VC 15 (Vitamin C) Prescriber's Guide

9 Jul, 14

VC 15 (Vitamin C) Prescriber's Guide

Introduction to Topical Vitamin C

Vitamin C (L-ascorbic acid) is the body's major aqueous-phase antioxidant and is vital for life. Most animals make their own vitamin C; only humans and other primates, the Indian fruit-eating bat, and the guinea pig lack the enzyme, L-gluconogamma- lactone oxidase, to synthesize vitamin C.

We humans obtain vitamin C solely from our diet- citrus fruits, black currants, and red peppers and other leafy green vegetables. Because active transport from the gastrointestinal tract is limited, unfortunately, even massive oral doses do not increase the concentration to optimal levels in the skin.

Exposure to sunlight and environmental pollution actually depletes vitamin C from the centre layers of the skin. Even minimal ultraviolet (UV) exposure of 1.6 minimal erythema dose (MED) decreases the level of vitamin C to 70% of the normal level, and exposure to 10 MED decreases vitamin C to 54%. Exposure to 10 ppm of ozone in city pollution decreases the level of epidermal vitamin C by 55%.¹

Oral supplementation with vitamin C does little to increase its skin concentration. Therefore, topical application of vitamin C is the preferred method to increase its presence in the skin.²

Role of Topical Vitamin C

Chemically ascorbic acid is an alpha-ketolactone with the structure shown in Fig. 1.³ At physiologic pH ascorbic acid exists as the monovalent hydroxyl anion. This and its polar moieties restrict ascorbate to aqueous compartments.

Figure. 1: Chemical structure of ascorbic acid

Vitamin C has multiple actions as discussed below:

Antioxidant²

Vitamin C or L-ascorbic acid is the most plentiful antioxidant in human skin. This water-soluble vitamin sequentially donates electrons thereby neutralizing free radicals present in the aqueous compartment of the cell. Following the donation of the first electron a more stable ascorbate free radical is formed and after the second electron is donated dehydroascorbic acid remains. Dehydroascobic acid can be enzymatically converted back to L-ascorbic acid or broken down. Vitamin C also helps regenerate the oxidative form of vitamin E a potent lipid-soluble antioxidant

Collagen Synthesis^1,2

Vitamin C is essential for collagen biosynthesis. Ascorbate is a cofactor for prolyl and lysyl hydroxylase the enzymes responsible for stabilizing and cross-linking collagen. Vitamin C also influences collagen synthesis independently of hydroxylation. Studies have demonstrated that ascorbate can stimulate collagen synthesis directly by activating its transcription and stabilizing the pro-collagen messenger ribonucleic acid (mRNA). Scurvy serves as a prototype for the physiologic changes that occur when vitamin C is lacking and collagen biosynthesis is impaired. Ascorbate also inhibits elastin synthesis which may contribute to its role in treating photoaged skin.

In addition to its ability to enhance collagen production, vitamin C may also help preserve existing collagen. Topically applied L-ascorbic acid has been shown to downregulate the enzymes responsible for collagen degradation.

Studies In vitro compared fibroblasts in newborns with those in the elderly (80 to 95 years old). Elderly cells proliferate in vitro at only one-fifth of the rate of newborn cells. However, when vitamin C is added to the culture medium, the elderly cells proliferate better than normal newborn fibroblasts. Even the newborn fibroblasts proliferate almost four times better when exposed to vitamin C.⁴

Not only do fibroblasts increase proliferation in the presence of vitamin C, but they also synthesize more collagen. Newborn fibroblasts synthesize a larger percentage of collagen than the elderly cells, but, again, when the elderly cells are exposed to vitamin C in vitro, they produce more collagen than the normal, newborn fibroblasts. Surprisingly, even newborn cells double the amount of collagen synthesized.⁴

In contrast to the increased synthesis of collagen, in vitro studies suggest that vitamin C may inhibit elastin biosynthesis by the fibroblasts. This may be advantageous in reducing the solar elastosis seen in photodamage.⁵

Topical vitamin C has also been shown to enhance collagen production in human skin In vivo.⁶ Postmenopausal women who applied 5% vitamin C to one arm and half of the neck, with placebo on the other side showed an increase in mRNA of collagens I and III. Tissue levels of the inhibitor of metalloproteinase-l (MMP-I) were also increased, thus decreasing UV-induced collagen breakdown. However, mRNA levels of elastin, fibrillin and the tissue inhibitor of MMP-2 remained unchanged. Clinically, a significant decrease was observed in deep furrows and substantiated by silicone replicas. Histology showed elastic tissue repair.

