Enhanced systemic bioavailability of curcumin through transmucosal administration of a novel microgranular formulation

 

Anticancer Res. 2015;35(12):6411–6418. PMID: 26637850

 

Head and neck cancer is the cancer of the head and neck portion of the body and is developed through a multi-step process of genetic, epigenetic, and metabolic changes resulting from carcinogen exposure. Curcumin is a promising nutraceutical for chemoprevention of head and neck squamous cell carcinoma (HNSCC). However, the bioavailability of the capsular formulations of curcumin is one of the limiting factors for its proper application in the treatment of the same. Various formulations have been developed aiming to improve the systemic bioavailability of the curcumin. The microgranular curcumin is one such formulation devised to improve the curcumin bioavailability.

 

Objective:

To determine the bioavailability, efficacy, and safety of microgranular curcumin formulation, with transmucosal absorption property, in cancer subjects and healthy volunteers.

 

Methods:

The study was carried out in 8 healthy volunteers and 15 head and neck squamous cell carcinoma patients. The curcumin formulation consists of curcumin C3 Complex in the form of small beadlets (microgranules), manufactured by Sabinsa. Following the standard diagnostic incisional biopsy, patients were self-administered C3 Complex microgranules (4 g) and were instructed to hold it in the mouth for 10 minutes. Serum was collected at 15 min, 30 min, 1 h, 2 h, and 4 h after administration. The final serum collection occurred between days 21-28 after patients completed a 3-4 week regimen of 4 g twice-daily dosing of curcumin. Serum levels of curcumin were measured by HPLC. The biological activity of curcumin was assessed with Multiplex Immunoassay and immunohistochemistry.

 

Results:

  • Higher serum levels of curcumin were observed compared to other trials using capsular formulation
  • In cancer patients, a significant decrease in expression of fibroblast growth factor-2 (FGF-2) in post-biopsy samples and decreased serum levels of FGF-2, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-17 (IL-17) (p<0.05) were observed

 

Conclusion:

Transmucosal administration of microgranular curcumin leads to enhanced curcumin bioavailability, which is associated with significant biological effects.

Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids

Pharmaceutics.2017 Oct 12;9(4).pii: E45

 

Curcuminoids, curcumin, calebin-A and Tetrahydrocurcumin (THC), found in turmeric (Curcuma longa) have multitude pharmacological activities and are used as health supplements. They have been explored to establish their anticancer properties also. By virtue of P-glycoprotein inhibitory activity curcumioinds are used as adjuvant drugs in cancer therapy. Further, studies have found that curcumin and calebin-A act at the genetic level to inhibit histone acetyltransferase (HAT) and modulate mitogen-activated protein-kinase (MAPK) pathway, respectively. Despite being effective, both curcumin and calebin-A suffer from poor oral bioavailability. THC is an active metabolite of curcumin that has greater stability at the physiological condition and improved aqueous solubility than curcumin. With improved benefits over curcumin, THC is also being explored for its anticancer potential.

 

Objective:

To describe the pharmacokinetic characteristics of THC in vivo and anticancer effects along with curcumin and calebin-A, in vitro.

 

Methodology:

Drug disposition for THC (500 mg/kg) was characterized using surgically-modified, exposed jugular vein-catheterized, adult male CD Sprague-Dawley rats (250–300 g) fasted 12 hours prior to single oral dose. The blood and urine sample were collected at certain intervals until 72 hours post-dosing. The drug was quantified in serum and urine samples obtained from rats administered with THC using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC–MS/MS) to characterize its pharmacokinetics in rats after oral administration. Curcuminoids (THC, curcumin and calebin-A) were assessed for pharmacological potential in vitro, including antioxidant, anti-inflammatory (cyclooxygenase (COX), lipooxygenase (LOX) and tumour necrosis factor (TNF)-alpha inhibition, HDAC1 and PCAF inhibition as well as cellular growth inhibition. Curcuminoids (THC, curcumin and calebin-A) used in this study were by Sabinsa Corporation.

 

Results

The study results indicate that

  • Un-optimized formulations of THC will be poorly absorbed after oral administration and are primarily excreted via non-renal routes; as glucuronide conjugates in bile
  • All the curcuminoids tested had exhibited multiple pharmacological effects in vitro, including potent antioxidant activity as well as inhibition of CYP2C9, CYP3A4 and lipoxygenase activity without affecting the release of TNF-α
  • Curcuminoids show a marginal COX inhibition; with curcumin being highly selective to COX-2 than COX-1 isoenzyme, while the calebin-A and THC had an equal propensity to both the isoenzymes
  • Both curcumin and calebin-A show direct inhibition of HDAC1 and PCAF as well as displayed a weaker growth inhibition activity against T-cell lymphoblastic lymphoma Sup-T1 cells

 

Conclusion:

This study concludes that both curcumin and calebin-A has anticancer potential by direct inhibition of HDAC1 and HAT PCAF mechanisms, while the THC has different anticancer mechanism maybe by virtue of its anti-inflammatory and antioxidant activities.

Pharmacokinetics of liposomal curcumin (Lipocurc) infusion: effect of co-medication in cancer patients and comparison with healthy individuals

Cancer Chemother. Pharmacol.2019 Feb;83(2):265-275

 

"Curcumin is being explored by numerous studies for its anticancer properties. However, its utility is limited by poor oral bioavailability. It has a shorter half-life and rapid systemic elimination following parenteral administration due to metabolism. Nano-formulations of curcumin developed to improve its bioavailability were also found efficacious to suppress the pancreatic tumour growth, lymphocyte count as well as to increase the scavenging cells. With the availability and efficacy of nano-formulations of curcumin, it became imperative to study about the influence of co-medication on the pharmacokinetic profile of liposomal curcumin formulation (containing 6.0 mg/mL curcumin) in cancer patients."

