Oral administration of many nutrients, vitamins, minerals, and other bioactive compounds is limited by poor absorption, degradation in the digestive system, and low permeability of the intestinal epithelium, which results in low bioavailability and, consequently, the absence of the expected effect. One of the innovative approaches developed to overcome these limitations is the creation of so-called proliposomes – a dry, free-flowing powder composed of phospholipids and an active substance that spontaneously forms a liposomal (vesicular) suspension upon the addition of water. 

Why liposomes?

Liposomes are vesicles made up of one or more phospholipid bilayers, capable of encapsulating both hydrophilic and hydrophobic substances (substances soluble in water and those soluble in fats), protecting them from degradation, and releasing them at the target site. Despite the advantages of this well-known technology, classic (liquid) liposomal suspensions are prone to physical-chemical instability – hydrolysis, oxidation, sedimentation, aggregation, and vesicle fusion during non-lyophilized storage, and production in large batches while maintaining stability presents a particular challenge. In response to these shortcomings, the literature describes the concept of proliposomes – a dry powder that spontaneously reorganizes into a multilamellar liposomal suspension in an aqueous medium.

Scientific background of proliposomes

According to the review by Singh et al., proliposomes are defined as "dry, free-flowing granular products composed of an active substance and phospholipids which, with the addition of water, disperse and form a multilamellar liposomal suspension." The authors state that proliposomes were developed as a simple, reproducible, and reliable production technique for large batches of liposomal dispersions, based on the property of hydrated membrane lipids to spontaneously form vesicles upon contact with water.

The literature states that proliposomes are "almost as good as, and perhaps better" than conventional liposomes, with stability significantly superior to liposomes, making them more suitable for the delivery of drugs and nutrients. Key advantages of the dry powder form include: greater storage stability, convenience in transport, distribution, processing, and packaging, the possibility of formulation into a solid dosage form (e.g., capsules), dosage flexibility, and stability during sterilization procedures. Liposomes formed by rehydration of proliposomes are described as similar to conventional liposomes and more uniform in size. Available literature describes several groups of methods for the preparation of proliposomes/liposomes: lipid film deposition on a carrier, spray drying, the fluidized bed method, the use of supercritical fluids, dual asymmetric centrifugation, and lyophilization. Each of these methods has specific advantages and limitations, and available data suggest that lyophilization, spray drying, and high-pressure/temperature processes are described in the literature as methods that can disrupt the liposome structure, change vesicle size, leave traces of solvents, or require energy-intensive and time-consuming steps (thereby increasing the product cost). A production approach that avoids these steps – i.e., without heat, pressure, chemicals, and without spray drying/lyophilization – is consistent with the general goal of proliposomal technology described in the literature: obtaining a stable dry powder that, upon hydration, yields a uniform liposomal dispersion with minimal damage to the active substance and the lipid bilayer.

Liposomes in clinical and preclinical research

Sinha et al. conducted a pilot clinical study of oral administration of liposomal glutathione (phosphatidylcholine liposomes, two doses – 500 and 1000 mg/day) in 12 healthy adults. The results showed a statistically significant increase in glutathione levels after just one week, with the largest increases after two weeks: up to ~40% in whole blood, ~25–28% in erythrocytes, ~28% in plasma, and up to ~100% (double) in peripheral blood mononuclear cells. At the same time, reductions in markers of oxidative stress were recorded: the ratio of oxidized to reduced glutathione decreased by up to ~18–20%, and plasma 8-isoprostane by up to ~35%. An improvement in indicators of immune function was also recorded: NK-cell cytotoxicity increased by up to ~400%, and lymphocyte proliferation by up to ~60% after two weeks of administration. The authors state that no serious adverse effects or differences in the safety profile between the two tested doses were observed. It is known that oral glutathione is otherwise subject to degradation in the acidic environment of the stomach, which is why a liposomal formulation has been proposed as a potentially more effective way of its oral delivery.