Photoprotection

Vitamin C has also been proven to be photoprotective. Vitamin C in itself not a sunscreen because it does not absorb light in the UV spectrum; however, as an antioxidant, it deactivates UV-induced free radicals and decreases UVB erythema by 52%.⁷ This protection is confirmed histologically - treatment with topical 10% vitamin C decreases the number of abnormal "sunburn cells" by 40-60% and reduces UV damage to DNA 8- hydroxydeoxy-guanosine (8-OHdG) by 62%.⁷

Anti-Inflammatory

Vitamin C also has anti-inflammatory property. In vitro studies with human cells in vitamin C-enriched media demonstrated decreased activation of the transcription factor nuclear factor-kappa beta (NF- kß) the factor responsible for many pre-inflammatory cytokines such as the tumour necrosis factor alpha (TNF- a) and interleukins ll-l 11-6 and 11-8.8 In fact topical vitamin C has been used by dermatologists to treat acne rosacea and to decrease erythema after laser abrasion.⁹

Depigmentation

By directly decreasing inflammation post-inflammatory hyperpigmentation is reduced. Also vitamin C is itself an excellent depigmenting agent because it inhibits the enzyme tyrosinase to decrease melanin production. In a clinical trial topical vitamin C (5%) demonstrated lightening of melasma after 3 months of daily application.¹⁰

Protective Barrier Function/Moisturization¹

Another important action of vitamin C on the skin is that topical vitamin C increases the synthesis of several specific lipids of the skin surface. Thus not only does vitamin C help the natural moisturization of the skin but it also enhances the protective barrier function.

Percutaneous Absorption of Topical Vitamin C11

L-ascorbic acid or its derivatives were applied to the skin of Yorkshire pig. Skin levels of l-ascorbic acid were measured to determine percutaneous delivery. Experiments were conducted on Yokshire pigs because of the similarity of their skin to humans.

pH

The 15% formulations of L-ascorbic acid were tested at pH levels between 2 and 5. Tissue levels of L-ascorbic acid were enhanced only at a formulation with pH levels less than 3.5. Thus L-ascorbic acid must be formulated at pH levels less than 3.5 to enter into the skin.

Figure. 2: Effect of pH on percutaneous absorption

Concentration

Formulations containing 5%, 10%, 15%, 20% or 25% vitamin C were tested; the 20% formulation resulted in the highest concentration levels with maximized concentration in the skin even after 3 days of once-daily application (See Fig. 3). For unknown reasons concentration levels higher than 20% resulted in decreased tissue levels.

Figure. 3: Effects of concentration on percutaneous absorption

Kinetics

For 1-5 days 15% of L-ascorbic acid at pH 3.2 was applied daily. After 3 days tissue levels were saturated. This concentration was more than 20 times the control values.

Figure. 4: Time course of percutaneous absorption

Washout

After 5 days of 15% of L-ascorbic acid applications skin levels were measured at daily intervals with no further topical applications. The half-life of L-ascorbic acid in tissue was found to be approximately 4 days.

Figure. 5: Washout of skin L- ascorbic acid

Ascorbic Acid Derivatives

Because it is difficult to formulate a stable form of L-ascorbic acid more stable derivatives like magnesium ascorbyl phosphate and ascorbyl-6-palmitate have been utilized in the topical formulation. Accordingly 15% L-ascorbic acid

10% ascorbyl-6-palmitate and 12% magnesium ascorbyl phosphate were applied to pig skin for 24 hours and the concentrations in the skin were measured. Neither of the esters increased L-ascorbic acid levels in the skin significantly.

Figure.6: Percutaneous absorption of ascorbic acid derivatives

Distribution

Topical absorption has been proved by radioactive labelling studies in pigs.

After treatment with 10% vitamin C cream, 8.2% was found in the dermis and 0.7% was in the blood.⁷

So, topical L-ascorbic acid provides a safe and effective supplement to normal tissue stores. It must be formulated at high concentrations and at a pH lower than 3.5 to be effective.

Clinical Efficacy Studies on Topical Vitamin C

Photodamaged Skin

Use of topical ascorbic acid and its effect on photodamaged skin topography

In a 3-month randomized, double-blind, vehicle-controlled study, 19 patients with mild to moderate photodamaged skin were enrolled. Coded and unmarked medications were randomly assigned to the left and right sides of each subject's face - one containing the topical vitamin C (L-ascorbic acid) and the other, the vehicle serum. Three drops (0.5 ml) of each formulation were applied daily to the randomly assigned hemi-faces over the 3-month study period.

Figure. 7: Clinical investigator's assessment

Clinical assessment demonstrated a statistically significant improvement with active treat ment greater than the control for fine wrinkling tactile roughness coarse rhytides skin laxity/tone shallowness/yellowing and overall features. Altogether 84.2% of vitamin.

Figure. 8: Subject self - appraisal of overall improvement

The above graph summarizes the patient questionnaire results. The active side was preferred over the control side by 84.2% of the subjects. Photographic assessment showed that the active treatment was preferred over the control side by 57.9% of patients.

Conclusion

This 3-month study demonstrated a topographic improvement in photodamaged facial skin treated with topical Vitamin C (L-ascorbic acid).

