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A Review of the Applications of Vitamin C to
Treat Human Diseases
Xiaoke He1
#
Wanting Zhang1
#
Yonglong He1Yuxin Jiang1Jiabing Xu2
Wei He1
1Department of Pharmaceutics, School of Pharmacy, China
Pharmaceutical University, Nanjing, People’s Republic of China
2Department of Traditional Chinese Medicine, Taizhou Institute for
Drug Control, Taizhou, People’s Republic of China
Pharmaceut Fronts
Address for correspondence Jiabing Xu, MSc, Taizhou Institute for
Drug Control, 6 Xinglin Road, Yiyaogaoxin District, Taizhou 225300,
People’s Republic of China (e-mail: xujiabing2@sina.com).
Wei He, PhD, School of Pharmacy, China Pharmaceutical University,
639 Longmian Avenue, Jiangning District, Nanjing 211198, People’s
Republic of China (e-mail: weihe@cpu.edu.cn).
Introduction
Vitamin C (VC), also known as L-ascorbic acid (AA), one of the
water-soluble vitamins, is an essential substance for main-
taining the normal physiological state of the h uman body. VC
plays a critical role in physiological functions such as pro-
moting collagen production, enhancing immunity, and im-
proving fat metabolism. Therefore, VC has a wide range of
applications in the medical field.
In nature, VC can be synthesized by most animals and
plants, but the gene for L-gluconolactone oxidase, which
synthesizes VC, is mutated in humans, resulting in the
inability to synthesize VC.1The primary source of VC for
humans is through the daily diet. Approximately 90% of the
daily intake of VC in the general population is derived from
fruits and vegetables. The VC content of common fruits and
vegetables is listed in ►Table 1.2A plasma concentration of
VC below 10 μmol/L is associated with the development of
scurvy, which presents with symptoms such as impaired
wound healing, gingivitis, and ecchymosis.3–5The deficiency
of VC is mainly cau sed by inadequate dietary intake, although
other factors, including smoking, pregnancy, age, genetic
susceptibility, and some metabolic diseases such as hyper-
tension and diabetes, also contribute to its prevalence.3,6 The
Keywords
►vitamin C
►ascorbic acid
►free radicals
►antioxidant
►biological activities
Abstract Vitamin C, a ubiquitous water-soluble vitamin, has been demonstrated to have several
biological activities, including the promotion of collagen production, enhancement of
immunity, facilitation of iron absorption, and improvement of fat metabolism. Thus, it
has a multitude of applications in the medical field, such as whitening, antioxidation,
and the prevention of a wide range of diseases. Conversely, its lack of stability and low
permeability limit its applicability. This review presents a summary of the physico-
chemical properties, delivery strategies, and biological activities of vitamin C. Addi-
tionally, this review provides an overview of its preventive and therapeutic effects on
diseases such as cataracts, tumors, and cardiovascular conditions. Finally, this review
explores the prospective applications of vitamin C as a pharmaceutical agent. A variety
of vitamin C derivatives and delivery systems have been developed to overcome the
instability and low permeability of vitamin C. However, several challenges persist,
including the uncertain efficacy of derivatives and the complexities associated with the
implementation of delivery systems. It is anticipated that future advancements will
facilitate the development of delivery forms and the utilization of vitamin C in novel
applications.
#
These authors contributed equally to this work .
received
September 18, 2023
accepted
September 9, 2024
DOI https://doi.org/
10.1055/s-0044-1791542.
ISSN 2628-5088.
© 2024. The Author(s).
This is an open access article published by Thieme under the terms of the
Creative Commons Attribution License, permitting unrestricted use,
distribution, and reproduction so long as the original work is properly cited.
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THIEME
Review Article
Article published online: 2024-10-21
recommended dietary allowance for women and men is 75
and 90 mg/d, respectively.7For most adults, 200 mg/ d is the
optimal intake.6,8
Due to its stro ng water solubility and elect ronegativity, VC
cannot penetrate the lipid bilayer easily. Therefore, the
absorption of VC does not depend on simple diffusion, but
rather on facilitated diffusion mediated by glucose trans-
porters (GLUT) and active transport mediated by sodium-
dependent VC transporter (SVCT).9In the intestine, VC can be
oxidized to dehydroascorbic acid (DHA), which is then
immediately reduced to AA after it is transported into the
cell via GLUT.10,11 This process is known as the AA cycle.12
Two distinct forms of SVCT are present in the human body:
SVCT1 and SVCT2. These transporters facilitate the uptake of
AA into cells.9SVCT1 is subject to feedback inhibition by AA
concentration,13,14 whereas SVCT2 is responsive to changes
in intracellular AA levels, which may be crucial for main-
taining intracellular AA homeostasis.14,15
When the daily intake of VC exceeds 400 mg, the plasma
concentration of VC is fully saturated, resulting in a steady-
state plasma concentration of 80 μmol/L.16 Excessive VC is
usually excreted in the urine. VC is well tolerated by the
human body; however, short-term supplementation of VC
has been associated with gastrointestinal adverse reactions,
including abdominal distension, flatulence, diarrhea, and
abdominal pain. At the same time, VC participates in the
metabolic process, whereby it produces oxalic acid. Conse-
quently, the risk of developing kidney stones is elevated
when individuals consume a substantial amount of VC
over an extended period. In addition, the ingestion of large
quantities of VC may also result in relative deficiencies of
other vitamins in the body.3,17
This article will provide an overview of the physicochem-
ical properties, biological activities, and delivery mode of VC.
In conjunction with developments in clinical and research
practice, this article will examine the preventive and thera-
peutic effects of VC in the management of skin conditions,
cataracts, tumors, cardiovascular diseases (CVDs), and other
diseases.
