be an aqueous solution, emulsion, dispersion or melted material. The only restriction is that the material to be encapsulated produces no chemical reaction with the wall-forming material.
Microcapsule and microsphere technologies share some similarities in drug release. After undergoing processing with these techniques, drugs are encapsulated within polymers, making them less prone to easy release and thereby reducing toxicity to surrounding tissues. By controlling the slow dissolution of the polymer in physiological conditions, the encapsulated drugs can be released at a controlled rate within the body as needed, achieving prolonged drug release and treatment over a time frame ranging from several days to several months.
Microcapsule technology is primarily applied to small molecule drugs, represented by medications such as Sandostatin (octreotide injection), Risperdal Consta (risperidone injection), Somatuline (lanreotide injection), and Vivitrol (naltrexone extended-release microspheres), etc.
The only PLGA microsphere formulation used for large-molecule proteins is Nutropin Depot (long-acting growth hormone, Genentech, approved in 1999). Despite its advantage of having a prolonged release time, allowing for injections at intervals of two weeks or even once a month, the intense local reactions caused by the injections made it difficult for patients to tolerate. Simultaneously, due to the immature state of polymer encapsulation technology and manufacturing challenges, there were instances of sudden growth hormone release, negatively impacting the efficacy. In the end, Nutropin Depot withdrew from the market four years after its launch.
Summary and Outlook
LAI technology ensures the continuous therapeutic effects of drugs in the body and has provided crucial support for the treatment of conditions such as schizophrenia, hormonal imbalances, and substance abuse over the past few decades. As our understanding of diseases deepens, LAI technology also demonstrates significant potential in treating chronic conditions such as Parkinson's disease and Alzheimer's disease. However, compared to standard injection solutions, the development of LAI formulations is more complex with higher technological barriers.
References:
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[4] Kalicharan R W B M. Where does hydrolysis of nandrolone decanoate occur in the human body after release from an oil depot?[J]. International Journal of Pharmaceutics, 2016,515(1a2).
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