Combination Therapy for

Skin Lightening:
An Update on Recent Researches
Dr. Widya Widita, Sp.KK(K), M.Kes

Department of Dermatology and Venereology

Faculty of Medicine, Hasanuddin University
Wahidin Sudirohusodo Hospital
Makassar, Indonesia
 Definition

Skin lightening
agent : Routes Aims
01 • The use of 02 • Topical 03 • For
substances to • Oral hyperpigmentation
reduce melanin in the skin
concentration • Even out skin tone
of the skin • Achieve an overall
lighter skin
complexion

Burger P, Landreau A, Azoulay S, Michel T, Fernandez X. Skin Whitening Cosmetics: Feedback and Challenges in the Development of
Natural Skin Lighteners. Cosmetics. 2016; 3(4):36. https://doi.org/10.3390/cosmetics3040036
 Physiology of Melanogenesis

● Melanogenesis is a complex process that involves a series

of enzymatic and chemical reactions
● Melanin is primarily synthesized in melanosomes in
melanocytes
● Determines the colour of our skin, eyes, and hair, as well as
protects the skin from sunlight exposure

Qian W, Liu W, Zhu D, Cao Y, Tang A, Gong G, Su H. Natural skin-whitening compounds for the treatment of melanogenesis. Experimental
and therapeutic medicine. 2020 Jul 1;20(1):173-85.
 Physiology of
Melanogenesis

Qian W, Liu W, Zhu D, Cao Y, Tang A, Gong

G, Su H. Natural skin-whitening compounds
for the treatment of melanogenesis.
Experimental and therapeutic medicine.
2020 Jul 1;20(1):173-85.
 Available Skin Lightening Agents
Hydroquinone Vitamin C

Kojic Acid Glutathione

Azelaic Acid Tranexamic Acid

Glycolic Acid
Licorice
N-acetyl Glucosamine
Arbutin
Botanical Extracts
Retinoids
Melatonin
Niacinamide
Cysteamin
Galactomyces Ferment Filtrate

Couteau, C.; Coiffard, L. Overview of Skin Whitening Agents: Drugs and Cosmetic Products. Cosmetics 2016, 3, 27.
https://doi.org/10.3390/cosmetics3030027
 Available Skin Lightening Agents
Mechanism of Action Molecules
Inhibition of tyrosinase Tretinoin, glucosamine, retinol, retinaldehyde, N-acetyl
transcription glucosamine

Hydroquinone, mequinol, arbutin, azelaic acid, kojic acid,

Tyrosinase inhibition
ellagic acid, resveratrol, oxyresvaretral

Vitamin C, vitamin E, thioctic acid, retinoids, lactic acid,

Epidermal turnover accelerant
glycolic acid, salicylic acid, liquiritin
Inhibition of melanosome
Linoleic acid
transfer
Anti-inflammatory Niacinamide, soy milk
Free radical trapping agents Topical steroids, glycyrrhetinic acid

Couteau, C.; Coiffard, L. Overview of Skin Whitening Agents: Drugs and Cosmetic Products. Cosmetics 2016, 3, 27.
https://doi.org/10.3390/cosmetics3030027
 Indications of Skin Lightening Agents

Hyperpigmentation

Pigmented Senile / Post-Inflammatory

Melasma Age Spots Hyperpigmentation
Acne Scars Solar
Lentigo

Ong, Michal & Maibach, Howard. (2014). Skin Whitening Agents

Juliano, C.C.A. Spreading of Dangerous Skin-Lightening Products as a Result of Colourism: A Review. Appl. Sci. 2022, 12, 3177.
https://doi.org/10.3390/app12063177
 Cysteamine Hydrochloride
Cysteamine is the simplest aminothiol physiologically
produced in human cells as intracellular degradation product of L-
cysteine .

Acts as a natural antioxidant as well as a potent depigmenting agent.

Previous studies → cysteamine can inhibit the melanogenesis process

without exhibiting any melanocytotoxic activities.

Besouw M, Masereeuw R, van den Heuvel L, Levtchenko E. Cysteamine: an old drug with new potential. Drug Discovery Today. 2013 Aug
1;18(15-16):785-92.
Cysteamine Hydrochloride

Double enzyme inhibition:

tyrosinase and peroxidase
inhibitors
•
Dopaquinone quenching:
removing dopaquinone
from the pathway
•
Reduction of melanin in
the stratum corneum into
a lighter form through
antioxidant effect
 PIH secondary to Contact Dermatitis,
PseudofolliculitisBarbae/
Cysteamine 5% x 15 min
3 months duration

PIH post Acne Vulgaris

Cysteamin 5%
3 months duration
 Tranexamic Acid

Tranexamic acid (TA), commonly used as a hemostatic agent due to its anti fibrinolysis
action is also promoted as a skin lightening agent, can be used as topical, oral or
intradermal injections for melasma

Tranexamic acid (TA) is competitive inhibitor of plasmin activation, Blocks conversion of

plasminogen to plasmin, Blocks binding of plasminogen to keratinocytes → downregulates
prostaglandin, a stimulator of tyrosinase, resulting in a decline in tyrosinase activity and
melanogenesis.

