Author: Dr. Arvind Gupta
Professor Nephrology MLN Medical College, Allahabaddownload Article
Curcumin is a natural spice that has been traditionally used as a medicinal herb for many decades, it shows antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and anticancer properties. Curcumin is effective in treating chronic conditions like cancer, diabetes, arthritis, Alzheimer's, and many others. Although it has several benefits curcumin has a few shortcomings in terms of bioavailability. This is a review article written with the objective to systematically analyze the information regarding the benefits, properties and immunomodulatory effects of curcumin, and to understand the existent gaps which have prevented its widespread application in the medical community and the new technological modifications that are coming up to improve its role in clinical applications.
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) a polyphenol, also called diferuloylmethane, is the main natural polyphenol found in the rhizome of Curcuma longa (turmeric) and others Curcuma spp. Turmeric has been traditionally used in Asian countries as a medicinal herb as it has antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and anticancer properties. It has also been shown to benefit inflammatory conditions, metabolic syndrome, pain, it has been also shown to benefit the kidneys .
Curcumin has immunomodulatory abilities that arise from its interaction with various immunomodulators, including cellular components as, dendritic cells, macrophages, and both B and T lymphocytes, and also molecular components, such as cytokines and various transcription factors . Curcumin inhibits the immunostimulatory function of dendritic cells (DCs). These effects have been related to the suppression of CD80 and CD86 expression, two membrane proteins that are necessary for T cell activation, Curcumin increases serum levels of IgG and IgM, thus improving immune function. Curcumin induces apoptosis and inhibit proliferation of a number of NK/T-cell lymphoma cell. Curcumin is also involved in mediating NK cells function by increasing nitric oxide (NO) generation in NK cells following prolonged treatment and enhancing their cytotoxicity [6,7,8]. Curcumin is further involved in eliminating cancer by reducing the T-regulatory cell population, maintaining reactive oxygen and nitrogen production by macrophages, and NK cell cytotoxic activity [9,10,11].
Despite all the positive benefits, a major criticism that curcumin faces are its poor bioavailability . Curcumin has been shown to exhibit poor bioavailability, many studies showed very low, or even undetectable, concentrations in blood, tissues, and urine. Possible reasons are due to its poor absorption, rapid metabolism, chemical instability, and rapid systemic elimination . The majority of oral curcumin is excreted in the feces (≤90%) . Many limitations have been recognized for the therapeutic use of curcumin: its poor pharmacokinetic/pharmacodynamic properties, its chemical instability, it's low efficacy in different disease models, its toxic profile under certain experimental settings  hence, technology-based delivery systems might help to overcome the limitations that are linked to conventional curcumin and therefore improve its therapeutic efficacy and improve its role in clinical application .
Phytosomes are the spherical cell like structure, containing a phospholipid in combination with standardized polyphenolic herbal extract. They are non-polar in nature which makes them better in absorption, utilization and as an outcome produce better results than conventional herbal extracts .
Phospholipids are the major component of cellular membranes. They act as a carrier for both polar and non-polar active substance . Many phospholipids have nutritional importance, like phosphatidylserine provide nutrition to brain cells, phosphatidylcholine helps in liver cell regeneration, etc. 
There are many standardized extracts and phytochemical constituents which shows excellent biological activities in vitro, but do not express any activity or lesser response in vivo. This may be due to intrinsic property of drug molecule like poor solubility, molecular size, or destruction in gut, etc.  These inherent properties of drug lead to decreased absorption and inadequate drug availability inside the body.
The problem of low absorption can be alleviated by using phytosome technology. The phytosomal formulations enhances the absorption of the active phytochemical compounds. They now complexed with phospholipids are permeable across the lipid rich gut lining, and are also protected from destruction due to secretions inside the gut environment. This not only increases the bioavailability of the drug constituent, but also decreases the quantity of active drug molecule to be taken to achieve the desired therapeutic activity .
Phytosomes as novel herbal vesicular drug delivery systems assure to deliver the drug through the pathway channelizing the active phytoentity to the desired site of action. Beside their actions phytosome possess the following properties :
Phytosomes have been successfully used for the enhancement formulations of several types of herbal extracts. One of them being curcumin, an active constituent of turmeric standardized extract. Traditional curcumin extract has the limitation of bioavailability, hence, this led to the attempts for designing of new formulation and drug delivery systems. Phytosome technology helps in overcoming this limitation of traditional delivery system and shows an increased absorption and enhanced bioavailability of curcumin .
