Liponax® sol, A Patented Food Supplement in
Liquid Dosage Form: Study of Pharmacokinetics Parameters of R-α-Lipoic Acid in Healthy Volunteers
Nicola D’Anzi1*, Erika Amore1, Eduardo Sommella2, Cristina Esposito3, Emanuele U Garzella3, Cristina Santarcangelo3 and Maria Daglia3,4
1Savio Industrial, Italy
2Department of Pharmacy, School of Pharmacy, University of Salerno, Italy
3Department of Pharmacy, University of Naples Federico II, Italy
4International Research Center for Food Nutrition and Safety, Jiangsu University, China
Submission:February 02, 2021; Published: March 15, 2021
*Corresponding author: Nicola D’Anzi, Savio Industrial, via del Mare 36, 00040, Pomezia, Italy
How to cite this article: Nicola D’A, Erika A, Eduardo S, Cristina E, Emanuele U G, et al. Liponax® sol, A Patented Food Supplement in Liquid Dosage
Form: Study of Pharmacokinetics Parameters of R-α-Lipoic Acid in Healthy Volunteers. Open Acc J of Toxicol. 2021; 5(1):555651.
α-Lipoic acid (LA) is a strong antioxidant compound widely used in oxidative stress-related clinical conditions. LA exists in two enantiomeric forms, R-(+)-lipoic acid (R-LA) and S-(-)-lipoic acid (S-LA). Nowadays LA is synthetized mainly by a chemical processes that produce the racemic mixture, but only the R-LA is the biological active form. A lot of different formulation of LA are available on the market and the majority of them contains the racemic mixture, and few data are available on the impact of the inactive enantiomer on the pharmacokinetic profile. However, it is known that the S-LA is somewhat impacting the PK of the products. This study aims to evaluate the pharmacokinetic profile of a new patented oral liquid formulation (Liponax® sol) containing 300 mg of R-LA in 10 healthy volunteers. Blood samples were collected up to 180 minutes after the consumption of 300 mg R-LA in fasting subjects. Plasma concentrations of R-LA were determined by ultra-high performance liquid chromatographic coupled with mass spectrometer (UHPLC-MS). R-LA was rapidly absorbed showing a Cmax value higher than the commonly recognized lipoic acid therapeutic effect activation threshold and a high AUC if compared to other published data where 600 mg racemic LA tablets were administered.
Keywords: R- α-lipoic acid; UPLC-MS; Pharmacokinetics; Blood samples, Liponax sol
Abbreviations: LA: Lipoic Acid; UHPLC-MS: Ultra-High-Performance Liquid Chromatographic Coupled with Mass Spectrometer; LOD: Limits of Detection; LOQ: Limit of Quantification; SIR: Single Ion Recording; SD: Standard Deviation; AUC: Area Under the Concentration–Time Curve; NA: Naproxen
α-lipoic acid (LA), also known as thioctic acid or 1,2-dithiolol-3-pentanoic acid, is a small amphiphilic organosulfur molecule produced by plants, animals, and humans . Due to the chiral carbon in C6 position, LA exists as two enantiomeric forms: R-(+) lipoic acid (R-LA) and S-(-) lipoic acid (S-LA), of which R-LA is the naturally exsisting compound. In fact, R-LA is covalently bound to lysine residues as lypoyllysine and occurs in many vegetable (i.e. spinach, broccoli, peas and tomatoes) and animal foods (i.e. kidney, heart, and liver), in very low amounts, ranging from about 1 mg/g to 22 mg/g and 2 mg/g to13 mg/g, respectively . R-LA is an essential cofactor for mitochondrial enzymes involved in energy production and cellular metabolism (i.e. pyruvate dehydrogenase,
α-ketoglutarate dehydrogenase, and branched chain α-ketoacid dehydrogenase complex) . In humans, due to the extensive tissue diffusion capacity, LA crosses the blood-brain barrier and is localized at cerebral cortex level . The most important feature of this molecule is its powerful antioxidant activity. Along with its reduced form (dihydro-lipoic acid, DHLA), it is a potent redox couple with a redox potential of -320 mV  which makes it able to directly regenerate other natural antioxidants, such as oxidized form of glutathione (GSSG/GSH couple with a redox potential of -140 mV ) and vitamin C, and indirectly vitamin E. Moreover, DHLA can be recycled from LA [7,8] and for this reason the LA/DHLA couple has been called the “universal antioxidant”. R-LA can exert its antioxidant activity in both cellular membranes and cytosol, differently from other endogenous antioxidants,
which exert their activity only in hydrophilic or hydrophobic
environment. This molecule shows metal-chelating capacity
[9,10] and the ability to scavenge hydroxyl radicals, hypochlorous
acid, and single oxygen . R-LA activates the insulin signaling
pathway in insulin responsive tissues , stimulates glucose
uptake by translocating and regulating the intrinsic activity of
GLUT4 , participates in lipid metabolism [14,15], increases
insulin sensitivity [16,17].
