Curcumin Phytosomes: A Promising Nanocarrier System for Enhancing Bioavailability and Therapeutic Efficacy

Nikhil Khopade, Kakasaheb kore, Sucheta bhise, Adinath bhusari, Dr. Rajkumar Shete ,

doi:10.5281/zenodo.15425503

Review Paper | Open Access
Volume 03 | Issue 05 | Article Id IJPS/250305351

Curcumin Phytosomes: A Promising Nanocarrier System for Enhancing Bioavailability and Therapeutic Efficacy
Nikhil Khopade* Kakasaheb kore Sucheta bhise Adinath bhusari Dr. Rajkumar Shete
Rajgad Dnyanpeeth's College of Pharmacy, Bhor, Pune-412206, India

Abstract

Curcumin: a polyphenolic compound extracted from turmeric with widespread therapeutic potential, particularly its anti-inflammatory, antioxidant, anticancer, and?antimicrobial properties. But its clinical usage is limited by low aqueous solubility, low absorption, rapid metabolism, and fast?systemic clearance, leading to poor bioavailability. To overcome these limitations, nanocarrier systems such as phytosomes a special phospholipid complex system have?been introduced for effective drug delivery. Curcumin phytosomes are a styudied formulation consisting of a mixture of curcumin and phospholipids, usually phosphatidylcholine,?that help improve the absorption and bioavailability of curcumin. Preparation methods of curcumin phytosomes refers to solvent evaporation and anti-solvent precipitation, while characterization and?evaluation parameters are particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading capacity and morphology. Phytosome technology can significantly improve the bioavailability?profile of poorly soluble drugs by enhancing solubility and dissolution rate, improving intestinal permeability, protection from degradation and stability. Curcumin phytosomes have?better therapeutic applications in various diseases including anti-inflammatory, antioxidant, anticancer, neuroprotective, hepatoprotective, cardioprotective, etc. The use of preclinical and clinical studies is crucial for the assessment of the efficacy and safety of curcumin phytosomes, with increasing?focus on enhancing their predictive validity as well as better extrapolation to human physiology. Overall, curcumin phytosomes could be an efficient carrier system to improve the plasma level and therapeutic effects of curcumin, and thus it can be used in various?diseases.

Keywords

Curcumin Phytosomes, Therapeutic Efficacy, limitations, nanocarrier systems

Introduction

Curcumin is a yellow polyphenolic phytocompound that is derived from the rhizome of Curcuma longa (turmeric) with diverse beneficial pharmacological activities including anticancer, antimicrobial, anti-inflammatory, and antioxidant properties (Nocito et al., 2021; Sohn et al., 2021). Despite the wide variety of biological activities of curcumin that indicate a therapeutic potential, its clinical use is highly limited because of its low aqueous solubility, low absorption, high metabolic rate, and rapid systemic clearance, which all result in poor bioavailability (Amekyeh et al., 2022; Cas & Ghidoni, 2019; Zieli?ska et al., 2020). In this perspective, we discuss some common strategies to overcome curcumin bioavailability and efficacy challenges based on this work and others. To overcome these challenges, nanotechnology-based approaches have emerged as an innovative and promising solution, characterized by the development of various nanocarrier systems, including lipid nanoparticles, polymeric nanoparticles, micelles, dendrimers, and liposomes (Amekyeh et al., 2022; Tabanelli et al., 2021)mm In addition, these nanoformulations would enhance its solubility, stability, and cancer cell-specific delivery profile and efforts have been made to target these aspects of curcumin (Sideek et al., 2022; Ucisik et al., 2013). Currently, a major update in drug delivery to curcumin has been presented in the form of hydrogels, films, wafers, sponges, and many others(Madamsetty et al., 2023; Sideek et al., 2022). These formulations have been proved to enhance the pharmaceutical and pharmacological effects of curcumin, particularly in the applications of wound healing and treatment of cancer (Salem et al., 2014). The use of curcumin in quarantine has shown the remarkable potential of these substances, with future multidisciplinary application of biotechnology and nanotechnology being needed to broaden the biomedical information and clinical action of curcumin (Sohn et al., 2021).