A comprehensive review of surface modifications of oral liposomes (Jin et al.) states that the combination of proliposomal technology with D-α-tocopheryl polyethylene glycol succinate (TPGS) further enhances the oral absorption of poorly soluble bioactive substances. Specifically, for myricetin (a flavonoid with hepatoprotective activity) formulated as TPGS-modified proliposomes (MRC-TPGS-PL), an increase in bioavailability of approximately 99% compared to unmodified liposomes and approximately 701% compared to a free (non-encapsulated) myricetin solution was recorded, with a maximum plasma concentration (Cmax) of 14.88 μg/mL versus 7.56 μg/mL (unmodified liposomes) and 2.39 μg/mL (free substance), respectively, and a prolonged elimination half-life. Although preclinical data and small clinical studies suggest potentially improved systemic exposure of certain bioactive compounds administered in liposomal form, direct clinical comparisons with non-encapsulated forms are currently few.

This year, a review article on vitamin C (Yoon et al., 2026) was published, in which liposomal formulations of vitamin C are specifically discussed in the context of oral administration above typical dosage ranges. It is stated that liposomal vitamin C implies ascorbate incorporated into phospholipid vesicles or lipid-based carriers and that some such products may alter pharmacokinetic exposure or gastrointestinal tolerability compared to classic forms; however, the authors emphasize that available studies differ significantly in composition, encapsulation efficiency, particle size, phospholipid source, stability, and sampling design, which is why findings obtained for one product should not be generalized to all preparations. It is also highlighted that the term "liposomal" does not in itself define the source or quality documentation of the ascorbic acid used and that the production origin should be judged based on reproducibility, impurity control, regulatory standards, and the quality of certificates of analysis, rather than assuming clinical superiority solely on the basis of a liposomal declaration. This cautious conclusion is also relevant for the interpretation of any commercial liposomal formulation, including vitamin C, and suggests that claims of improved absorption should be accompanied by transparent pharmacokinetic and analytical documentation specific to each product.

Conclusion

Proliposomal technology – a dry, free-flowing powder of phospholipids and active substance that forms a liposomal dispersion upon hydration – is described in peer-reviewed literature as an approach that overcomes the main limitations of classic liquid liposomes in terms of stability, storage, and the possibility of formulation into a solid dosage form. Production procedures that avoid heat, high pressure, chemicals, and spray drying or lyophilization are generally consistent with the purpose of this technology, as the literature links these very steps to possible disruption of the liposome structure and loss of stability. Clinical and experimental data on the liposomal delivery of bioactive compounds consistently show improved systemic exposure and/or biological effect compared to non-encapsulated forms. At the same time, the literature on liposomal vitamin C warns that findings obtained for one formulation should not be automatically generalized to all liposomal products; rather, each product requires its own analytical and, preferably, clinical documentation. Nevertheless, it is expected that future clinical research on various active substances will be conducted on a larger number of subjects to prove that a technologically more advanced formulation, such as proliposomes, truly achieves better clinical effects as well.

References

1. Singh N, Kushwaha P, Ahmad U, Abdullah M. Proliposomes: An Approach for the Development of Stable Liposome. Ars Pharm. 2019;60:231–40.

2. Jin P, Wu S, Wang Y, Ni Y, Ruan Q, Yuan Z, Yao H, Li J. Surface modification strategies of oral liposomes: functional design and barrier enhancement. Front Pharmacol. 2026;17:1801527.

3. Sinha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr. 2018;72:105–11.

4. Srikrishna T, Gobinath M, Nivedhitha S, Dhana Lakshmi K, Harshitha A, Bhargavi M, Pavani Kalyani M, Chathana C. Innovative Approaches in Liposomal Drug Delivery Systems: A Comprehensive Review of Novel Strategies and Advancements. Intern J Zool Invest. 2025;11:729–36.

5. Yoon Y, Hwang J, Yang C-M, Kim S, Lee J, Lee J-J, Moon M, Lam KHS. Vitamin C—Beyond Deficiency: Mechanisms, Clinical Applications, Formulation and Dosing Considerations, and Safety Across Stress-Responsive Conditions. Nutrients. 2026;18:2319.