Although R-LA is the naturally occurring and most active form
it is rarely used due to its intrinsic susceptibility to polymerize.
Nowadays, LA is synthetized mainly by a chemical process that
produce the racemic mixture (more stable) that is widely used as
drug or food supplement ingredient [18,19].
A lot of different formulation of LA are available on the
market and the majority of them contains the racemic mixture,
and not much has been investigated on the impact of the inactive
enantiomer on the pharmacokinetic profile. It is known that the
S-LA is somewhat impacting the PK of the products due to its
influence on the polymerization susceptibility of the R-LA few
literature data underline the potential negative effects of the S-LA
Administered intravenously, LA achieves the maximum
plasma level leading to beneficial effects in the treatment
of symptomatic diabetic polyneuropathy and other diabetic
related conditions. The pioneering ALADIN study  shows
that intravenous LA in diabetic patients with neuropathy causes
a significant improvement in symptoms, such as burning,
paraesthesia and pain, compared to placebo. On the other hand,
LA is a food supplement available only for oral administration
usually as tablets or capsules containing 600 mg racemic LA
. Unlike the intravenous administration, the bioavailability
of LA tablets is lower through the oral route. In the past, the
bioavailability of various solid formulation was investigated and
it was established a low grade of LA absorption around 30%
. Indeed, phenomena such as reduced solubility in acidic
environment and enzymatic degradation, which characterize
its gastric and hepatic passage when administered orally, limit
the potential of LA. Moreover, the oral administration involves
various aspects that restrict the amount of LA absorbed, such as
the disintegration of the solid formulations, the first pass effect in
the liver, the inter-individual variability [10,23]. For this reason,
various chemical interventions and formulations have been tested
to achieve greater plasma bioavailability of LA even after oral
administration and to ensure better therapeutic effects [18,24-
27]. To date, there is only one patented oral liquid formulation on
the market containing 300 mg of the R-(+) enantiomer stabilized
as Na salt in water and co-solvent . This formulation has
shown improved pharmacokinetic parameters in experimental
animals when administered orally at 50mg/kg dose and in an
experimental model of diabetes induced in Sprague Dawley rats
it resulted to improve nerve conduction velocity, hyperglycaemia
and hypertriglyceridemia . Nowadays, an improved liquid
formula, Liponax® sol, is available as food supplement and its
biological activity, tolerability and safety were tested in different
In a group of 38 patients with peripheral neuropathy of various
etiologies treated for 4 weeks with R-LA liquid formulation a
significant reduction in the total value obtained using NPS (Italian
Neuropathic Pain Scale) was registered . Despite performed
on a limited number of patients, this study confirms that the
liquid solution of R-LA provides relief from the pain symptoms
of peripheral neuropathy. Beside confirming the efficacy of LA in
the relief of symptoms in neuropathic pain, the results obtained
may be attributed also to the improved bioavailability of the new
formulation. The aim of the present investigation is to confirm
the high bioavailability of the liquid formulation Liponax®
sol evaluating its pharmacokinetics parameters in human,
considering that according to literature, beneficial effects of LA
were also correlated to a threshold of activation reached with a
maximum concentration (Cmax) of 4-5 μg/mL and an area under
the curve (AUC) of 171 min × μg/mL (Hermann et al., 1996). For
this purpose, Liponax® sol was administered in fasting healthy
adult at 300 mg dose of R-LA.
To evaluate pharmacokinetic parameters (Tmax, Cmax, AUC
and T1/2) a clinical study was performed by Comegen Medical
Cooperative (Naples, Italy) on a healthy adult population. Blood
samples were collected after the consumption of an oral dose of a
food supplement (Liponax® sol) containing 300 mg of R-LA after
an overnight fast of 12 h. The subjects received oral and written
information concerning the study before they gave their written
consent. Protocol, letter of intent of volunteers, and synoptic
document about the study were submitted to the Scientific Ethics
Committee of ASL NA 1, Naples, Italy. The study was approved
by the Ethics Committee and the chairperson was Silvana Perna
(Protocol N°122). The study was carried out in accordance with
the Helsinki declaration of 1964 (as revised in 2000).
