Liposomal Formulations in Clinical Use: An Updated Review

Purpose: Liposomes are the first nano drug delivery systems successfully translated into clinical use, but many formulations still face limitations in biodistribution, toxicity, stability, and target selectivity. An updated review was needed to summarize liposome technologies, marketed clinical products, formulation aspects, and ongoing clinical trials.

Hypothesis: As a review, there is no single experimental hypothesis. Central thesis: if liposomal formulations are optimized using technologies such as stealth/PEGylation, non-PEGylated liposomes, DepoFoam, and thermosensitive liposomes, then they can improve the therapeutic index of drugs by altering pharmacokinetics, reducing toxicity, and enabling controlled or targeted delivery across cancer, fungal infections, pain management, photodynamic therapy, and vaccines.

Aims: Provide a concise picture of liposome-based products available in the market. - Describe key liposome technologies used in clinical products: stealth liposome technology, non-PEGylated liposome technology, DepoFoam technology, and lysolipid thermally sensitive liposome technology. - Review formulation aspects of clinically used liposomal products. - Summarize ongoing clinical trials of liposomal formulations as monotherapy or in combination with other agents/therapies.

Delivery system: Platform types: conventional liposomes, PEGylated/stealth liposomes, non-PEGylated liposomes, multivesicular DepoFoam particles, lysolipid thermosensitive liposomes, virosomes, cationic liposomes, immunoliposomes, sphingosomes, and lipoplexes. - Payloads: doxorubicin, daunorubicin, cytarabine, mifamurtide, vincristine, irinotecan, amphotericin B, verteporfin, morphine sulfate, bupivacaine, hepatitis A antigen, influenza hemagglutinin, siRNA, p53 gene, and antisense oligonucleotides. - Key lipid components: HSPC, cholesterol, PEG-DSPE, DSPC, DOPC, DPPG, DMPC, DMPG, DSPG, DOPE, egg phosphatidylcholine, sphingomyelin, cardiolipin, DOTAP, and triolein/tricaprylin. - Targeting/functional strategies: passive EPR-based targeting; PEGylation for prolonged circulation; DepoFoam for sustained release; thermosensitive release for heat-triggered drug delivery; virosome technology for vaccine delivery.

Approach: Review of marketed liposomal products and clinical trials. No primary experimental study. Covers approved products and products in Phase I–III clinical trials across cancer, fungal infections, photodynamic therapy, pain management, and viral vaccines. Includes tables of clinical products, lipid compositions, indications, administration routes, and companies.

Key methods: Literature and clinical trial synthesis; pharmacokinetic parameters (AUC, clearance, volume of distribution, half-life, Cmax); encapsulation efficiency; drug-to-lipid ratios; tumor drug concentration; clinical efficacy endpoints such as survival, progression-free survival, FEV, tumor response, and toxicity profiles.

Key results: Doxil was the first FDA-approved PEGylated liposomal nano-drug in 1995. It has 80–100 nm vesicles, >90% doxorubicin encapsulation, clearance of 0.1 L/h vs 45 L/h for free drug, volume of distribution 4 L vs 254 L, and biphasic half-lives of 2 h and 45 h. Tumor doxorubicin concentration was 4–16 times higher than free drug. - DaunoXome has ~45 nm particles, AUC 11–12-fold higher than conventional daunorubicin, elimination 10.5 vs 233 mL/min, and half-life 4–5.6 h vs ~0.77 h for free drug. - Depocyt maintained cytotoxic CSF cytarabine levels for >14 days; terminal half-life was 141 h vs 3.4 h for standard cytarabine. - Myocet has 150–250 nm liposomes and >99% entrapment efficiency; tumor concentrations were 2–3 times higher than free doxorubicin, and up to 10 times higher in an ascitic model. - Mepact increased six-year net survival from 70% to 78% in osteogenic sarcoma. - Onivyde has 110 nm liposomes, >90% irinotecan encapsulation, drug-to-lipid ratio >800 g/mol phospholipid, and drug release half-life of 56.8 h. In the NAPOLI-1 trial, median survival was 6.1 months with Onivyde plus fluorouracil/leucovorin vs 4.2 months with fluorouracil or leucovorin alone. - ThermoDox achieved 25-fold higher drug concentration at the target site than normal IV infusion and 5-fold higher than standard DOX liposomes. - Lipoplatin achieved up to 200-fold higher tumor concentration compared with cisplatin alone. - Epaxal protected more than 95% of adults for >20 years after booster vaccination. - Several clinical trials failed or were terminated, including Stimuvax Phase III and T4N5 Phase III.

Interpretation: Liposomes have moved successfully from concept to clinic since Doxil’s approval in 1995, with applications ranging from cancer and fungal infections to pain management and vaccines. Different liposomal technologies demonstrate intense research and clinical translation. Although many products show preclinical promise, only formulations that demonstrate efficacy in clinical trials will ultimately reach the clinic. The liposomes currently in clinical trials may benefit diverse patient populations across multiple therapeutic applications.

Limitations: This is a review, not a primary experimental study. Several liposomal products failed in advanced clinical trials despite promising preclinical data, including Stimuvax and T4N5. Clinical translation remains challenging due to formulation stability, manufacturing, regulatory, and efficacy hurdles. The review is not a systematic or comprehensive analysis of all liposomal products. Long-term safety and efficacy data for some formulations remain limited.