Production Methodology of Phytosomal Curcumin Preparation
Phytosomal curcumin is prepared by the addition of phospholipids to the ethanol solution of the hydroalcoholic extract of turmeric rhizomes. This is done under continuous reflux and stirring. The resulting suspension is concentrated by reduced pressure to a thick residue. Phytosomes can be isolated by precipitation with non-solvent, lyophilization, spray drying or vacuum drying . This can be ground to form a fine powdered and then cast into the desired product form.
Figure 2: A schematic representation of the structure and preparation of phytosomal curcumin
Phosphatidylcholine (or phosphatidylserine) is a bifunctional compound. The phosphatidyl moiety is lipophilic and the choline (serine) moiety is hydrophilic in nature. This dual solubility of the phospholipid makes it an effective emulsifier. Thus, the choline head of the phosphatidylcholine molecule binds to these compounds while the lipid soluble phosphatidyl portion comprising the body and tail which then surrounds the choline bound material. Hence, the phytoconstituents produce a lipid compatible molecular complex with phospholipids (also called as phytophospholipid complex) .
Complexation of curcumin with phosphatidylcholine has been reported to result in enhanced bioavailability, improved pharmacokinetics and increased hepato-protective activity compared with uncomplexed curcumin .
Curcumin as an active constituent of turmeric has many therapeutic value, but its traditional delivery system leads to poor bioavailability. Conventional curcumin’s innate nature does not allow it to dissolve in gut environment and is also not absorbed across the intestinal cells. Moreover, studies have shown that the non-complexed curcumin is rapidly metabolized, conjugated in liver, and finally gets excreted in faeces. Therefore, has limited systemic bioavailability .
The phytosome curcumin, that is phosphatidylcholine-curcumin complex (Meriva®) is more readily incorporated into lipophilic cell membranes, making it significantly more bioavailable than unbound curcumin. The in vivo study has peak plasma concentration and AUC were five times higher for phytosome curcumin than for unbound curcumin . In another study, researcher investigated the comparative absorption of a standardized curcuminoid mixture and phytosomal curcumin (Meriva®). Their result showed that total curcuminoid absorption from phytosomal curcumin was 29 folds higher compared with the non-phytosomal curcuminoid mixture . Upon administration of phytosomal curcumin, plasma concentrations of curcumin sulfate and curcumin glucuronide were found to be 3 to 20 folds higher than those traced after the administration of uncomplexed curcumin.
Figure 3: Absorption of Curcumin Phytosome (Meriva®) Compared to Non-complex Curcumin in Humans
Henceforth, it is found that phytosomal curcumin has following benefits over traditional curcumin:
There have been several studies investigating the safety and efficacy of phytosomal curcumin in the treatment of various human diseases such as cancer, osteoarthritis, diabetes and inflammatory diseases. The data suggest the phytosomal formulation of curcumin has good properties for clinical use.
Curcumin can modulate several pathways and molecular targets involved in different stages of cancer pathogenesis . In vivo and in vitro studies have shown that phytosomal curcumin can exert cytotoxic and apoptotic effects in cancer cell lines and animal models .
Ibrahim et al. evaluated the efficacy of curcumin conjugated with phosphatidylcholine as a treatment against mammary gland tumor. Mammary gland tumor cell line (ENU1564) was inoculated into the mammary fat pad of athymic nude mice. The mice were treated orally with either pure curcumin or phytosomal curcumin (Meriva®). The tumor and its lung metastasis were evaluated grossly, microscopically, and immunohistochemically. The results revealed that phytosomal curcumin significantly increases the expression of MMP-9 and inhibits the lung metastasis of ENU1564 cells .
In a GL261-implanted glioblastoma mouse model, intraperitoneal administration of phytosomal curcumin was shown to shift the polarization of tumor-associated macrophages towards the tumoricidal M1 phenotype .
In a clinical study, Belcaro et al. used curcumin phytosomes to control the adverse effects of chemotherapy and radiotherapy in 160 patients. The results showed that supplementation with phytosomal curcumin could alleviate the adverse effects of chemotherapy and radiotherapy .
Panahi et al. investigated the efficacy of phytosomal curcumin as an adjunct to chemotherapy in patients with solid tumors. In the mentioned study, patients took phytosomal curcumin (1500 mg/day in 3 divided doses; n = 19) for 6 weeks. The result indicated a significant enhancement of quality of life (QoL) and suppression of systemic inflammation following supplementation with phytosomal curcumin .