R-LA, naproxen (NA), acetic acid (analytical grade 99% pure),
methanol (analytical grade 99% pure) and human heparinized
plasma were purchased from Sigma Aldrich (Missuri, United
States). Water and acetonitrile were LC/MS pure grade >99.9%
and were purchased from Merck (Merck Company, Germany).
Blood samples were collected in 10-mL EDTA coated tubes
(Becton Dickinson, Plymouth, United Kingdom). Liponax® sol
was supplied by I.B.N. SAVIO (via del Mare 36, Pomezia, 00040,
R-LA stock solution (1mg/mL) was prepared in methanol
and stored at 4°C. The calibration curve was obtained in a
concentration range of 0.05 – 5.00 μg/mL with six concentration
levels and performing triplicate analysis for each level. Naproxen
(NA) was selected as internal standard at the concentration of
5μg/mL. All the solutions were stored at 4°C until the beginning
of the analysis and there was no change in stability after 30 days
(data not shown).
UHPLC-MS analyses were performed on an Acquity I class,
equipped with a QDa single quadrupole mass detector (Waters,
Milford (MA), U.S) system. The separation was performed on a
Kinetex® Biphenyl 100 Å column with geometry (L × I.D) 10 cm
× 2.1 mm, 2.6 μm (Phenomenex®, Bologna, Italy) employing as
mobile phases: A) 0.1% CH3COOH in H2O and B) ACN, with the
following gradient: 0 min, 45% B, isocratic for 2.50 min, 2.51 min,
99 % B, isocratic for 1 min. Returning to 45 % in 1.50 min. The
flow rate was set to 0.4 mL/min. Column oven was set to 40°C, 5
μL of extract were injected.
The ESI was operated in negative mode. Source temperature
was 600°C, Probe voltage -3.5 kV. Nitrogen was used as nebulizer
gas (10 L/min). MS analysis were conducted in selected ion
recording (SIR) mode, employing 205.0 m/z for R-LA and 229.0
m/z for NA.
Study participants were recruited by the Cooperative of
physician, Comegen (Naples, Italy). Subjects of both sexes, aged
18-65 years, were considered eligible for enrolment if they are in
healthy status with a BMI < 25 kg/m2. Pregnant women, women
suspected of being pregnant, women who hoped to become
pregnant, breastfeeding, subjects with R-LA allergy, smokers,
subjects exposed to a high risk of cardiovascular events, subjects
suffering from endocrine disorder (e.g. hypothyroidism, Cushing’s
syndrome, polycystic ovary syndrome or PCOS), subjects taking
corticosteroids, subjects who have taken food supplements in the
two weeks before recruiting, subjects suffering from liver disease,
and not self-sufficient were excluded from the study.
Blood samples (2.5 mL) for the determination of R-LA plasma
concentration were collected at the time of 0, 2, 5, 10, 15, 20, 25,
30, 40, 50, 60, 90, 120, and 180 min after oral administration as
reported in Figure 1.
The pharmacokinetics parameters calculated for each subject
included: maximum plasma concentration (Cmax) of R-LA after oral
administration of Liponax® sol (10mL), time to reach maximum
concentration (Tmax), area under the concentration–time curve
(AUC) equivalent to the total amount of R-LA that reaches the
systemic circulation unmodified, and elimination half-life (t1/2).
Sample preparation: To an aliquot of 200 μL of plasma in
a 1.5mL Eppendorf plastic tube, 30μL of the internal standard
(100μg/mL) were added to achieve the concentration of 5μg/
mL. The solution was vortexed for 15 seconds. Then, 370μL of icecold
acetonitrile were used for protein precipitation, vortexed for
30 seconds and centrifuged at 14.000rpm for 15 min. Thus, the supernatant was filtered (0.45μm pore size) and injected in the
Linearity: The linear regression was used to generate
the calibration curve that correlates peak area versus analyte
concentrations with values of correlation coefficient R2 ≥
0.999. The peak areas were converted to the corresponding
concentrations (μg/mL) and the amount of R-LA was expressed
as μg of analyte per mL of plasma.