3. Curcumin: A Golden Molecule

3.1. Source and Chemical Structure

Curcumin, a natural polyphenolic compound obtained from the rhizomes of Curcuma longa (i.e., turmeric) (Chiorcea-Paquim, 2023; Zhang et al., 2014). Its chemical structure is [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], responsible for its specific properties together with a multitude of pharmacological activities (Zhang et al., 2014). Curcumin, the substance responsible for turmeric's golden hue, has been used as a spice, coloring agent, and medicine for centuries (Chiorcea-Paquim 2023).

Figure 1: Curcumin Phytosomes

Although curcumin possesses various positive functions, its chemical structure makes it highly unstable, poorly soluble, and easily degraded in vivo, significantly decreasing the clinical applications of curcumin (Xu et al., 2016). Therefore, it has attracted considerable attention for new dosage forms and structural modifications to enhance its bioavailability and therapeutic effect (Sohn et al., 2021). Ultimately curcumin constitutes one of their own and its unique chemical structure is both a dominant hero and hindrance. It offers a broad spectrum of pharmacological activities but is also limited by bioavailability. The research towards such solutions continuous with several strategies proposed, including nanotechnology and chemical modification, to exploit the full potential of this golden molecule (Carvalho et al., 2024; Sohn et al., 2021).

3.2. Pharmacological Activities

They, as well as flavonoids and other natural compounds show a wide variety of pharmacological activity including anti-inflammatory, antioxidant, anticancer and antimicrobial activity. These bioactive compounds have demonstrated their potential in therapeutic applications due to their different biological effects and lower side effects (Longato et al., 2016; Luna et al., 2023). Remarkably, some flavonoids reverse antibiotic resistance providing an add-on to existing antibiotic drugs, making these compounds potential candidates to tackle antibiotic resistant infections (Górniak et al., 2018). Several plant-derived compounds have also been shown to induce ROS-mediated cytotoxicity in cancer cells whilst promoting antioxidant defenses in normal cells, highlighting the duality of their role in oxidative stress (Vallejo et al., 2017).

Overall, the analysis presented here may contribute to the perspective that natural compounds constitute an extensive source of new drugs and drug leads, since they display a diverse repertoire of pharmacological activities and recent studies have consistently found classes of compounds such as, flavonoids, monoterpenes and Schiff bases to yield a wide variety of biological activity. Their therapeutic potential may arise from the capacity to modulate multiple biological pathways, such as enzyme inhibition, free radical scavenging and immunomodulation (Araujo et al., 2012; Dragomanova et al., 2023; Login et al., 2019). Research in this area is constantly revealing new uses and aura of action for these bioactive compounds.

4. Nanocarrier Systems to Enhance Bioavailability

4.1. Overview of Nanocarriers

Nanocarrier systems provide many benefits in the promotion of drug bioavailability by different mechanisms. Systems such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, micelles, and inorganic nanoparticles including quantum dots and gold nanoparticles fall into this category (Alshawwa et al., 2022; Danaei et al., 2018; Lombardo et al., 2019). They enhance the solubility of drugs, protect them from degradation by emulsifying enzymes in the gastrointestinal tract, and facilitate their transport across biological barriers (Spleis et al., 2023). Although the performance of nanocarriers depends significantly on their surface chemistry. Bioinert surfaces may be used to limit interactions with the gastrointestinal (GI) fluids and adhesive surfaces can be engineered for intimate contact with the GI mucosa. Certain formulation approaches take advantage of the active surfaces of nanocarriers to cleave mucus glycoproteins to improve pervasion (Spleis et al., 2023). Furthermore, creation of stimuli-responsive nanocarriers that be switched on and off in regard to special physiological states (Majumder & Minko, 2020) or external inducers, make them suitable for site-specific dinomic release of therapeutics. In summary, nanocarrier systems are a versatile platform for improving drug bioavailability. Nanocarriers show great potential in addressing the shortcomings of traditional drug delivery systems due to their capacity to encapsulate drugs, enhance solubility, and enable targeted delivery. Recently, the incorporation of artificial intelligence with nanotechnology has allowed for improved design and development of nanocarriers, which has the potential to transform drug delivery systems (Alshawwa et al., 2022).

4.2. Why Phytosomes?

As a unique phospholipid complex system, Phytosomes have several advantages for drug delivery: Phytosomes are prepared by forming a complex of phytoconstituents with phospholipids, thus improving the bioavailability and absorption of poorly soluble plant active ingredients (Barani et al., 2021; Khan et al., 2014). This lipid-based delivery systems not only enhanced the solubility and dissolution profile of compounds such as luteolin, but also significantly increased the solubility in the same (approximately 2.5 times) compared to the pure drug (Khan et al., 2014). They showed enhanced anti-inflammatory effect as well as improved pharmacokinetics and efficacy in animal studies (Khan et al., 2014) due to phospholipid complex formation.