Overview
The Structure and Properties of Vitamin C
VC is an acidic polyhydroxyl compound comprising carbon,
hydrogen, and oxygen with a molecular formula of C
6
H
8
O
6
and an IUPAC name of 2,3,4,5,6-pentahydroxy-2-hexenoide-
4-lactone, with a mo lecular weight of 176.1 g/mol. The
structural formula is shown in ►Fig. 1.
The structure of VC contains enediol groups, of which C
3
–
OH exhibits strong acidity. This is influenced by the conju-
gation effect (pK
a
¼4.17). In contrast, C
2
–OH is weakly acidic
due to intramolecular hydrogen bonding (pK
a
¼11.75). Ac-
cordingly, VC exists in the form of anion under physiological
conditions.14 The structure of VC contains conjugated struc-
tures, which result in ultraviolet absorption. The maximum
absorption wavelength is 245 nm, wh ich provides a meth-
od for the detection of VC content. The double bond between
C
2
and C
3
yields two electrons, which are subsequently lost
by VC to generate AA free radicals (semi-hydroascorbic acid).
The majority of these free radicals have a lifetime of less than
a millisecond and exhibit reduced activity.18 When VC loses
its second electron, it forms a substance that is more stable
than the ascorbate radical: DHA. Both AA free radicals and
DHA can be reduced to AA. Once the five-membered loop of
DHA is hydrolyzed and broken to produce 2,3-diketo-1-
gulonic acid (this process is irreversible), the reduction of
DHA to AA is no longer possible. The detailed oxidation
process of VC is shown in ►Fig. 2.
Some biological processes within the human body may
result in the production of highly reactive and potentially
harmful free radicals, and these free radicals can be removed
by VC. In this process, VC itself is converted to less active
ascorbate radicals. These results indicate that AA is an
effective antioxidant and free radical scavenger.19
Commercially Available Formulations and Delivery
Systems for VC
Most VC-related dosage forms are oral preparations, external
dosage forms, and injections. A large number of VC products
Table 1 Food sources of vitamin C
Fruit
Source (portion size) Vitamin C
content (mg)
Strawberries (1 cup, sliced) 95
Papaya (1 cup, cubes) 85
Kiwi (1 medium) 75
Orange (1 medium) 70
Cantaloupe (1/4 medium) 60
Honeydew melon (1/8 medium) 40
Fresh grapefruit (1/2 fruit) 40
Vegetables
Source (portion size) Vitamin C
content (mg)
Raw pepper, red or green (1/2 cup) 65
Broccoli, cooked (1/2 cup) 60
Kale, cooked (1 cup) 55
Fresh snow peas, cooked (1/2 cup) 40
Mustard greens, cooked (1 cup) 35
Baked sweet potato (1 medium) 30
Cauliflower, raw or cooked (1/2 cup) 25
Source: Reproduced with permission from Levine et al,2copyright 1999
American Medical Association.
Fig. 1 The structure of vitamin C.
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
are approved by the National Medical Products Administra-
tion (NMPA) annually. The VC-related preparations approved
by NMPA from 2021 to 2023 are shown in ►Table 2.Toreduce
VC degradation, achieve targeted drug delivery, and improve
therapeutic efficacy, researchers have developed different
drug delivery systems to deliver VC, such as polymeric
nanoparticles, liposomes, microemulsions, and micelles
(►Fig. 3).
Nanoparticles made of natural polymers have low toxici-
ty, high biocompatibility, and sufficient degradability.1Chi-
tosan is a kind of hydrophilic polysaccharide. Chitosan-based
drug delivery systems have the following advantages: in-
creased solubility, controlled drug release, enhanced drug
targeting, and improved absorption.20 Alishahi et al21
adopted the ionotropic gelation method and used tripoly-
phosphate as a cross-linking agent to prepare VC-chitosan
nanoparticles, which realized the encapsulation of VC within
the nanoparticle. The obtained nanoparticles improved the
stability of VC in the gastrointestinal tract and showed
consistent VC release for up to 48 hours.
Liposomes are phospholipid bilayer vesicles composed of
amphiphilic molecules, which can load hydrophobic and
hydrophilic molecules and have the advantages of low
toxicity and high biocompatibility.22,23 Orally administered
VC is easily degraded in the gastrointestinal tract, and lip-
osomes can provide a hydrophilic–hydrophobic interface to
avoid VC degradation.24,25 Liposomes can also reduce gas-
trointestinal interference and prolong the release of VC.26
Jiao et al27 used chitosan-coated liposomes to deliver VC and
folic acid, which improved the antioxidant efficacy of the
preparation. Therefore, the use of liposome delivery tech-
nology can improve the bioavailability of VC to a certain
extent and avoid the risks associated with intravenous
administration.26,28,29
Microemulsion is a transparent, thermodynamically sta-
ble colloidal system formed spontaneously from oil, water,
and emulsifier, with an average particle size of 10 to 100 nm.
The microemulsion has low surface tension, high interfacial
tension, and solubilization properties.30 In addition to the
above nano-preparations, currently, researchers use VC to
develop new drug delivery systems to achieve targeted drug
delivery. Sawant et al31 used polyethylene glycol phosphati-
dylethanolamine to prepare palmitoyl ascorbate micelles,
which improved the solubility of palmitoyl ascorbate and
increased the accumulation of palmitoyl ascorbate at the
tumor site through the high permeability and enhanced
permeability and retention effect (EPR effect) of solid
tumors, showing good antitumor activity. Xiao et al32 used
AA derivatives as liposome ligands and used VC to bind to the
receptor-ligand of GLUT1 and SVCT2 to deliver drugs tar-
geted to the brain, indicating that AA has the potential to
enhance brain targeting of drugs in the central nervous
system. Luo et al33 used ascorbate-coupled polylactic acid-
hydroxyethyl copolymer to promote oral drug absorption
through SVCT1. Inoue et al34 used AA derivative ascorbic acid
2-phospho-6-palmitate trisodium to form micelles and used
as drug carriers to improve drug skin permeability.