Precision, accuracy and absolute recovery: Precision was
evaluated using the measurements of the repeatability (intraday)
and intermediate precision (inter-day). Repeatability was
established by five replicate injections of sample and solutions
at low, medium, and high concentration levels of the calibration
curve with the same chromatographic conditions and analyst
at the same day and within three consecutive days. The results
are expressed as the relative standard deviation percentage of
the measurements (R.S.D. %). Accuracy of the method in term
of recovery was measured by comparing the peak area of the
spiked samples at three different concentration levels. Accuracy
is given as a percentage of the recovered amounts, comparing
experimental peaks with those obtained from the calibration
curve. Limits of detection (LODs) and quantification (LOQs) were
calculated by the ratio between the standard deviation (SD) of the
regression line and analytical curve slope multiplied by 3.33 and
The specificity was evaluated using blank plasma samples from
healthy subjects to assess the interferences. The matrix effect was
estimated through the comparison of the results obtained from
analysis of standard R-LA solutions at different concentrations
ranging from 0.5 μg/ml to 5 μg/ml and R-LA spiked post-extracted
plasma samples at the same concentrations. The matrix effect was
calculated by the following formula:
Where, as was the area under peak of the standard R-LA
solution and Ap was the area under peak of the R-LA occurring in
post-extracted plasma samples.
The first aim of this study was to develop an ultra-high
performance liquid chromatographic coupled with mass
spectrometer (UHPLC-MS) method useful to determine the
concentration of R-LA in human plasma after the oral consumption
of Liponax® sol in healthy subjects. Figure 2 shows Single Ion
Recording (SIR) chromatograms of R-LA and Naproxen obtained
from the analysis of the standard compound in methanol (A),
spiked plasma sample (B) and plasma from a healthy subject who
consumed Liponax® sol (C). R-LA and NA peaks resulted to be
well separated under the used experimental conditions. R-LA and NA were identified using the standard compound retention times
(1.12 and 1.33 min, respectively) and m/z values obtained from
parent ions (for R-LA m/z [M-H]- = 205.0, for NA m/z [M-H]- =
To determine R-LA plasma concentration, a calibration curve
was obtained in a concentration range of 0.05 – 5 μg/mL with
six concentration levels and performing triplicate analysis for
each level. Naproxen was selected as internal standard in the
concentration of 5 μg/mL. Linear regression analysis showed
a high correlation coefficient (R2 of 0.9997; y = 0.1257x -
0.0033), proving a good linearity of the method in the selected
The values obtained from intra- and inter-day precision and
accuracy showed good repeatability in terms of retention time
and concentration, as reported in Table 1. Intra-day RSD % value
relative to R-LA spiked in human plasma, ranges from 1.174 to
1.880 and inter-day RSD % value ranges from 1.694 to 3.914,
respectively (Table 2).
The R-LA absolutely recovery from plasma was 120.00 %,
105.21 % and 102.23 % at the concentrations of 0.5, 1.0 and 5.0
μg/mL, respectively. The matrix effect calculated, as reported in
materials and method, resulted to be on average 21%. The limits
of detection (LOD) and the limit of quantification (LOQ), calculated
as reported in Material and Method, were 0.012 and 0.038 μg/mL,
A total of 10 healthy subjects (6 female and 4 male) were
included in the pharmacokinetic study. The subjects were
recruited one a day for 10 days in fasted state. Each subject
consumed 10 ml of Liponax® sol in an outpatient setting. Then
blood samples were collected at the time of 0, 2, 5, 10, 15, 20,
25, 30, 40, 50, 60, 90 and 180 min after the oral administration
of the food supplement. The blood samples were prepared as
reported above. The mean plasma concentration versus time
profile of R-LA following a single 300 mg oral dose in 10 subjects
were shown in Figure 3. As reported in the Table 3, R-LA is rapidly
absorbed as highlighted by the Tmax value of 11 min. Moreover,
R-LA reaches high plasma concentrations with a mean Cmax of 8 μ/
mL. R-LA distribution in various tissues and its clearance confirm
the plasma pharmacokinetic profile shown in Figure 3.
LA is a strong antioxidant compound widely used in oxidative
stress-related clinical conditions (e.g. diabetic complications,
mechanical compression neuropathies, neurodegenerative and
cardiovascular pathologies, physical and mental impairment,
obesity, etc) [11,24,29-33]. Despite its beneficial properties,
standard solid LA formulations for oral use have pharmacokinetic
limitations such as high Tmax and low bioavailability (Table 4).