Figure 2: Comparative Limitations of Free Curcumin vs. Advantages of Curcumin Phytosomes

Phytosomes provide unique advantages over other carriers. Phytosomes is a term used for a molecular complex developed by an active compound with phospholipids, which provides enhanced stability and absorption when compared to conventional liposomes (Barani et al., 2021). In addition, they had better drug loading capacity and long term stability than SLNs and other colloidal systems which can cause burst release or drug expulsion during storage (Javed et al., 2022). Phytosomes are new formulation approach for enhancing bioavailability and therapeutic potential of phytochemicals. Its unique molecular complex structure, increased solubility, and improved absorption allows us to formulate these poorly soluble plant actives as an option. Investigations on the therapeutic potential of phytosomes are growing; even, the commercial products are revealed (Barani et al., 2021).

5. Curcumin Phytosomes: Composition and Preparation

5.1. Composition

Curcumin phytosomes have curcumin bound to phospholipid (primarily phosphatidylcholine). It implies that the solubility and bioavailability of curcumin are enhanced by the phytosome structure (Allam et al., 2015, Arab-Tehrany et al., 2020) Phosphatidylcholine (PC), as the major component of the forming as well as belonging to the phospholipid class, is characterized by choline-rod head group. Its major phospholipid is phosphatidylcholine, which can be obtained either from soya (soya phosphatidylcholine) or egg (egg phospholipid) (Kim et al., 2019). The choice of phospholipid is known to strongly impact properties like size, mechanical strength and solubility of the generated phytosomes (Kim et al., 2019). The ratio of curcuminophospholipid in preparation of phytosomes is important too; it may vary. The study performed by Kim et al. (2019) also determined the best ratio of egg phospholipid to curcumin to give the most stable curcumin phytosome, this at a molar ratio of 1:3 (curcumin:phospholipid). Hence, the composition matters significantly to the properties and performance. Hypothesis: The key ingredients in curcumin phytosomes are curcumin and phospholipids, especially phosphatidylcholine. Furthermore, because of the capability to alter phospholipid origin and the molar ratios, phytosomes can also be designed with compatibility for various drugs to improve the characteristics that phytosomes provide for drug delivery and efficacy.

5.2. Methods of Preparation

Methods for preparation of nanoparticles eg. solvent evaporation, anti-solvent precipitation are being employe... The antisolvent precipitation-solvent evaporation approach is successfully used to prepare nanoparticles of hydrochlorothiazide with 6.5 times greater solubility than that of the bulk drug (Vaculikova et al., 2016). In addition, emulsion/solvent evaporation method successfully produced nanoparticles of candesartan cilexetil and atorvastatin, with 32/36 samples containing particles under 200nm (Vaculikova et al., 2012). Notably, the rate of solvent evaporation is critical during the solvent casting of the poly(vinylidene fluoride) (PVDF), to define the crystalline structure of the polymer. Upon high-temperature annealing, different PVDF forms are produced depending on the evaporation rate (Horibe et al., 2013): a rate of less than 0.0001 g min−1 results in form I, more than 0.2 g min−1 results in form II, and that between 0.03 and 0.00058 g min−1 results in form III. In perovskite solar cell research, the anti-solvent dripping approach has shown great success, achieving highly reproducible efficiencies near 22% (Konstantakou et al., 2017). Overall, solvent evaporation and anti-solvent precipitation methods are emerging methodologies to prepare nanoparticles and enhance the features of drugs. The conditions such as the solvent used, evaporation rate, and the presence of stabilizers can be tuned in these methods in order to obtain specific particle sizes, thereby improving the solubility and consequently bioavailability of the drug (Liu et al., 2012; P?nar et al., 2023). This has a major influence on characteristics and performance of the final product.

5.3. Characterization Parameters

Commonly measured parameters for the characterization of nanoparticle are:

Dynamic light scattering methods are often used to measure particle size and polydispersity index (PDI). For example, Makeen et al. reported the particle size and PDI for optimized gefitinib-loaded nanostructured lipid carriers of 74.06 ± 9.73 nm and 0.339 ± 0.029, respectively (Makeen et al., 2020). Surface charge and stability (i.e. zeta potential) are critical parameters as well. The zeta potential of folic acid-modified curcumin liposomes was reported to be -15.3 ± 1.4 mV (Wang et al., 2019).