In general, these drug delivery systems address the lim-
itations of VC, namely its poor stability and strong hydrophi-
licity, through enhanced encapsulation and targeted drug
delivery thereby improving the absorption of VC in vivo.
However, the current industrial technologies impose con-
straints on the large-scale clinical application of these deliv-
ery systems.
Biological Activity
VC Promotes Collagen Formation
VC plays a pivotal role in the posttranslational modification
of procollagen, a crucial coenzyme factor in collagen biosyn-
thesis.35 VC facilitates the synthesis of collagen, a fundamen-
tal protein in the extracellular matrix, by regulating the
structure and secretion of procollagen.36 Procollagen is
synthesized in the endoplasmic reticulum and consists of
Fig. 2 Oxidation of ascorbic acid.
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
Table 2 Approved vitamin C commercial formulations from 2021 to 2023
Dosage form Drug name Active agent Specification Number of
manufacturers
of the same
type
The most
recent approval
date
Indications
Tablets Vitamin C tablets Vitamin C 25 mg;
50 mg;
100 mg;
584 2023-03-27 Scurvy;
chronic iron poisoning ;
idiopathic methemoglobinemia;
liver cirrhosis;
acute hepatitis
Tablets Vitamin C Yinqiao
tablets
Vitamin C;
acetaminophen;
chlorpheniramine maleate
Each tablet contains 49.5 mg
of vita min C, 105 mg of
acetamin ophen, and 1.05 mg
of chlorpheniramine maleate
292 2022-07-22 Influenza caused by exogenous
wind-heat
Tablets Vitamin E and C
chewable tablets
Vitamin C;
vitamin E
Each tablet contains 100 mg
of vitamin E and 200 mg of
vitamin C
3 2021-10-11 Prevent and treat disease caused by
vitamin E and vitamin C deficiency
Tablets Aspirin vitamin C
enteric-coated tablets
Aspirin;
vitamin C
Each tablet contains 0.2 5 g of
aspirin and 25 m g of vitami n
C
10 2023-02-24 Used to relieve fever, headache, and
body aches caused by cold or flu
Tablets Compound rutin
tablets
Rutin;
vitamin C
Each ta blet contains 2 0 mg of
rutin and 50 mg of vitamin C
60 2022-05-09 Used for capillary hemorrhage with
increased fragility, and also used for
adjuvant treatment of hypertensive
encephalopathy
Tablets Diavitamin and
glucuronolactone
tablets
Glucuronide;
vitamin C;
vitamin B
Each t ablet contains 5 mg of
glucuronide, 10 mg of
vitamin C , 110 mg of vita min
B
8 2021-03-29 Used for adjuvant treatment of liver
damage in acute and chronic
hepatitis and chronic poisoning
such as arsenic, mercury, lead,
benzene
Tablets Vitamin C effervescent
tablets
Vitami n C 0.5 g;
1g
13 2022-06-28 Infectious diseases;
scurvy
Tablets Vitamin C chewable
tablets
Vitamin C 50 mg;
0.1 g
39 2021-02-26 Scurvy;
infectious diseases;
purpura
Tablets Aspirin and vitamin C
effervescent tablets
Aspirin;
vitamin C
Each tablet contains 0.4 g of
aspirin and 24 m g of vitami n
C
3 2023-04-18 Used for heating, including cold
caused by fever, headache, sore
throat, toothache, and other pain,
etc.
Tablets Paracetamol and
vitamin C dispersible
tablets
Paracetamol;
vitamin C
Each tablet contains 330 mg
of para cetamol and 200 mg
of vitamin C
2 2023-02-21 Antipyretic and analgesic
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
Table 2 (Continued)
Dosage form Drug name Active agent Specification Number of
manufacturers
of the same
type
The most
recent approval
date
Indications
Tablets Paracetamol and
vitamin C effervescent
tablets
Paracetamol;
vitamin C
Each tablet contains 330 mg
of para cetamol and 200 mg
of vitamin C
3 2023-01-03 Antipyretic and analgesic
Tablets Paracetamol vitamin C
tablets
Paracetamol;
vitamin C
Each tablet contains 330 mg
of para cetamol and 200 mg
of vitamin C
1 2022-09-14 Antipyretic and analgesic
Tablets Compound trivitamin
and calcium hydrogen
phosphate tablets
Calcium hydrogen phosphate;
calcium lactate;
vitamin B1;
vitamin B2;
vitamin C
Each ta blet contains 7 5 mg of
calcium hydrogen
phosphate, 45 mg of calcium
lactate, 0.05 m g of vitam in
B1, 0.0015 mg of vitamin B2,
and12mgof
vitamin C
5 2021-01-13 Used for calcium supplementation
in children and pregnant women
Injections Vitamin C injection Vitamin C 2 mL: 0.5 g ;
10 mL: 1 g ;
5mL: 0.5g;
20 mL: 2.5 g ;
2mL: 0.1g;
2mL: 0.25g;
5mL: 0.5g
214 2023-06-26 Scurvy;
chronic iron poisoning ;
idiopathic methemoglobinemia
Injections Vitamin C for injection Vitamin C 0.25 g;
0.5 g;
1.0 g;
17 2022-9-14 Scurvy;