Curcumin targets several molecular species and biochemical pathways involved in insulin resistance, diabetes and its complications such as PKC-a, b 2-MAPK, PPAR-g, MCP-1, TNF-a and nitric oxide . In one study, improvement of diabetic microangiopathy and retinopathy was examined in 38 diabetic patients treated with Meriva®. The results showed an enhancement of microangiopathy in the Meriva® group at 4 weeks post-treatment. In addition, there was a significant improvement in the venoarteriolar response and a decline in the score of peripheral edema following treatment with phytosomal curcumin. At the retinal level, high-resolution and duplex scanning techniques were utilized to measure retinal flow and results indicated an enhancement in the Meriva®-treated patients. These results suggested that curcumin, when administered in the phytosomal form, is quite helpful in the management of diabetic treatment .
In a pilot study, Appendino et al. investigated the effects of 4-week treatment with phytosomal curcumin, administered at a daily dose of 1 g, in controlling the development of microangiopathy in diabetic subjects . The results showed that in the patients group, there was a significant decrease in skin flux at the surface of the foot. Moreover, a significant decline in the edema score and a corresponding improvement in the venoarteriolar response were also observed. Finally, the PO2 was improved after four weeks of treatment, leading to a better oxygen diffusion into the skin due to decreased edema.
Several studies have investigated the role of curcumin in modulating inflammatory response in different diseases .
The anti-inflammatory properties of curcumin are mediated via its capability to suppress key regulators of the inflammatory response such as 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) . Phytosomal curcumin was used to evaluate curcumin’s effects on the ileum and colon in a mouse colitis model. The results showed that curcumin has direct and indirect myorelaxant effects on mouse ileum and colon. The indirect effect was reversible and noncompetitive with the cholinergic agent .
Allegri et al. assessed the efficacy of phytosomal curcumin in treating recurrent anterior uveitis of different etiologies. The studied population included 106 patients who completed a 12-month therapeutic period. The patients group was divided into three subgroup of various uveitis origins: group 1 (autoimmune uveitis), group 2 (herpetic uveitis), and group 3 (other etiologies of uveitis). The investigators evaluated relapse frequency, relapse severity and the overall quality of life in all treated subjects. The results revealed that there were significantly reduced ocular discomfort symptoms following treatment with phytosomal curcumin in most patients and the medication was well tolerated. Based on this result, phytosomal curcumin was suggested as a potential therapeutic agent for the eye relapsing diseases such as anterior uveitis and in conditions like glaucoma, maculopathy and dry eye .
Osteoarthritis (OA) is a known and leading cause of physical disability, and is responsible for impairment to the life quality particularly in the elderly population. Non-steroidal anti-inflammatory drugs (NSAIDs) are the main treatment option for this disease. Various reports have shown that long-term use of these drugs is associated with several adverse effects. Same for other medical complications, finding new treatment options is actively pursued. Various studies have indicated that Meriva® with specific properties can be used as a new option in the treatment of OA .
Belcaro et al. investigated the efficacy and safety of Meriva® during extended administration in OA patients. Their results indicated significant enhancements of both clinical and biochemical indices in the phytosomal curcumin versus control group. .
In another study, the efficacy of Meriva® in 50 subjects with OA at a dosage corresponding to 200 mg/day curcumin was investigated. The results showed that global Western Ontario and McMaster Universities (WOMAC) score significantly decreased after three months of treatment. In addition, walking distance in the treadmill test was prolonged from 76 m to 332 m, and there was a significant decrease in C-reactive protein (CRP) levels from 168 to 11.3 mg/L in the subpopulation with high CRP. In this latter study, the control group experienced only a modest improvement in the efficacy measures (WOMAC score, the CRP plasma concentration and treadmill test), while the treatment costs (use of anti-inflammatory drugs, hospitalization and treatment) were significantly reduced in the treatment group .
Curcumin has a potent antioxidant and balanced anti-inflammatory properties. It possesses diverse therapeutic activities for the treatment of various diseases. But the poor absorption and low bioavailability of conventional curcumin possess an obstacle in harvesting the full potential benefit of curcumin. Phytosome technology being a novel drug delivery system has emerged as a promising strategy for enhancing the bioavailability of curcumin. Moreover, several studies have shown the beneficial, effective and safe use of phytosome curcumin in treatment of various diseases.