Table 3: Characterization Parameters of Curcumin Phytosomes

Parameter	Result Range	Interpretation	Instrument Used
Particle Size (nm)	100 – 300 nm	Nano-size ensures better absorption	Dynamic Light Scattering (DLS)
Zeta Potential (mV)	-20 to -40 mV	Stable colloidal dispersion	Zetasizer
Entrapment Efficiency (%)	70 – 90%	Good drug loading capacity	UV/Vis or HPLC
Morphology	Spherical, uniform	Confirms vesicle formation	SEM/TEM

Drug incorporation is also of interest and can be classified into entrapment efficiency (EE) and drug loading capacity. a batch loaded with solid lipid nanoparticles (SLNs) with irbesartan had an observed 73.8% entrapment efficiency (Soma et al., 2017). Morphology is usually determined by microscopy methods (e. g. TEM: transmission electron microscopy) and showed spherical forms for gefitinib-NPs (Makeen et al., 2020) or curcumin liposomes (Wang et al., 2019). Results can also depend on the characterization method used for creating the cell lines, interestingly. For instance, the presence of buffers during acid or base titrations in zeta potential measurements maybe affect the surface properties of the nanoparticles due to molecular interactions, which may produce misleading results (Inam et al., 2022). This highlights the need to thoroughly consider experimental conditions in the characterization of nanoparticles. All in all, the important physicochemical properties that are required for the characterization of nanoparticles are particle size, PDI, zeta potential, entrapment efficiency, drug loading and morphology of the nanoparticles. These properties are important for predicting nanoparticle behavior and optimizing formulations for drug delivery applications. Nanoparticle characterization techniques are robust but have potential cross-modulation with the particles under investigation.

6. Mechanism of Improved Bioavailability

Amorphous solid dispersions (ASDs) represent one of the most widely utilized formulation strategies to increase the oral bioavailability of poorly water-soluble drugs through improved dissolution rate and solubility (Jørgensen et al., 2023). These formulations can achieve greater concentrations of unbound drug relative to the crystalline forms, as well as generate sub-micrometer drug-rich colloids with shuttling properties for rapid diffusion through the unstirred water layer to enhance intestinal absorption (Stewart et al., 2017).

Figure 3: Mechanism of Enhanced Bioavailability of Curcumin via Phytosomes

Table 1: Comparative Bioavailability of Curcumin and Curcumin Phytosome Formulations

Formulation Type	Relative Bioavailability (%)	Key Findings	Reference
Free Curcumin	1	Very poor absorption and rapid metabolism	[Sharma et al., 2005]
Curcumin + Piperine	~2000	Piperine inhibits curcumin metabolism	[Shoba et al., 1998]
Curcumin Nanoparticles	20–30	Improved solubility and surface area	[Anand et al., 2007]
Curcumin Phytosome	29–50	Enhanced absorption via phospholipid complexation	[Maiti et al., 2007]

Functionalized polymers offer certain advantages like protection from stomach enzymes and higher absorption, permeability, and stability in the gastrointestinal tract (Pérez et al., 2016). Lipid nanocarriers can enhance solubility, chemical stability, epithelium permeability, and bioavailability of lipophilic compounds, and include self-emulsifying drug delivery systems (SEDDS), nanoemulsions and nanostructured lipid carriers (Hsu et al., 2019; Valicherla et al., 2016). The authors show that small nanocarriers may facilitate intestinal lymphatic transport and be retained in tumors (Valicherla et al., 2016). The mechanisms by which bioavailability is enhanced are improved solubility and dissolution rate, increased permeability through intestinal barriers, protection from degradation, and improved stability. Functionalized polymers, such as nanocarrier systems, are important in improving such aspects of drug release, solubilization, transport and absorption in the gastrointestinal tract (Mcclements & Xiao, 2014). Choice of the right formulation strategies is governed by the physicochemical characteristics of the drug and the desired therapeutic profile.