chronic iron poisoning ;
idiopathic methemoglobinemia
Injections Water-soluble vitamin
for injection
Thiamine nitrate;
riboflavin sodium phosphate;
nicotinamide;
pyridoxine hydrochloride;
sodium pantothenate;
vitamin C sodium;
biotin;
folic acid;
vitamin B12
Each b ottle conta ins 3. 1 mg
of thiamine nitrate, 4.9 mg of
riboflavin sodium phosphate,
40 mg of nicotina mide,
4.9 mg o f pyr idoxine
hydrochloride, 16.5 mg of
sodium pantothenate,
113 mg of
vitamin C sod ium, 60 μgof
biotin, 0.4 mg of folic acid,
and 5.0 μgofvitaminB12
33 2022-11-03 One of the components of
parenteral nutrition
Capsules Compound trivitamin
and linolic acid soft
capsules
Linoleic acid;
vitamin B6;
vitamin C;
inositol
Each capsule contains
350 mg of linole ic acid , 2 mg
of vita min B6, 25 m g of
vitamin C, and 1 0 mg of
inositol
26 2021-03-17 Used for adjuvant treatment and
prevention of atherosclerosis
(Continue d)
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
Table 2 (Continued)
Dosage form Drug name Active agent Specification Number of
manufacturers
of the same
type
The most
recent approval
date
Indications
Capsules Vitamin C granules Vitamin C 0.1 g 12 2021-04-25 Scurvy;
chronic iron poisoning ;
idiopathic methemoglobinemia
Capsules Compound trivitamin
and linolic acid soft
capsules I
Linoleic acid;
vitamin B;
vitamin C;
vitamin E;
inositol;
soy phospholipid;
methyl hesperidin
Each capsule contains 0.35 g
of linoleic acid, 62 mg of
vitamin B, 25 mg of vitamin
C, 1.67 mg of vitamin E,
10 mg of inositol, 24 mg of
soy phospholipid, and 10 mg
of methyl hesperidin
2 2021-03-16 Used for adjuvant treatment and
prevention of atherosclerosis
Granules Vitamin E and C
granules
Vitamin C;
vitamin E
Each capsule contains 0.1 g
of vitamin E and 0.2 g of
vitamin C
13 2021-09-23 Used to prevent and treat diseases
caused by vitamin E and vitamin C
deficiency
Granules Aurantium and
vitamin C granules
Vitamin C;
hesperidin
Each b ag (7 g ) co ntains
100 mg of vitam in C and
60 mg of hesperidin
13 2021-08-25 Used for diseases caused by vitamin
C and hesperidin deficiency
Granules Compound bifendate
granules
Bifendate;
inosine;
vitamin C
Each bag (10 g) contains
15 mg of bifendate, 100 mg
of inosine, and 50 mg of
vitamin C
13 2021-04-30 For chronic and persistent hepatitis
with elevated alanine
aminotransferase
Pills Vitamin C pills Vitamin C 50 mg;
0.1 g
16 2021-07-27 Used to prevent and treat scurvy
and various acute and chronic
infectious diseases or other
diseases
Powders Oral four vitamins and
glucose
Vitamin B1;
vitamin B2;
vitamin C;
vitamin D2;
glucose
Each gram contains 11.2 mg
of vita min B1, 20. 8 mg o f
vitamin B2, 20 mg of v itamin
C, 23 μgofvitaminD2,and
10 g of glucose
12 2021-08-25 For nutrition and energy
supplementation for patients with
vitamin deficiency
Powders Oral five vitamins and
glucose
Vitamin B1;
vitamin B2;
vitamin C;
vitamin D2;
nicotinic acid;
glucose
Each gram contains 0. 12 mg
of vitamin B, 0.08 g of
vitamin B2, 2 mg of vitamin
C, 0.002 mg of vitamin D2,
1 mg of nicotin ic aci d, and
glucose appropriate
36 2022-03-11 Used in various diseases caused by
vitamin deficiency
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
proline-rich amino acid repeats, which are essential for its
structural integrity. Specifically, proline and lysine residues
undergo hydroxylation and conversion to hydroxyproline
and hydroxylysine, respectively. This hydroxylation process
requires VC as a cofactor.18 Collagen has a triple helix
structure, and the presence of hydroxyproline is essential
to stabilize this structure.35 Without hydroxyproline, fibro-
blasts cannot secrete collagen properly. Hydroxylysine is
necessary for collagen cross-linking, and its absence can
also lead to structural instability.37 A computer simulation
experiment was condu cted to study the effect of VC on amino
acid sequence and interaction forces during collagen forma-
tion.38 In the presence of VC, collagen was synthesized, while
in the absence of VC, hydroxyproline dissociates from prolyl-
5-hydroxylase and the reaction stops. Therefore, VC can be
considered a cofactor for prolyl-5-hydroxylase, which is
responsible for the conversion of proline to hydroxyproline.
VC is conducive to the hydroxylation process, which facili-
tates the formation of a stable triple helix structure in
collagen and promotes collagen formation.
