Recent advances in lipid-based long-acting injectable depot formulations (2023)


Long-acting injectables (LAIs) are drug formulations designed for sustained or controlled drug release through parenteral administration, which allows for prolonged drug action [1], [2]. These formulations are usually administered via subcutaneous (SC) or intramuscular (IM) route to achieve systemic effects, or via the intra-articular (IA) and intraocular routes (IO) to achieve localized effects, depending on the condition being addressed. LAIs are ideal for drugs or biomolecules that exhibit short biological half-lives, poor oral absorption, gastrointestinal instability, and rapid metabolism [3]. Compared to conventional formulations, LAIs have several advantages, including reduced dosages and administration frequency, long-lasting therapeutic effect, and the ability to use active pharmaceutical ingredients (APIs) with dose-limiting toxicity. These benefits not only improve patient compliance and treatment adherence but also reduce overall healthcare cost [2], [4], [5], [6].

For last few decades, LAIs have been utilized to treat a variety of chronic illnesses, such as diabetes, schizophrenia, hormonal disorders, and cancer. Ongoing research is focused on developing LAIs for the treatment of HIV, Parkinson’s and Alzheimer’s disease [2], [7], [8], [9]. Advances in material science have led to the development of numerous polymeric and lipid-based depots for the management of chronic disease conditions. Among these, lipid-based injectables have garnered significant interest due to their biocompatibility, non-immunogenicity and safe degradation profile, making them an ideal option for parenteral administration. Lipidic LAIs offer numerous advantages as drug delivery carriers, such as improved drug solubility, sustained drug release, ability to encapsulate both small molecules and large biomolecules, improved half-life, and stability of therapeutic agents. The drug release from such systems can be tailored by altering the lipid composition and concentration, ensuring the desired duration of therapeutic effect [10], [11], [12]. Oil depot injectables of antipsychotics have been in use for decades, successfully managing and reducing relapse in patients with schizophrenia, eliminating the need for daily oral medication and regular patient monitoring, enhancing medication acceptance and adherence in schizophrenic patients, and simplifying the treatment protocol [13].

(Video) Long-Acting Injectable Antipsychotics

Lipid-based LAIs cover a wide range of formulations, including oil solution, suspension, oleogels, liquid crystalline phase (LCP), liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), phospholipid phase separation gel (PPSG), lipid prodrugs, vesicular phospholipid gel (VPG), and lipid-polymer hybrid system (Fig. 1) [12], [14], [15], [16], [17], [18], [19], [20], [21], [22]. Recently, in situ forming lipid-based depots have been gaining interest as controlled and sustained drug delivery systems that overcome the challenges of syringeability and injectability. These systems typically have a low viscosity due to the presence of small amount of organic solvent. However, upon injection, the solvent diffuses out into the surrounding environment, causing the system to undergo a phase transition and form a semi-solid depot like structure at the injection site. Alternatively, low viscosity, stimuli-responsive precursors can be employed, resulting in the formation of highly viscous phases after administration via the self-assembly of the lipid molecules in response to various biological stimuli such as hydration, pH, temperature, solutes, and ions [17], [23]. The concept of in situ phase transition was first described by Mueller et al., where reverse micellar solutions transitioned into a liquid crystal system upon contact with aqueous media [24]. Despite the significant benefits of lipid-based depots, few products have been commercialised. The reason could be the challenges associated with their development, such as complex manufacturing processes, sterilisation and stability issues, and the lack of well-established in vitro release guidelines for LAIs. Understanding the drug release kinetics of depot formulations through in vitro release testing methods is immensely helpful for their early and successful development. However, as there is no guideline specified, researchers have reported different in vitro release testing methods to investigate the release kinetics of lipid-based LAIs. In vitro release models that mimic the physiological conditions and have in vitro in vivo corelation (IVIVC)] are critical for quality control of LAIs during manufacturing and scale up. However, establishing IVIVC is much more difficult and challenging for parenteral depots. For example, the nonavailability of sink conditions at injection site causes the drug to diffuse slowly from LAIs, but mimicking these conditions in vitro is not possible. Additionally, the interaction of depot system with the surrounding environment at injection site plays a crucial role in drug absorption process, which is complex to simulate under in vitro conditions. This review provides detailed insight into recent advances in lipid-based LAIs for delivering small and large molecules for the treatment of various chronic diseases, including the influence of formulation and physiological factors on drug absorption. The review also includes list of approved and ongoing clinical trials, as well as provides overview on patents available for lipid-based LAIs. Moreover, it provides a detailed description of various in vitro release testing methods used for lipid-based LAIs and an analysis of the IVIVC studies performed. Finally, the review addresses the challenges associated with the development of lipid-based LAIs.

