The Role of Depot Injections in Modern Pharmaceutical Sciences: An Evidence-Based Review

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Technical Review Article | Open Access | Published 8th October 2025

The Role of Depot Injections in Modern Pharmaceutical Sciences: An Evidence-Based Review

Sweta S Koka, Sumeet Dwivedi, Saloni Yadav, Shraddha Mahajan*, G N Darwhekar

Acropolis Institute of Pharmaceutical Education and Research, Indore | EJPPS | 303 (2025) https://doi.org/10.37521/ejpps30304

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Abstract

Depot injections represent a pivotal advancement in sustained and controlled drug delivery systems, offering prolonged therapeutic effects, enhanced patient compliance, and reduced dosing frequency. This review comprehensively examines the formulation strategies, mechanisms of drug release, clinical applications, and recent innovations in depot injection technologies. Polymeric matrices, lipid-based systems, and in situ forming depots are discussed alongside their pharmacokinetic and pharmacodynamic implications. Furthermore, the challenges associated with manufacturing, stability, and regulatory considerations are addressed. With over 45 referenced studies, this paper highlights the transformative potential of depot injections in treating chronic diseases, hormonal disorders, and psychiatric conditions while identifying future research directions for optimizing their efficacy and safety.

Keywords: Depot injections, Sustained drug delivery, Parenteral formulations, Pharmacokinetic modeling

Introduction

In the irrefutable management of chronic diseases, inadequate patient compliance and adherence to prolonged treatment regimens pose significant barriers to therapeutic advancements. The World Health Organization reports that patient adherence in industrialized nations is merely 50%, which raises concerns for poorer and emerging countries. (Sabaté, 2003). Poor adherence and compliance may be linked to several variables, including the necessity for regular examinations and medication administrations, as well as the expenses involved with prolonged therapy. In addition to issues regarding patient burden, another difficulty with standard therapies for chronic diseases is the erratic medication concentration profile. Most conventional drug delivery techniques do not maintain a steady plasma concentration, resulting in adverse side effects. The variable concentrations of the delivered medication in the bloodstream generate unpredictable peaks and troughs. The peaks may result in detrimental side effects, whilst the troughs may yield unpleasant sub-therapeutic results.

To address these challenges, researchers investigated the concept of "sustained-release" or "controlled-release" drug delivery systems. Drug delivery methods designed to release the active medicinal component over a specified duration are termed depot formulations. The principal objective of developing this drug delivery system is to maintain a consistent concentration of the therapeutic agent in the bloodstream, hence reducing the necessity for frequent dosing and enhancing patient compliance.

The first long-acting depot injections were antipsychotics of fluphenazine and haloperidol. The concept of a depot injection arose before 1950 and originally was used to describe antibiotic injections that lasted longer to allow for less frequent administration (Priest, WS; Smith, JM (1949).

Depot injections are specialized parenteral formulations designed to release active pharmaceutical ingredients (APIs) over extended periods, ranging from weeks to months (Paavola et al., 2000). These systems minimize peak-trough fluctuations, reduce side effects, and improve therapeutic outcomes (Jain et al., 2014). The European Journal of Parenteral and Pharmaceutical Sciences has documented significant progress in this field, emphasizing biocompatibility and controlled release kinetics (Breitenbach, 2002). These systems offer several advantages, including:

Reduced dosing frequency, enhancing patient adherence.
Stable plasma drug levels, minimizing side effects associated with peak-trough fluctuations.
Improved bioavailability for poorly soluble drugs.

This review provides a comprehensive analysis of depot injection technologies, covering:

Formulation strategies (polymeric microspheres, lipid-based systems, in situ forming depots).
Mechanisms of drug release (diffusion, erosion, degradation).
Clinical applications across therapeutic areas.
Regulatory and industrial challenges in manufacturing and stability.
Emerging trends, including smart depots and 3D-printed formulations.

2. Type of Depot Formulation:

2.1 Injectables

Injectable suspensions are the earliest approach to depot formulations. For instance, fluphenazine decanoate, the first-ever antipsychotic-based depot formulation was based on injection for administration. Injectables come in various forms such as suspensions, emulsions and microparticles.