VC Promotes HIF-1 Hydroxylation
Hypoxia-inducible factor-1 (HIF-1) is a nuclear protein with
transcriptional activity that plays an important role in
physiological processes such as erythropoiesis, cell survival,
and angiogenesis.18 HIF-1 can induce the formation of new
blood vessels around hypoxic cells and tissues thus promot-
ing cell survival. Consequently, HIF-1 exerts a significant
influence on fetal development, yet it also serves as a key
promoter of a range of pathological conditions, including
inflammatory diseases, lung disease, heart disease, diabetes,
and cancer.39
HIF-1 consists of an active αsubunit and a structurally
expressed βsubunit. Proline residues on the HIF-αsubunit
are hydroxylated by the prolyl hydroxylase domain (PHD)
and undergo rapid degradation by ubiquitin protease under
normal oxygen conditions. Under hypoxia conditions, PHD is
inhibited.40 VC plays an important role in the hydroxylation
of proline residues by PHD. PHD is a nonheme iron-depen-
dent dioxygenase, its catalytic activity can be enhanced by
VC.41,42 In vitro experiments have shown that VC has a
significant inhibition effect on HIF-1, and can block HIF-1-
induced gene transcription, thereby delaying the develop-
ment of the disease.43,44 In summary, by influencing the PHD
to regulate HIF-1 levels, VC can diminish symptoms and delay
the progression of the disease.
VC Enhances Immune Function
VC regulates immune function by enhancing various cellular
functions of both the innate and acquired immune systems,
regulating redox-sensitive cell signaling pathways, or direct-
ly protecting important cellular structural components.45
The immune system is composed of immune organs (e.g.,
bone marrow, spleen, and lymph), immune cells (e.g., lym-
phocytes, mononuclear phagocytes, and neutrophils), and
immunologically active substances (e.g., antibodies and
complements) that protect the host from a range of patho-
gens.46 The immune system can be divided into two
Table 2 (Continued)
Dosage form Drug name Active agent Specification Number of
manufacturers
of the same
type
The most
recent approval
date
Indications
Solutions Five vitamins and
lysine hydrochloride
oral solution
Vitamin A;
vitamin D;
vitamin C;
vitamin B6;
niacinamide;
lysine hydrochloride
Each ( 10 mL) co ntains 3,00 0
unitsofvitaminA,2,200
unitsofvitaminD,50mgof
vitamin C, 2 mg of vitam in
B6, 20 mg of nia cinamide,
and60mgoflysine
hydrochloride
2 2021-03-22 Used to prevent and treat many
diseases caused by the lack of
multiple vitamins in children
Solutions Tri-vitamins and cod
liver oil emulsion
Cod liver oil;
vitamin A;
vitamin D3;
vitamin C
Each gram contains 10 mg of
cod liver oil, 30 units of
vitamin A, 13.5 units of
vitamin D3, and 1.5 4 mg of
vitamin C
7 2022-01-04 Used for the prevention and
treatment of various diseases
caused by vitamin A, D, and C
deficiency in adults
Note: Data in Table 2 was acquired from the National Medical Products Administration da tabase (https://www.nmpa.gov.cn/).
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
categories: nonspecific immunity and specificimmunity.
These categories can be further delineated into three main
aspects: physical barriers such as skin and mucosa, immune
cells, and antibodies.47
VC has been shown to protect the skin from environmen-
tal oxidative stress by promoting clearance of oxidants,48
thereby strengthening the physical skin barrier. The infiltra-
tion of neutrophils into infected tissues is the early step of
innate immunity. VC can accumulate in phagocytes such as
neutrophils, enhance the chemotaxis and phagocytosis of
neutrophils, produce reactive oxygen species (ROS), and
eventually kill microorganisms.45 Oxidants can activate nu-
clear factor κB(NF-κB), which triggers a signaling cascade
that leads to the continued synthesis of oxides and other
proinflammatory mediators.49,50 VC has been shown to
reduce the production of oxidants and the activation of
NF-κB in dendritic cells in vitro.51 In addition, research has
demonstrated that VC enhances the immune system’sre-
sponse to infection by stimulating T lymphocyte prolifera-
tion, increasing cytokine production, and promoting
immunoglobulin synthesis.45 The Changxing team at West
Lake University found that VC can facilitate plasma cell
differentiation and humoral immune response by enhancing
TET2/3-mediated DNA demethylation.52
A chronic deficiency of VC can lead to impaired immune
function, rendering individuals more susceptible to infec-
tion. The inflammatory and metabolic demands associated
with infection can significantly reduce the body’s ability to
absorb VC. Therefore, timely and appropriate supplementa-
tion of VC can help enhance the body’s immune response.53
VC Improves Fat Metabolism
The fatty acids pro duced by the hydrolysis of fat in the human
digestive tract are activated as fatty acyl CoA in the endo-
plasmic reticulum and the outer membrane of mitochondria.
The enzymes that catalyze fatty acid oxidation are located
within the mitochondrial matrix. Therefore, the activated
fatty acyl CoA must enter the mitochondria to be oxidized.
Long-chain fatty acyl CoA cannot penetrate the inner mito-
chondrial membrane and requires carnitine for transport
into the mitochondria.54
Carnitine is a quaternary ammonium that exists in two
stereoisomers, designated as D-type and L-type. The D-
isomer, also known as D-carnitine, is physiologically inac-
tive. The primary function of L-carnitine is to transfer long-
chain fatty acids to the mitochondria for β-oxidation, a
process by which the body derives energy.55 Carnitine also
binds to acyl residues produced by amino acid intermediate
metabolism, assisting in the removal of amino acids.54 This
mechanism enables the clearance of abnormal organic acids.
L-carnitine is synthesized from lysine and methionine, and
the final step of the synthesis requires AA and iron ions to
participate as cofactors.55 Several in vivo experiments have
proved that AA is involved in carnitine biosynthesis.56–58
Hence, a lack of VC affects carnitine levels, which affects fat
metabolism. Furthermore, Yuan et al59 investigated the role
of DNA demethylase ten-eleven translocation protein 1
(Tet1) in the development of obesity and found that VC, a
cofactor of the Tet protein family, normalizes DNA methyla-
tion levels and promotes lipolysis.