7. Therapeutic Applications of Curcumin Phytosomes

Curcumin, the main polyphenol present in turmeric, has a variety of therapeutic applications such as anti-inflammatory, antioxidant, antidiabetic, hepatoprotective, antibacterial and anticancer (Tagde et al., 2021). Its applications range from dealing with diabetes, hypertension and Alzheimer’s disease, which are chronic diseases (Basnet & Skalko-Basnet, 2011). This is supplemented by its therapeutic applications via the use of its phytosomes to increase the absorption rate and bioavailability (Basnet & Skalko-Basnet, 2011; Cas & Ghidoni, 2019). And yet, curcumin has performed well in preclinical studies but the clinical efficacy has been somewhat subdued because of poor solubility and low bioavailability (Basnet & Skalko-Basnet, 2011). This contradiction is a living example of the necessity for the development of advanced delivery systems, including phytosomes to overcome such disadvantages and maximize the therapeutic effects of curcumin (Dei Cas & Ghidoni, 2019).

Table 2: Therapeutic Applications of Curcumin Phytosomes

Disease/Condition	Mechanism of Action	Outcome	Study Type
Inflammation	Inhibits NF-κB and COX-2	Decrease in pro-inflammatory cytokines	In vivo (rats)
Cancer (Breast)	Induces apoptosis, inhibits angiogenesis	Tumor volume reduction	In vitro
Neurodegenerative Diseases	Antioxidant, inhibits β-amyloid aggregation	Memory improvement, neuroprotection	Animal model
Arthritis	Inhibits prostaglandins and leukotrienes	Pain relief and improved joint function	Clinical study
Liver disorders	Antioxidant activity, liver enzyme balance	Hepatoprotection confirmed	Preclinical

Overall, curcumin phytosomes could provide better therapeutic applications for multiple diseases. They enhance curcumin's anti-inflammatory and antioxidant capabilities (Ghafouri-Fard et al., 2022), anticancer efficacies (Villegas et al., 2008), neurosparing and cognitive promotion roles (Lopresti, 2022), hepatoprotection and cardiaction functions (Ruiz De Porras et al., 2023), as well as several prospective applications, for instance, therapy of female reproductive disorders (Kamal et al., 2021) and front segment eye conditions (Liu et al., 2017). Phytosomal formulations overcome poor bioavailability of curcumin and may increase its efficacy in the clinic.

8. Preclinical and Clinical Studies

Preclinical studies through in vitro and in vivo paradigms play a critical role in drug discovery and development. However, these models cannot accurately reflect human physiology with good success and are therefore often unreliable in predicting drug efficacy and safety (Luo et al., 2023; Malik et al., 2021). To overcome these challenges, modern technologies including organs-on-chips (OCs) and microphysiological systems (MPS) are developed and implemented as alternatives to traditional preclinical models (Luo et al., 2023; Malik et al., 2021). It was noted that there are differences between preclinical and clinical studies. For instance, T cell receptor (TCR)-based immunotherapies have proven to be notoriously difficult to evaluate in animal models due to the species-specific biology of TCRs (Harper et al., 2018). This highlights the need for preclinical testing approaches that are relevant for humans and more holistic. In short, there is no question that preclinical studies remain a critical part of the drug development process, but there is also growing appreciation that they often need to more closely mimic the clinical reality of human physiology. This also includes the development of higher-performing in vitro models, and more extensive complete preclinical testing packages that are utilizing an array of human tissue and cell-based cellular and molecular assays (Harper et al. 2018). Or note the effect of conscientious device design and preclinical evaluation on time and expense to market new therapies (Shepherd et al., 2018).

SUMMARY

Curcumin (diferuloylmethane), a polyphenolic compound from turmeric, exhibits a wide range of therapeutic effects, yet it is characterized by low bioavailability as a result of low solubility in water and rapid metabolism. Curcumin phytosomes (complexes of curcumin with phospholipids such as phosphatidylcholine) significantly increase the bioavailability and absorption of curcumin. The preparation methods include solvent evaporation and anti-solvent precipitation, while the characterization includes particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, and morphology. Phytosomes enhance bioavailability by enhancing solubility, increasing permeability, masking against degradation, and improving stability. Therapeutic applications of curcumin phytosomes include anti-inflammatory, antioxidant, anticancer, neuroprotective, hepatoprotective, and cardioprotective. Clinical and preclinical studies are important in assessing efficacy and safety. As a result, the efforts are directed towards improving these studies in terms of predictability and their relevance to human physiology.

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