 

Objective:

To investigate the impact of co-medication on the plasma levels of curcumin and Tetrahydrocurcumin (THC) in cancer patients compared to healthy individuals following intravenous infusion of liposomal curcumin.

 

Methodology:

Freshly isolated red blood cells (RBCs), cryopreserved hepatocytes obtained from male Beagle dog and male human donors were used in this study for in vitro distribution experiments with liposomal curcumin. The pharmacokinetic profiles of curcumin and THC in healthy individuals (phase I) and cancer patients (phase Ib) were also compared by analyzing the plasma profiles.

 

Results and discussions:

  • Among the medications studied, the medication affecting rennin—angiotensin system were found to elevate the normalized plasma levels of curcumin and THC in patients with cancer, while the rest of the medications did not show major alterations
  • The presence of ACE inhibitor during the incubation has decreased the levels of curcumin in human RBCs, hepatocytes and RBC medium, while it was increased in the dog RBCs (p<0.01), RBC medium (p<0.01) and hepatocytes
  • The levels of THC were decreased in human RBCs but slightly increased in human hepatocytes and RBC medium. The levels of THC were contrastingly changed in dog cells and dog cell medium, i.e., they have increased in dog RBCs as well as hepatocytes (p<0.01), but decreased in RBC medium (p<0.01)
  • The plasma levels of curcumin in cancer patients increased with increased infusion rates compared to healthy individuals
  • The elimination of curcumin was faster with a shorter terminal half-life, also showed a smaller volume of distribution in patients with cancer than healthy individuals
  • Despite the lower infusion rates of curcumin in cancer patients, the plasma concentrations of curcumin during infusion were in a similar range as those of healthy individuals

 

Conclusion:

It was found that the co-medications and health status, either or both, impact the pharmacokinetics of curcumin in the cancer patients.

Distribution and Metabolism of Lipocurc (Liposomal Curcumin) in Dog and Human Blood Cells: Species Selectivity and Pharmacokinetic Relevance

Anticancer Res.2017 Jul;37(7):3483-3492

 

Liposomal curcumin is a nano-formulation (contains 6 mg/mL) that was developed for parenteral administration. Studies have revealed marked species differences of the plasma disposition of curcumin and its active metabolite Tetrahydrocurcumin (THC). Curcumin is known to interact with the blood cells, however, the impact of this interaction on its plasma pharmacokinetics is not known. The liver is the key metabolic site for curcumin. Former studies have shown that THC, a reductive active metabolite of curcumin, was measured in the plasma of whole blood incubated with liposomal curcumin.

 

Objective:

To investigate and compare the disposition of liposomal curcumin (Lipocurc) and its major metabolite THC in blood cells. For comparison, the cellular distribution of curcumin was also investigated in cryopreserved hepatocytes from Beagle dogs and humans.

 

Methodology:

Curcumin (~2 µM) was incubated at 37°C for 15 min individually with red blood cells (RBCs), peripheral blood mononuclear cells (PBMCs), and hepatocytes obtained from male Beagle dog and male human donor sources.

 

Results and discussions

  • Blood cell distribution, metabolism of liposomal curcumin and factors impacting the pharmacokinetics of curcumin were observed successfully in this study
  • Species difference was noted between the distribution of curcumin and THC in blood cells from Beagle dog and human
    • Concentrations of curcumin were significantly higher in human RBCs and hepatocytes than that of the dogs, while it was opposite for PMBCs; higher in dog cells than that of the human cells
    • The measurement of THC in RBCs and PBMCs suggest that during the incubation period curcumin must have entered these cells and metabolized there to THC
    • The levels of THC were significantly higher in dog RBCs and PBMCs compared to human, while it was opposite for hepatocytes; higher in human cells than dog cells. This suggests the higher presence of reductase activity in dog RBCs and PBMCs as well as human hepatocytes
  • The ratio of THC to curcumin found in the RBC medium following incubation of 15 minutes was significantly higher for dog (6.3) compared to human (0.006), while there was no such marked species difference for PBMCs and hepatocytes.

The in vitro results obtained in this study were compared with in vivo data from published studies done in Beagle dogs and phase I human trials with liposomal curcumin. It was found that there was a very good correlation between the species differences of RBC metabolism of curcumin to THC and in vivo plasma levels of curcumin and THC from human studies.

 

Conclusion:

There were species dependence and an excellent correlation between the in vitro disposition of curcumin and THC following incubation with RBCs and in vivo plasma levels of curcumin and THC in dog and human following intravenous infusion.

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About Author

Muhammed Majeed, Ph.D.

Dr. Muhammed Majeed holds a doctorate (1986) in Industrial Pharmacy from St. John’s University, New York. He has over 15 years of pharmaceutical research experience in the United States with leading companies such as Pfizer Inc., Carter-Wallace and Paco Research.

Subsequent to the formation of his company, Sabinsa Corporation in 1988, he has pursued his interest in phytochemistry and pharmaceutical sciences. He has led a team of scientists, both in India & USA, and obtained 115 US and International patents so far. He is aggressively pursuing his interest in natural products and continues to develop new products for the US and International markets.

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About Sabinsa

Sabinsa Corporation is a manufacturer, supplier and marketer of herbal extracts, cosmeceuticals, minerals, dietary supplements and specialty fine chemicals for the nutritional, cosmetic, pharmaceutical and food industries.

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