VC Promotes Iron Absorption
Iron is a vital component in numerous biological processes,
from oxygen transport to the synthesis of DNA. Its most
important function is the transport of oxygen in hemoglobin.
The primary form of dietary iron intake is iron trivalent,
which is less bioavailable than ferrous iron. The absorption of
iron from food is generally enhanced by the addition of iron
absorption enhancers, among which AA is the most exten-
sively studied.
The role of VC in promoting iron absorption is attributed to
its ability to reduce and chelate iron. VC has the capacity to
Fig. 3 The delivery system of vitamin C.
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
reduce trivalent iron to ferrous, thereby promoting the ab-
sorption and utilization of iron.60 The extent of this reduction
is influenced by the pH value. Studies have shown that in the
range of pH 2.6 to 6.0, the reduction rate of VC decreases as
the pH increases. At a pH range of 6.8 to 7.4, AA is unable to
effectively reduce the trivalent iron.61 Subsequent studies
demonstrated that duodenal cytochrome B is an iron regula-
tory protein with iron-reductaseactivity, which plays a critical
role in dietary iron absorption.62 Several studies identified
duodenal cytochrome B promoting iron reduction in a VC-
dependent manner,63–65 indicating that VC’s primary role is in
promoting iron dissolution. Furthermore, studies demonstrat-
ed that the administration of VC a few hours before the
consumption of an iron-containing meal did not increase
iron absorption, suggesting that VC must be taken with iron
to promote iron absorption.66,67
Applications in Human Diseases
VC has many preventive and therapeutic effects in the field of
medicine. This section will mainly discuss its application in
cataracts, cancer, CVD, and skin disease (►Fig. 4).
Cataracts
Cataracts are a leading cause of vision impairment and
blindness worldwide.68 Population projections indicate
that by 2025, cataracts could affect 40 million individua-
ls.69 The underlying mechanisms of cataract formation
remain unclear, but oxidative stress is a prominent hy-
pothesis. The free radicals generated by oxidative stress,
such as glutathione (GSH), superoxide dismutase, and ROS,
will damage the lens composition, resulting in lens opacity
andthuslensdamage.
70 Although cataract surgery is
considered to be one of the safest surgeries, the prevention
of cataracts has become a research focus due to the
complications that can arise from the procedure, including
recurrent or persistent inflammation, glaucoma, and pos-
terior capsule opacification.71
The balance between antioxidants and free radicals
determines the state of appropriate physiological function,
if the level of free radicals rises uncontrollably, oxidative
stress will appear.72 The literature indicates that VC, as a
nonenzymatic antioxidant, may have certain preventive
effects on cataracts, although this is limited to nuclear
cataracts.73 Nuclear cataracts are located in the center of
the lens and are usually caused by advancing age.74 VC is
present in high amounts in the aqueous humor and is
therefore thought to play a role in protecting the lens
from oxidative stress in the aqueous humor.75 Astatistical
survey has shown that dietary intake of VC can reduce the
risk of age-related cataracts.76 Moreover, several studies
and case–control studies have shown that individuals with
a high dietary intake of VC exhibit a reduced risk of
developing cataracts.77–80 However, it is worth noting
that the VC has the potential to generate free radicals
intermediates and strong oxidizers, which can inflict dam-
age to the biological tissue.73 It has been demonstrated that
VC can facilitate the formation of advanced glycation end
products, which are responsible for the chemical aging of
lens proteins.81,82 Besides, high doses of VC have been
shown to increase the prevalence of age-related cataracts
in women.73 Consequently, the effectiveness of VC for
cataracts may be limited to a role in the prevention of
nuclear cataracts.
Tumor Treatment
Epidemiological evidence suggests that VC or foods rich in VC
may play a role in cancer prevention, as they have been
shown to reduce the incidence of various tumors.83,84 For
example, Campbell et al85 demonstrated that administering
a high dose of VC daily was able to maintain optimal levels of
AA within 48 hours, while simul taneously downregulating
the activity of the HIF-1 pathway within tumor tissue.
Nevertheless, there is a lack of consensus regarding the
efficacy of VC in treating tumors. Two previous studies
yielded disparate results.86–89 Cameron and Pauling showed
that high-dose VC improved the average survival rate of
patients with advanced cancer. Conversely, two clinical trials
by Creagan and Moertel indicated that VC did not confer a
benefit in cancer treatment. A deeper examination of VC
pharmacokinetics may elucidate the discrepancy in out-
comes between the two administration methods. In the
initial experiment, intravenous administration was used,
while in the latter, oral administration alone was used.
When doses of oral VC exceed 200 mg, the absorption of
VC decreases, urinary excretion increases, and the bioavail-
ability of VC decreases.90 In contrast, intravenous adminis-
tration bypasses intestinal absorption, resulting in a plasma
concentration of VC that can reach pharmacological levels
and thus exert efficacy.91 Given that AA is susceptible to a
pH-dependent autooxidation reaction to produce hydrogen
peroxide (H
2
O
2
)(H
2
O
2
is toxic to a variety of tumor
cells92–94), high-dose intravenous AA can be used as a
Fig. 4 The applications of vitamin C.
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
prodrug to deliver H
2
O
2
to tumors, thereby treating cancer.95
Potential mechanisms of action for VC in cancer therapy
include:
•AA is an important free-radical scavenger. The oxidation
of a large dose of A A to DHA has been demonstrated to
increase ROS, trigger oxidative stress, and lead to the
apoptosis of tumor cells.96 Yun et al97 have provided
evidence that human colorectal cancers carrying either
KRAS or BRAF mutations are sensitive to high levels of VC.