Injectable suspensions consist of solid active pharmaceutical ingredients dispersed in a liquid such as oil or aqueous medium. Once injected, the system gradually dissolves to release the API slowly over time, ranging from days to months. This results in slow and sustained release of the drug, maintaining a steady concentration of the drug in the bloodstream. Microparticles are developed based on the concept of encapsulation, where the API is trapped inside a biodegradable polymer matrix such as polylactic-co-glycolic acid (PLGA) or polylactic acid (PLA). Once inside the body, the polymer matrix undergoes gradual degradation to release the drug. An example of a microparticle-depot formulation is the Lupron depot (leuprolide acetate) (Tunn et al., 2013). This drug is primarily used to treat hormone-sensitive conditions such as prostate cancer, endometriosis and uterine fibroids. While microparticles offer versatility in their designs, the process of their production involving drug encapsulation and polymer synthesis is costly, which serves as the major hindrance to their advancements.

Emulsions are systems consisting of two immiscible liquids such as oil-in-water (O/W) or water-in-oil (W/O) with one liquid containing the drug. The choice of liquid which acts as the drug carrier is decided based on the drug’s solubility and desired release profiles. The drug diffuses from the dispersion phase into the continuous phase over time, leading to the sustained release of the drug. However, the phase separation could lead to stability issues if precise control of formulation and surfactant selection is not maintained. Some examples of emulsion systems include DepoCyt (cytarabine) for the treatment of meningitis and Doxil (doxorubicin) for breast cancer (Salehi et al., 2020)

2.2 Implantable Devices

While research for depot systems started in the early 20th century, the first implantable depot came to the market in the 1980s when Norplant was introduced as an implantable contraceptive (Segal, n.d.). Since then various innovations have led to the development of implantable depots for pain management and hormone therapies. Implantable depots could be broadly categorised as biodegradable and non-biodegradable implants.

Biodegradable implants are produced from materials that could be broken down by the body with no formation of toxic by-products. For instance, these could be biodegradable polymers such as PLA or PLGA. The general mechanism of action of these implants is the erosion or hydrolysis of the polymer matrix to release the drug slowly over extended periods of time. The major advantage with this type of depot system is the long time period, ranging in years, over which the drug could be released without needing another implant. To give an example, Nexplanon (etonogestrel) is a contraceptive implant which could provide effective contraception for up to three years (Palomba et al., 2012) and the first implant, Norplant, worked for up to five years (Segal, n.d.). Moreover, advancements in smart delivery systems that respond to physiological conditions such as pH or temperature changes have been incorporated into implant systems, making room for more precise drug delivery (Morsada et al., 2021).

Non-biodegradable implant systems are usually made from materials that do not undergo degradation inside the body such as silicone or metals. They are intended to remain at the surgical site for determined periods and their mechanism of action include the gradual diffusion of the drug into the target site. A well-known example of such an implant is Implanon which releases etonogestrel over three years (Mascarenhas, 1998). Previously discussed Nexplanon could be said to be an advanced version of Implanon. However, these implants are not the most favorable choice as they need to be removed surgically after the defined period which could result in patient burden.

2.3 Oral Depot Formulations

Oral depot formulations generally involve tablets and capsules which provide sustained release of the drug in the gastrointestinal tract. This is achieved through various formulation strategies such as reservoir systems, matrix systems or osmotic pumps which will be discussed in detail in further sections of this article. Notable examples of oral depot formulations include opioids such as OxyContin and anti-hypersensitive drugs such as nifedipine (Liu et al., 2018; Vadivelu et al., 2016). The use of depot formulations for opioids is such a beneficial strategy to address addiction and drug abuse associated with opioids. While oral depot formulations look favorable to address illnesses associated with the gastrointestinal tract, dose dumping is a major concern where a random release of the drug could take place leading to toxicity. Additionally, their design and production are costly.

Table 1. Examples of Depot formulation

Type of formulation	Type of formulation	API	Example	Therapeutic Application
Injectables	Suspension Microspheres Lipid-Based In situ Forming Gel	Medroxyprogesterone acetate Leuprolide acetate Bupivacaine Leuprolide acetate	Depo-Provera Lupron Depot Exparel Eligard	Contraception Prostate cancer, endometriosis Post-surgical pain management Prostate cancer
Implants	Subdermal Subdermal Intravitreal Intracranial	Etonogestre Levonorgestrel Dexamethasone Carmustine	Nexplanon Norplant (discontinued) Ozurdex Gliadel Wafer	Contraception Contraception Macular edema, uveitis Brain cancer
Oral	Tablet (ER) Capsule (ER) Tablet (SR) Capsule (DR)	Oxycodone Methylphenidate Bupropion Omeprazole	OxyContin Concerta Wellbutrin SR Prilosec	Chronic pain ADHD Depression GERD, peptic ulcers