Section snippets

Lipid-based LAIs and biopharmaceutical aspects

Depot formulations are developed to deliver the therapeutic agents at a controllable and predetermined rate within the therapeutic range for a specified duration, primarily for treating chronic diseases. Lipid-based depots consist of natural lipids, such as phospholipids and triglycerides, along with other additives that encase therapeutic agent with different physicochemical properties. SC and IM injections are frequently used to administer depot formulations, enabling a long-lasting

Clinically approved and recent trials ongoing on lipid-based LAIs

Regulatory authorities have approved number of LAIs developed using different formulation strategies such as implants, microspheres, lipidic LAIs, suspended solids etc. Table 2 summarizes the lipid-based LAIs marketed for the treatment of chronic diseases. Most of the approved lipid-based LAIs are simple oil solution formulations, mainly in the field of hormone replacement therapy and for treatment of schizophrenia. However, with the advancement in lipid-based technology such as DepoFoam® and

Patents on lipid-based LAIs

The development of lipid-based LAIs began with the use of an oil solution, proposed by Ulrich et al., in 1980, which provided long-term anti-contraceptive activity of progesterone for 13 weeks [189]. Parallelly, a patent was granted for an oily solution containing anticancer drugs, including carmofur, 5-FU, mitomycin C, aclarubicin HCl, and ancitabine [190]. Chauhan et al., also developed oleogels and emulsion-based oleogels consisting of ethyl cellulose and soybean oil for long-lasting release

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In vitro release consideration and IVIVC

Although drug release from formulations can be directly determined through in vivo studies, it is time-consuming, costly, and requires a considerable amount of effort. In this scenario, reliable in vitro methods can be used as a quality control tools. In vitro release kinetics can help in the early assessment of formulation parameters and manufacturing processes, that enable effective and robust in vivo performance of the formulations. Developing a reliable in vitro release method is also

Challenges in the development of lipid-based LAIs

The potential of lipid-based depots to sustain the therapeutic concentration of drug in body over an extended time period is a well-established concept. An ideal depot delivery system should be able to incorporate a high drug load while keeping the injection volume as low as possible. However, there are several challenges associated with the development of lipid depot system related to its manufacturing, sterilisation, deliverability, stability and in vitro release characterization. The


LAIs formulations are increasingly being used in the clinical management of chronic diseases, providing an effective way to deliver drug compounds that are unstable, have low bioavailability, short half-lives, and require frequent administration. Lipid-based LAIs have gained significant interest due to their biocompatible nature, non-immunogenicity, less toxicity, and safe biodegradation profile. While early long-acting depots were based on simple oil solution technology, lipid-based LAIs now

(Video) Health disparities and the rollout of long-acting injectable ART and PrEP

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

(Video) Improved Long-Acting Drug Delivery: What are the Technologies? - Andrew Owen

© 2023 Elsevier B.V. All rights reserved.


What are depot formulations also known as? ›

Literature review current through: Apr 2023. This topic last updated: Jan 19, 2023. Depot medroxyprogesterone acetate (DMPA, also known as DepoProvera) is an injectable progestin-only contraceptive that provides highly effective, private, three-month-long reversible contraception.

What is a long acting injectable formulation? ›

Long Acting Injectables (LAIs) are a drug formulation option that provide a slow and sustained release of the Active Pharmaceutical Ingredient (API) after administration.

What are depot drugs examples? ›

Most depot medications belong to the older group of antipsychotics ('first generation' or 'typical' antipsychotics). These are Modecate, Depixol, Haldol, Piportil and Clopixol.

What is depot preparation of injectable drug? ›

What is a depot injection? A depot injection is a slow-release form of medication. The injection uses a liquid that releases the medication slowly, so it lasts a lot longer. Depot injections can be used for various types of drug, including some antipsychotics.

What are examples of depot injections? ›

Some examples of depot antipsychotic injections are flupenthixol decanoate (Fluanxol®), haloperidol decanoate (Haldol®), and zuclopenthixol decanoate (Clopixol®).

What is the generic name for depot injection? ›

Depo-Provera is a well-known brand name for medroxyprogesterone acetate, a contraceptive injection that contains the hormone progestin. Depo-Provera is given as an injection every three months.