As a consequence of elevated DHA intake, the uptake of
glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
was inhibited in cells with a high glycolytic rate and a
mutationineitherKRASorBRAF.
•VC can enhance immune function, thus enhancing tumor
immune surveillance during cancer initiation and pro-
gression.98 Magrì et al found that in murine cancer models
such as colorectal, breast, melanoma, and pancreatic
cancers, VC potentiates adaptive immune responses
against cancer cells and can be effectively combined
with immune checkpoint therapy.99
•Outside the cell, AA autooxidation produces H
2
O
2
. When
H
2
O
2
accumulates to a certain concentration, it can
diffuse across cells into tumor cells and inhibit tumor
growth.100
•Collagen in the extracellular matrix is an important
component of the physical barrier against cancer cell
invasion and metastasis. A A has been proven to promote
collagen formation and can inhibit cancer progression by
preventing cancer cell invasion at a high dose.100
Additionally, alternative perspectives posit that the anti-
cancer mechanism of VC may be classified into three distinct
categories: targeting redox imbalance,101 targeting epige-
netic regulators,102 and targeting HIF-1 signaling.103
Intravenous administration of VC can also be used as an
adjunct to chemotherapy or radiotherapy. VC has been
demonstrated to stimulate the production and activation
of immune cells, thereby enhancing the immunity of
patients.84 VC has been shown to improve the therapeutic
effect of certain cancer drugs. For example, Lee et al104
applied gefitinib and AA combination therapy to non-
small cell lung cancer cells, resulting in an additive effect
on inhibiting cell proliferation. Meanwhile, it can also
mitigate the general toxicity and cardiotoxicity of Adria-
mycin.105 Combination therapy helps improve a patient’s
quality of life and physical function and minimizes toxicity
associated with chemotherapy.106 However, the safety of
high-dose intravenous VC remains a topic of contention.
Complications associated with intravenous AA adminis-
tration include the formation of oxalate stones and hemo-
lysis in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency.107 Therefore, it is imperative to per-
form G6PD screening prior to intravenous VC
administration.
Cardiovascular Disease
Several studies have shown that the incidence of coronary
heart disease is inversely related to dietary VC intake, and
large VC supplementation can reduce the incidence of
CVD.108–110 Nitric oxide (NO) is a potent vasodilator, medi-
ating vascular smooth muscle relaxation and protecting
endothelial function.111,112 The current clinical trials
showed that the VC plays an important role in maintaining
the NO steady state in blood vessels. A single dose of VC has
been demonstrated to enhance endothelial nitric oxide
synthase (eNOS) activity, thereby promoting the synthesis
of NO, and facilitating vasodilation.113 Long-term supple-
mentation of VC has been shown to mitigate the decline in
vasodilation capacity associated with endothelial injury.114
The administration of VC has been linked to beneficial out-
comes in the context of vascular endothelial function as
evidenced in both healthy subjects and patients with CVD. 115
The production of NO in endothelial cells requires a
variety of cofactors, including tetrahydrobiopterin
(BH4).116 Studies have shown that VC can diminish vascular
oxidative stress and augment NO-mediated endothelium-
dependent relaxation, which may be achieved by chemically
stabilizing BH4 to enhance the activity of nitric oxide syn-
thase (NOS).117 Therefore, deficiency in VC affects the reduc-
tion status of BH4 and leads to decreased NO bioavailability,
thereby exacerbating the progression of CVD.
Ginter proposed that the mechanism of VC in preventing
CVD may also involve cholesterol metabolism, lowering
blood pressure, and antioxidant effects.118 High cholesterol
and hypertension are important risk factors for the develop-
ment of CVD. A deficiency in VC over an extended period will
result in a reduction in the activity of cholesterol metabolic
enzymes and thus reduce the conversion of cholesterol into
bile acids.119,120 This ultimately results in the accumulation
of cholesterol in the body which can contribute to elevated
cholesterol levels. Concurrently, long-term supplementation
of VC has been demonstrated to reduce the risk of hyperten-
sion. The potential mechanism underlying this effect is that
VC plays an antioxidant role, preventing the oxidation of
low-density lipoprotein (LDL; oxidized LDL contributes to
the vicious cycle of atherosclerosis [AS] by stimulating cell
adhesion, producing ROS, and decreasing NO), and inhibits
the proliferation of vascular smooth muscle involved in
AS.121–124 Furthermore, VC may also improve chronic in-
flammation through nonspecific antioxidant effects (chronic
vascular inflammation is a part of CVD pathophysiology125),
thereby improving the development of CVD.111
VC Promotes Skin Health
As the largest organ in terms of surface area in the human
body, the skin serves as a protective barrier between the
external environment and the body’s internal tissues. The
skin functions as a barrier to the invasion of the external
environment, while simultaneously providing physical and
chemical protection to the internal environment. VC has
been demonstrated to facilitate collagen synthesis, inhibit
melanin production, and protect against ultraviolet-induced
oxidative damage, thereby playing an important role in
maintaining optimal dermal health.126
VC mainly plays a role in promoting collagen synthesis in
the proline and lysine hydroxylation process; the ant ioxi dant
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
effect of VC is related to its structure, which can be reduced
by the action of oxidants; in addition, VC can interfere with
the action of tyrosinase, thereby affecting melanin produc-
tion.127 Tyrosinase is the rate-limiting enzyme in melanin
synthesis, catalyzing the hydroxylation of L-tyrosine to form
DOPA, which oxidizes to DOPA quinone. DOPA quinone is
cyclized to dopamine, which is tautomerization to 5,6-dihy-
droxyindole-2-carboxylic acid (DHICA), and finally forms the
DHICA-melanin subunit. VC interferes with melanin synthe-
sis by reducing oxidized DOPA quinone, blocking the oxida-