Taraz M, Niknam S, Ehsani AH. Tranexamic acid in treatment of melasma: A comprehensive review of clinical studies. Dermatologic
therapy. 2017 May;30(3):e12465.
 Niacinamide

Nicotinamide (niacinamide) is the amide form of water-soluble vitamin B3

Nicotinamide has also been used in the cosmetic field for decades to
prevent skin aging and brighten skin tone.

Niacinamide, ↓ pigmentation by reversibly preventing the transfer of

melanosomes from melanocytes to the keratinocytes.
It has no effect on tyrosinase activity

Bains P, Kaur M, Kaur J, Sharma S. Nicotinamide: Mechanism of action and indications in dermatology. Indian J Dermatol Venereol Leprol
2018;84:234-7.
 Galactomyces Ferment Filtrate

● Galactomyces Ferment Filtrate (GFF) efficaciously

suppressed melanization by deterring tyrosine
hydroxylase activity.
● GFF significantly alters the pH of the melanosome counter
to optimal tyrosine hydroxylase activity via
downregulation of ion transport proteins.
● GFF is dampening oxidative stress in normal epidermal
melanocytes.
 Our Current Researches

Combination #1
Cysteamine 1% + Tranexamic Acid
3% + Galactomyces Ferment
Filtrate 2% + Niacinamide 4% with
Addition of Cysteamin Mask 5%
on Dermal And Mixed Melasma
Patients
Combination #2
Cysteamine 1% with Combination
of Serum Tranexamic Acid 3% +
Niacinamide 4% + Galactomyces
Ferment Filtrate on superficial
Melasma .
 Research Results #1
1. Cysteamine 1% + Tranexamic Acid 3% + Galactomyces Ferment Filtrate
2% + Niacinamide 4% with Addition of 5% Cysteamine Mask

• Pre-post clinical trial, preliminary study

• 13 healthy Indonesian woman, age 30-50 years, Fitzpatrick skin types III-IV,
dermal and mixed melasma
• Morning : Serum + Day cream with Sunscreen
• Night : Cysteamine 5% as peel off mask + Serum + Night Cream
• Subjects were assessed every 10 days until 30 days
• Evaluation : L*value (Chromameter), melanin index and erythema index
(Mexameter®)and mMasi
RESULTS
• Significant reduction in erythema index and mMasi score
• Significant increment of skin brightness
• No side effects were noted.
 Research Results
Indeks eritema L value

As seen in this graph, P=0,01, which mean

there is a decrease in the value of the
Erythema Index in H30 compared to H0
There is a decrease in the melanin index,
there is a decrease in the value of mMASI
but it is not significant with a p value >
Score between H0 and H30.
0,086
 Research Results
A B A B

Figure 1. Photo of the patient on day 0 (A) and photo of the patient on day 30 (B). In both patients, it can be
seen that there is a difference in the level of facial brightness and reduced in mMasi
 Research Results #2
2. Cysteamine 1% with Combination Serum Tranexamic Acid 3% +
Niacinamide 4% + Galactomyces Ferment Filtrate 2%

• pre-post test clinical trial study

• 27 women with superficial melasma, Fitzpatrick type III-IV, ages : 30-50
years
• Serum cysteamine 1% combined with tranexamic acid 3%, niacinamide
4%, galactomyces ferment filtrate 2% on both melasma cheek patient
with forehead as control for 7 weeks.
➢ Evaluation:
o Melanin index and erythema index – by Mexameter
o L* value – by Chromameter
o mMasi Score – by parameter for Masi score.
 RESULTS #2

• Significant increment of skin brightness by

L*value and decreasing of mMASI Score.
• Approximately 11% experienced pruritus
and burning sensation during initial
therapy.
 Research Results

C omparing c ontrol groups with

treated groups , s ignific ant
inc reas ing in Week 5 (p = .005) and
Week 7 (p = .000)
 Research Results

No significant increasing in
54% reduction of MMASI SCOR
Erythema Index.
Research Results
Research Results
 #1 #3

Multiple Skin lightening

agents can be combined to Combination serum and
improve efficacy or to cream can be used as
decrease side effects alternating therapy for
Hidroquinone

Conclusion

#2 #4

Future research needs to be

Cysteamine and other done using serum and cream
lightening agent effective for with the same composition
hyperpigmentation but with a longer time limit
Thank You