How long do long acting injectables last? ›

But since you take them every 2 to 4 weeks (or sometimes even as long as every 3 months) instead of every day, the medicine stays in your body longer. These antipsychotic drugs come in a long-lasting form: Aripiprazole (Abilify Maintena) Aripiprazole lauroxil (Aristada)

What are the benefits of long acting injectables? ›

Long-acting injectables allow for the ability to target specific anatomical areas. They enable the delivery of drugs to targeted areas such as the knee, eye, ear, and others. When using long-acting injectables, higher drug concentrations can be maintained in the targeted area, thus reducing systemic exposure.

What is long acting injectable Aristada? ›

Aristada is a long-acting injectable (LAI) formulation of aripiprazole. It is one of two available formulations of LAI aripiprazole. It is FDA-indicated to treat adults with schizophrenia. Aristada can be given initially with Aristada Initio; refer to this tip on Aristada Initio.

How often are depot injections given? ›

each injection lasts for either 8 or 13 weeks. it does not interrupt sex. it's an option if you can't use oestrogen-based contraception. you do not have to remember to take a pill every day.

What is depot injection for addiction? ›

They are available as weekly or monthly doses and are given as subcutaneous (under the skin) injections, which slowly release the buprenorphine into the body. It is injected by a treatment provider or health professional as a liquid and, once inside the body, turns to a solid gel called a depot (dee-poh).

What is Depixol injection used for? ›

Depixol Injection is used for the treatment of schizophrenia and other psychoses. Your doctor, however, may prescribe Depixol Injection for another purpose. Ask your doctor if you have any questions about why Depixol Injection has been prescribed for you.

Why is it called a depot injection? ›

What is a depot injection? A depot injection is a long-acting form of medication. The nurse injects the medication into your muscle where it forms a store or 'depot'. This is then released slowly into your body over a period of weeks.

What are the five general types of injectable materials? ›

Summary. Overall, the U.S. Pharmacopeia recognizes drug injection, a drug for injection, drug injectable emulsion, drug injectable suspension, and a drug for suspension as five types of parenteral products. These five types of parenteral products do not apply to biological injectables due to their unique nature.

What is the difference between the standard IM injectable formulation and the depot IM injectable formulation? ›

Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called 'depot', are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism.

What are the 4 most commonly used injectable drugs? ›

Among the most popular in many countries are morphine, heroin, cocaine, amphetamine, and methamphetamine.

What is the most common injectable drug? ›

The most commonly injected drug is heroin, but amphetamines, buprenorphine, benzodiazepines, barbiturates, cocaine, and methamphetamine also are injected.

What are the 4 major injection sites? ›

Summary. There are four sites on your body that can be used to give yourself an intramuscular injection. These include the upper arm, thigh, hip, and buttocks. Make sure you are comfortable with the injection technique before you start giving yourself shots.

What are contraindications to depot injection? ›

Who should not take Depo-Provera Contraceptive Intramuscular?
  • breast cancer.
  • family history of breast cancer.
  • diabetes.
  • excessive fat in the blood.
  • porphyria.
  • depression.
  • high blood pressure.
  • a disorder of the blood vessels of the brain.

What hormones are in the depot injection? ›

The contraceptive injection releases the hormone progestogen into your bloodstream to prevent pregnancy. The 3 types are Depo-Provera, Sayana Press or Noristerat.

What is the generic for Lupron? ›

Generic Name: leuprolide acetate (6 month)

Which injectable lasts longest? ›

Juvederm and Restylane fillers last longer than other fillers. Juvederm and Restylane are currently the longest-lasting and most durable dermal fillers on the market. Juvederm and Restylane are families of hyaluronic acid fillers with numerous possible formulations.

Is there a filler that lasts 5 years? ›

Unlike other dermal fillers, Bellafill has been FDA approved and clinically proven to last for up to 5 years. Half a decade. Yes, use Bellafill once to fill in smile lines and it'll last up to 5 years.

Which fillers last 2 to 5 years? ›

Juvederm usually needs to be repeated after around 9 to 24 months, but Bellafill can last much longer — around five years.

What are long acting injectables for anxiety? ›

Long-acting injection (LAIs) allow for the slow release of medicine into the blood. Injectable medications used for individuals living with mental illness include Abilify Maintena®, Aristada®, Haldol decanoate®, Invega Sustenna®, Invega Trinza®, fluphenazine decanoate, Risperdal Consta®, and Zyprexa Relprevv®.

What is the primary advantage to using a long acting injectable lai antipsychotic? ›

Benefits of use of long acting injectable (LAI) antipsychotics: Increased medication adherence and steady blood level balanced with decreased need to take daily oral doses; clinic visit or nursing visit for injection allows for consistent relationship and monitoring by clinicians.