tion of DHICA, and interacting with copper ions in the active
site of tyrosinase.128
Clinically, VC is commonly used in the treatment of
atopic dermatitis, late-onset porphyrin skin disease, and a
range of dermatological conditions including herpes zos-
ter. Its primary role in cosmetics is to impart whitening
and antiaging effects. The main ingredients of MAS063DP
cream (Atopiclair) are grape seed extract, VC, vitamin E,
hyaluronic acid, glycyrrhetinic acid, and shea butter.129
Multiple clinical studies have demonstrated that this
formulation is a safe, well-tolerated, and effective nonste-
roidal therapy for the treatment of mild to moderate
atopic dermatitis.130–132 The drug is currently licensed
intheUnitedStatesandtheEuropeanUnionforthe
treatment of specific dermatological conditions, including
dermatitis and contact dermatitis. In the treatment of
other skin diseases, VC is employed in combination with
other pharmaceutical agents or as an adjunct to physical
therapy. Zinc, and clarithromycin combined with VC in the
treatment of acne continue to demonstrate antibacterial
efficacy against niacinomycin-induced acne, offering a
novel avenue for the clinical use of antibiotics in acne
therapy.133 However, due to the issue of poor permeabili-
ty, and stability,1,134 the application of the VC prototype in
topical skin preparations is limited. In general, it is neces-
sary to expand the application range of applications for VC
by designing VC derivatives or developing suitable dosage
forms.135,136 The emergence of microneedle technology
and ion import technology has recently improved the
permeability of VC, although there have been no large-
scale clinical applications to date. Hence, the stability and
permeability of VC must be improved to facilitate its
clinical application in topical preparations.
In addition to the studies mentioned above, a joint study
by the Chinese Academy of Sciences discovered that VC
supplementation may impede the aging of the spinal
cord.137 By integrating tran scriptomics, neurohistology, neu-
roelectrophysiology, and other disciplines, they identified a
particular subtype of CHIT1-positive microglia in the spinal
cord of older primates. These cells can activate SMAD signal-
ing in motor neurons through paracrine CHIT1 protein,
thereby contributing to the aging of the motor nerve. How-
ever, VC supplementation has been demonstrated to impede
the aging and degenerat ion of spinal cord neurons. This study
not only elucidates the potent ial role of VC in ner vous system
diseases but also indicates a novel avenue for postponing the
aging of the human spinal cord and the management of
geriatric diseases.
Perspectives and Conclusion
VC has a multitude of biological activities; however, its role
in the field of medicine is currently in the exploratory phase,
with only a limited number of large-scale clinical applica-
tions. These applications mainly focus on the role of adjuvant
prevention and treatment. The primary reason for this
situation lies in its extreme instability.138 VC is easily de-
graded in the presence of water, oxygen, and metal ions
under basic conditions, which undergoes a yellow color
change.1Currently, the primary control measures are: con-
trolling the oxygen content during the process, using
anhydrous/nonaqueous preparat ions, reducing the pH value,
adding antioxidants, and increasing the viscosity of the
system.134 In addition, the development of the delivery
system, as well as derivatives of VC, may prove to be
promising strategies to stabilize VC. The evolution of VC
derivatives went through a process from binding to ionic
salts to lipophilic derivatives. The structural modification
improves VC’s stability, but the majority of these derivatives
lack direct antioxidant activity and must be converted to VC
in vivo. As a hydrophilic esterified form of VC, magnesium
ascorbate phosphate is currently the most common VC
derivative with greater stability. However, the introduction
of phosphate groups results in an increase in charge and a
corresponding decrease in skin permeability.127,139 Addi-
tionally, a substantial number of in vitro and in vivo experi-
ments have been conducted with VC derivatives, yielding a
multitude of contradictory results.139 Consequently, further
experimentation is necessary to comprehensively assess the
overall impact of each derivative. The issue of permeability
can be effectively addressed through the use of carriers,
especially nanocarriers. Despite the promising potential of
nanocarriers, the limitations of industrial technology and e-
regulatory frameworks remain a significant challenge. Fur-
ther research is needed to address these issues. By consider-
ing the in vivo fate of the delivery system and focusing on the
composition, size, structure, and physical state of the carri-
er,24 a more sophisticated carrier structure can be developed
to ensure that VC has an optimal effect concentration at the
treatment site.
Furthermore, consideration should be given to the com-
patibility of VC with other drugs. Patients with hypertension
are at an elevated risk of developing cerebral hemorrhage,
and as a result, the concurrent administration of antihyper-
tensive drugs and VC has been demonstrated to exert a
protective effect against cerebral hemorrhage. The combina-
tion of VC with anticoagulants has been observed to reduce
the anticoagulant effect and shorten the prothrombin time,
which is incompatible.140 Therefore, although VC is a com-
mon vitamin, the use of VC should follow the advice and
guidance of physicians.
In conclusion, as a multifunctional compound, VC exhibits
a range of biological activities and has been demonstrated to
have preventive and therapeutic effects on a variety of
diseases. The stability and permeability of VC remain limi-
tations to its clinical application. It is anticipated that further
developments in the form of new applications of VC will
Pharmaceutical Fronts © 2024. The Author(s).
A Review of the Applications of Vitamin C to Treat Human Diseases He et al.
emerge in the future, with the potential to enhance the
treatment of a range of diseases.
Funding
This work was supported by the National Natural Science
Foundation of China (Grant No. 81872823 and 82073782).
Conflict of Interest
None declared.
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