Table 2. Manufacturing process for Depot Formulation

Method	Description	Examples	References
Emulsification-Solvent Evaporation	Drug + polymer (e.g., PLGA) dissolved in organic solvent, emulsified in aqueous phase, then solvent evaporated to form solid microparticles.	PLGA microspheres (e.g., Leuprolide Depot)	(Jain, 2020)
Spray Drying	Drug-polymer solution sprayed into hot air to form dry particles. Suitable for microspheres/nanoparticles.	Insulin-loaded PLGA microparticles	(Freitas et al., 2005)
Coacervation/Phase Separation	Polymer-drug solution phase-separated by adding non-solvent or salt, forming coacervate droplets hardened into microspheres.	Risperidone implants	(Burgess et al., 2004)
Melt Extrusion	Drug + polymer melted, extruded, and cooled to form implants/rods.	Subdermal implants (e.g., Nexplanon®)	(Dhumal et al., 2008)
In Situ Gel Formation	Liquid formulation (polymer + drug) gels after injection due to temperature/pH changes.	Poloxamer-based gels (e.g., ReGel®)	(Ruel-Gariépy et al., 2000)
Liposome Preparation	Lipid film hydrated with aqueous drug solution, sonicated/extruded to form vesicles.	Liposomal bupivacaine (Exparel®)	(Allen & Cullis, 2013)
Supercritical Fluid Technology	CO₂ used as solvent to precipitate drug-polymer particles (eco-friendly).	Paclitaxel-loaded PLGA microparticles	(Yadav et al., 2019)
3D Printing	Layer-by-layer deposition of drug-polymer mixtures for customized implants.	Personalized vaginal rings	(Trenfield et al., 2019)

3. Materials used for Manufacturing Depot Injections

Depot injections, which provide long-acting drug delivery, primarily utilize biocompatible and biodegradable materials such as polymers and lipids. These materials are formulated into solutions or suspensions that solidify or form a depot upon injection, releasing the drug slowly over time. The choice of material depends on factors such as the drug being delivered, desired release profile, and biocompatibility requirements.

3.1 Polymer-Based Depots often use Polymers such as:

Polymeric depots, particularly those using poly(lactic-co-glycolic acid) (PLGA), dominate sustained-release formulations due to their biocompatibility and tunable degradation kinetics (Anderson & Shive, 2012). The drug release profile depends on polymer molecular weight, copolymer ratio, and microsphere size (Okada, 1997).

PLGA (poly(lactic-co-glycolic acid)): A widely used biodegradable polymer that is biocompatible and can be used in FDA-approved long-acting release products.
PEG (polyethylene glycol): Another biocompatible polymer that can be used in depot formulations.
Poloxamers: These are also biocompatible polymers that can be used in depot formulations.

Important considerations include a burst release effect due to surface-associated drug (Zolnik & Burgess, 2008), and acidic microclimate formation, potentially degrading sensitive drugs (Grizzi et al., 1995).

Table 3: Commercially available Polymeric depot formulations

Drug Product	Polymer Used	Indication	Release Duration
Lupron Depot®	PLGA	Prostate cancer	1-6 months
Risperdal Consta®	PLGA	Schizophrenia	2 weeks
Nutropin Depot®	PLGA	Growth hormone def.	1 month

(Source: Anderson & Shive, 2012; Okada, 1997)

3.2 Lipid-Based Depots

Lipid-based systems, including liposomes and solid lipid nanoparticles (SLNs), enhance the delivery of hydrophobic drugs (Müller et al., 2000). These formulations improve drug stability and reduce systemic toxicity.

Lipid-based depots utilize various lipid components, including:

Oils: Such as sesame oil or castor oil, often used as a vehicle for the drug.
Oleogels: These are gels formed from oils and other lipid components, providing sustained release.
Liposomes: These are spherical vesicles composed of lipid bilayers that can encapsulate and release drugs.
Solid lipid nanoparticles: These are nanoparticles composed of solid lipids that can be used for drug delivery.
Nano thermodynamic lipid carriers: These are lipid-based carriers with specific structural characteristics for drug delivery.

Key Examples:

Bupivacaine liposome injectable suspension (Exparel®) – Provides prolonged local anesthesia post-surgery (Grant et al., 2018).

Liposomal cytarabine (DepoCyt®) – Used in neoplastic meningitis (Shi et al., 2010).