Why is injectable better than oral? ›

Compared with pills and tablets, a more efficient way of getting drug into the blood is to inject it directly into a vein. This way, all the drug gets circulated throughout the body and avoids degradation in the stomach.

Is lybalvi available? ›

There is currently no therapeutically equivalent version of Lybalvi available in the United States.

What is the difference between maintena and Aristada? ›

Aristada (aripiprazole lauroxil) and Abilify Maintena (aripiprazole) are both long-acting injections of Abilify (aripiprazole). Currently, Aristada is only FDA-approved to treat schizophrenia, but Abilify Maintena is approved for both bipolar I disorder and schizophrenia.

Is Abilify a long-acting injectable? ›

ABILIFY ASIMTUFII, a long-acting injectable, provides continuous delivery of medication and can maintain therapeutic plasma concentrations, which may help those living with schizophrenia and bipolar I disorder.

What is the injection in the buttocks for mental health? ›

Olanzapine depot injection is given every 2 or every 4 weeks as an injection into the muscle in your buttock. Some patients may need to continue oral olanzapine for a limited time after they start treatment with olanzapine depot injection, and at times when their symptoms are worse than usual.

What is depot injection used for in mental health? ›

A depot injection is a slow-release form of an antipsychotic medication. It's the same medication as the antipsychotic that comes in tablet or liquid form. But it is given as an injection in a liquid that releases it slowly, so it lasts a lot longer.

Where do you inject depot? ›

If a nurse or doctor is giving you your Depo shot in a health center, the shot will go in the outer part of your upper arm or your butt cheek. Your nurse or doctor may switch areas each time you get the shot. If you have the Depo shot that you can give yourself at home, you inject yourself in your belly or upper thigh.

Why is Depo illegal? ›

Questions have been raised about the size effects of this drug, and it was banned in the U.S. in 1978 because the authorities were seriously concerned about the possible carcinogenic effects of the drug. In Britain, Depo-Provera is only permitted in exceptional cases and under strictly controlled conditions.

What is Depot buprenorphine? ›

Depot buprenorphine is a new long acting formulation of an existing opioid pharmacotherapy, buprenorphine. There are two depot buprenorphine products at this time: Buvidal® and Sublocade®. Both are available on the Pharmaceutical Benefits Scheme (PBS) under a s100 opioid dependence listing.

How long does Sublocade Depot last? ›

Official answer. Sublocade is an injection that is given once a month. This means a single injection will last at least a month (28 to 30 days).

What is the other name for depot injection? ›

The contraceptive injection (Depo-Provera, Sayana Press or Noristerat) releases the hormone progestogen into your bloodstream to prevent pregnancy.

What is the name brand Depo? ›

Depo-Provera is the brand name of the medicine medroxyprogesterone acetate, which is given as an injection to prevent pregnancy.

What is the most common formulations available in the market? ›

The most significant formulation types by value in the crop protection market are SC (suspension concentrate), EC (emulsifiable concentrate), SL (soluble liquid concentrate), WG (water dispersible granule) and WP (wettable powder).

What is the difference between API and formulation? ›

APIs denote the dosage in a drug, or in other words the key chemicals that make the drug work, while finished formulation is the process in which different chemicals, including the active ingredient, are mixed in specified ratios to produce a specific drug.

What is the difference between formula and formulation? ›

In pharmacy, a formulation is a mixture or a structure such as a capsule, tablet, or an emulsion, prepared according to a specific procedure (called a "formula").

Why was Depo illegal? ›

Questions have been raised about the size effects of this drug, and it was banned in the U.S. in 1978 because the authorities were seriously concerned about the possible carcinogenic effects of the drug. In Britain, Depo-Provera is only permitted in exceptional cases and under strictly controlled conditions.

Is there a lawsuit for Depo-Provera? ›

Claims Filed in the Depo-Provera Lawsuit

Many Depo-Provera patients have already come forward and filed claims against Pfizer. These product liability lawsuits allege that the company was aware of the inherent risks of their products, but failed to adequately warn patients and healthcare providers.

Is Depo-Provera still on the market? ›

Although Depo-Provera has not been approved for use in the US, Upjohn manufactures the contraceptive in Belgium and France and estimates that more than a million women in 80 countries use the contraceptive. DMPA is still approved as adjunctive therapy for metastatic endometrial carcinoma and renal carcinoma.

How many types of Depo are there? ›

The contraceptive injection releases the hormone progestogen into your bloodstream to prevent pregnancy. The 3 types are Depo-Provera, Sayana Press or Noristerat.


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