This study evaluates the pharmacokinetic profile of the
patented oral liquid formulation containing 300 mg of the active
enantiomer R-LA, (Liponax® sol), in humans. The obtained
findings are in agreement with pharmacokinetic data obtained with
a liquid formulation of R-LA in Sprague-Dawley rats  and are
consistent with data obtained from the study on LA saline solution
for injection  confirming both the efficacy and the improved
PK parameters of the R-LA liquid formula. Carlson and co-workers
achieved the similar PK results in humans using freshly dissolved
R-LA Na salt in water that is not suitable as commercial formula
due to taste and stability issue . One explanation could be
that at low concentrations LA is actively transported by intestinal
protein carriers, such as the monocarboxylate transporter
usually involved for medium-chain fatty acids absorption .
On the other hand, at high concentration the passive diffusion
mechanism is favored for absorption . R-LA contained in
Liponax® sol thanks to the innovative and patented formulation
is completely dissolved in solution, stable over the time and in
the gastric environment . While the dissolution of traditional
tablets represents a crucial passage in absorption with an intense
hepatic metabolism , the immediate availability of R-LA in
Liponax® sol liquid formulation allows the transient saturation
of the first-pass metabolism in the liver showing an high Cmax.
Furthermore, the new formulation stabilizes and makes readily
available the only active enantiomer R-LA, without any possible
impact on PK value by the S-LA [18,19]. As reported in a recent
pharmacokinetic study , LA concentrations accumulated
in the cells were directly proportional to the plasma levels with
an increase of cellular glutathione levels and a decrease of the
oxidative stress. The approach proposed by these authors for
eliciting antioxidant activity at the cellular level is the use of a
formulation allowing the compound to reach its target at highest
concentration and in the shortest time. According to literature
data, LA results to be bioactive if reaches a threshold of activation
corresponding to a Cmax of 4-5 μg/mL and AUC of 171 min × μg/
mL . In light of this, the pharmacokinetics parameters of 300
mg R-LA dose contained in Liponax® sol promise better beneficial
results and, the liquid formulation could be a great alternative to
tablets with better patient.
A summary of the pharmacokinetic parameters of several
studies with healthy human volunteers is reported in Table 4. The
methods of analysis adopted in these studies are similar. Most
investigations studied the pharmacokinetic of tablets containing
600 mg of racemic mixture (R-S), whereas the liquid formula
tested here contained only 300 mg of the form R-LA. Liponax®
sol showed an improved of Cmax and a very high AUC. In 2011
Mignini’s et al.  demonstrated that a tablet consisting of 600
mg racemic of LA and B complex vitamins, manufactured with
a patented technology adopted also for other drugs, containing
surfactants, super disintegrating, maltodextrins and lecithin,
showed better results than traditional LA tablets but a Cmax lower
than that found for Liponax® sol. This approach demonstrated
that new technologies aimed to increase the absorption of LA
are important to obtain better pharmacokinetic parameters and
consequently to improve the clinical efficacy.
Taken together, these findings could explain the beneficial
activity of the liquid formulation of R-LA previously showed
in diabetic rats with neuropathy  and in different cases of
neuropathies in humans , strengthening the use of Liponax®
sol as a strong antioxidant compound for numerous diseases
related to oxidative stress. These results are promising and
encourage us to perform further studies to confirm the R-LA new
liquid formulation beneficial effects.
In conclusion, the liquid formula for oral use containing
300 mg of R-LA tested in human healthy voluntaries, showed
better pharmacokinetic parameters with a rapid absorption,
high bioavailability, and optimized half-life. The comparison of
literature data on pharmacokinetic parameters of traditional
LA tablets show that, in our experimental conditions, this liquid
oral formulation demonstrated to overcome the limitations
ascribed to oral lipoic acid supplementations. These promising
pharmacokinetic parameters will induce us to perform further
clinical trials to show the beneficial effects for the consumption
new liquid R-LA formulation.
The authors wish to sincerely thank Gaetano Piccinocchi MD
and the Comegen – Società Cooperativa Sociale, Naples, Italy, for
the organization and collection of blood samples. The generous
contributions of time and expertise are greatly appreciated.
Maria Daglia is a university professor and carried out as
consultant the execution of the study following the signing of a
research agreement with the Department of Pharmacy of the
Federico II University of Naples on behalf of Savio. Nicola D’Anzi
and Erika Amore are Savio employees. The other authors declare
no conflict of interest.
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