Table 4: Comparison of lipid-based depot systems

Formulation Type	Advantages	Limitations
Liposomes	High drug loading	Stability issues
Solid Lipid Nanoparticles	Improved stability	Burst release risk

(Source: Müller et al., 2000; Grant et al., 2018)

Advantages:

Enhanced drug solubility.
Reduced injection frequency.

3.3 In Situ Forming Depots

These formulations undergo sol-to-gel transition upon injection, forming a drug-releasing depot (Kempe & Mäder, 2012). Common triggers include temperature, pH, and solvent exchange.

Key Examples:

Atrigel® technology – Used in leuprolide acetate (Eligard®) for prostate cancer (D’Souza et al., 2015).

Thermosensitive poloxamers – Used in post-surgical pain management (Qiu & Park, 2012).

Table 5: Marketed in situ forming depots

Product Name	Trigger Mechanism	Active Ingredient
Eligard®	Solvent exchange	Leuprolide acetate
Atridox®	ATRIGEL system	Doxycycline

(Source: Kempe & Mäder, 2012; Dunn et al., 1990)

Advantages:

Ease of administration.
Customizable release profiles.

4. Drug Release Mechanisms

4.1 Diffusion-Controlled Release

The drug diffuses through the polymer matrix (Siepmann & Göpferich, 2001). Governed by Fick’s law of diffusion.

4.2 Erosion-Controlled Release

Surface or bulk erosion degrades the polymer, releasing the drug (Grizzi et al., 1995). PLGA-based systems follow this mechanism.

4.3 Osmotic Pump Systems

Implantable depots (e.g., DUROS® technology) use osmotic pressure for controlled release (Wright et al., 2001).

Table 6: Mathematical models for drug release

Model	Equation	Application
Higuchi	Q = k√t	Diffusion-controlled
Korsmeyer-Peppas	Q = ktⁿ	Complex systems

(Source: Siepmann & Göpferich, 2001)

5. Clinical Applications

5.1 Psychiatric Disorders

Paliperidone palmitate (Invega Sustenna®) – Monthly injections for schizophrenia (Nasrallah et al., 2010).
Olanzapine pamoate (Zyprexa Relprevv®) – Reduces relapse rates.

5.2 Hormonal Therapy

Medroxyprogesterone acetate (Depo-Provera®) – 3-month contraceptive (Kaunitz, 2001).
Testosterone undecanoate (Nebido®) – For hypogonadism.

5.3 Diabetes Management

Exenatide extended-release (Bydureon®) – Weekly GLP-1 agonist (Drucker et al., 2008).

5.4 Pain Management

Bupivacaine-meloxicam liposomal gel (HTX-011) – Postoperative analgesia (Ilfeld et al., 2016).

Table 7: Clinical outcomes of selected depot therapies

Medication	Condition Treated	Adherence Improvement
Paliperidone palmitate	Schizophrenia	58% reduction in relapses
Medroxyprogesterone	Contraception	92% continuation rate

(Source: Nasrallah et al., 2010; Kaunitz, 2001)

6. Challenges and Future Perspectives

6.1 Manufacturing & Stability Issues

Burst release – Requires surface modification.
Sterilization challenges – Gamma irradiation may degrade polymers (D’Souza et al., 2015).

6.2 Regulatory Considerations

FDA/EMA guidelines require rigorous in vivo release testing (Shi et al., 2010).

6.3 Emerging Technologies

3D-printed depots – Personalized dosing (Norman et al., 2017).
Stimuli-responsive depots – pH-/temperature-sensitive release (Qiu & Park, 2012).

Table 8: Emerging technologies in depot delivery

Technology	Potential Benefit	Development Stage
3D-printed depots	Personalized dosing	Preclinical
Smart depots	Stimuli-responsive	Phase I trials

(Source: Norman et al., 2017; Qiu & Park, 2012)

Conclusion

Depot injections offer a valuable method for delivering long-acting medications, improving treatment adherence and ensuring consistent therapeutic levels over extended periods. By minimizing the need for frequent dosing, they are particularly beneficial in managing chronic conditions such as schizophrenia, hormonal disorders, and certain infections. Despite some limitations, such as potential injection site reactions and less flexibility in dosage adjustments, the advantages of depot formulations make them a critical option in modern pharmacotherapy. Ongoing advancements in drug delivery technologies continue to enhance their safety, efficacy, and patient acceptability.

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