Double-Blind, Half-Face Study Comparing Topical Vitamin C and Vehicle for Rejuvenation of Photodamage¹³

In a double-blind, 90-day pilot study, 10 patients having tacial photodamage were recruited. The active vitamin C (L-ascorbic acid) complex was applied to one side of the face and the inactive placebo base was applied to the opposite side of the face once a day.

Clincial evaluation of wrinkling, pigmentation, inflammation, and hydration was per -formed prior to the study and at weeks 4, 8, and 12. At 12 weeks, 2 mm punch biopsies of the lateral cheeks were performed in 4 patients and stained with haematoxylin and eosin; in situ hybridization studies were also conducted using an anti-sense probe for mRNA for type I collagen. A questionnaire was also completed by each patient.

Table 1: Topical vitamin C: Average improvement in wrinkle scores

At the end of the study, when the two sides were compared statistically, a significant difference in the clinical scoring of facial wrinkles was detected in the perioral and cheek areas of the 10 patients.

There was also statistically significant improvement of the entire treated side, compared to its beginning point, and no significant change on the base side.

Biopsies of treated versus untreated areas confirmed the presence of increased amounts of collagen in those patients showing clinical improvement. No patients were found to have any evidence of inflammation. Hydration was improved bilaterally. While 4 patients felt that the vitamin C-treated side had improved unilaterally, no patient felt that the placebo side showed unilateral improvement.

Conclusion

This pilot study demonstrated that a properly formulated vitamin C topical product may play a significant role in the reversal of photodamage of the skin. This type of product may be used as part of an overall programme using other topical agents, with or without other procedures such as various ablative and non-ablative laser therapies, acid peel resurfacing or dermabrasion.

Melasma

A double-blind randomized trial of 5% ascorbic acid vs 4% hydroquinone in melasma¹⁰

In a randomized, double-blind comparative study, 16 female patients with a pair of bilaterally symmetrical lesions of melasma were enrolled. Their ages ranged from 23 to 43 years. While 8 patients had the epidermal type of lesions, another 8 had the mixed type. The patients were randomly assigned in a double-blind manner to apply, on the left or right side of the face, 5% vitamin C (L-ascorbic acid) or 4% hydroquinone water-oil emulsion. All the patients were supervised every 4 weeks during a 16-week period.

Colorimetric assessment was calculated by obtaining the melanin index difference between the targeted lesion and pre-lesion areas. This was performed initially and at the end of the study. There was no difference found between the two sides (p=0.052). The lightening effect of hydroquinone was evident as early as the first month of treatment, whereas that of vitamin C (L-ascorbic acid) was noted at the third month.

Figure. 9: Subjective improvement

As per the subjective assessment by patients, 93% of patients had good (50- 75%) to excellent (>75%) improvement with hydroquinone, compared to 62.5% with topical vitamin C (L-ascorbic acid).

A similar number of patients felt a 50- 75% improvement with both treatments.

With regard to adverse effects, 1 patient experienced irritation with vitamin C (L-ascorbic acid) (6.25%) and 11 patients with hydroquinone (68.75%)

Conclusion

Vitamin C (L-ascorbic acid) has a beneficial effect on melasma, with a minimum of adverse effects. Vitamin C (L-ascorbic acid) can be used for a longer period of time as part of the initial hyper pigmentation treatment and as a maintenance therapy.

Acne

Sodium L-ascorbyl-2-phosphate 5% lotion for the treatment ofocne vulgaris; a randomized double-blind controlled trial¹⁴

Figure. 10: Investigator's Global Assessment

By 12 weeks of treatment 61 % of subjects showed improvement in acne compared to only 38% of patients with placebo

Figure. 11: Subject's Global Assessment Score

As per the SGA 71 % of subjects showed improvement in acne by 12 weeks of therapy compared to 52% with placebo.

Figure. 12: Inflammatory lesion count

Vitamin C demonstrated a statistically significant decrease in inflammatory acne lesions.

Conclusion

This study demonstrates that 5% sodium L-ascorbyl-2-phosphate is efficacious as monotherapy for the treatment of acne. This therapy demonstrated minimal irritation.

APS may offer an ideal adjunct therapy to common acne regimens.

Open study comparing 5% Sodium L- ascorbyl 2- phosphate iotion versus 1% clindamycin phosphate iotion for acne vulgaris¹⁵

In a multicentre, open-label study, 70 patients with at least ten and fewer than fifty inflammatory lesions, at least ten and fewer than hundred non-inflammatory lesions and no more than two nodulocystic lesions on the face were enrolled.

Enrolled patients were randomized to apply either 5% sodium L-ascorbyl-2- phosphate (APS) lotion or 1 % clindamycin phosphate lotion (CL) in the morning and in the evening for 12 consecutive weeks.

Figure. 13: Percentage of patients with good and excellent improvement scores

75.7% of patients in the APS treatment group showed either good or excellent improvement compared to 54.5% in the CL treatment group

Figure. 14: Mean percentage reduction of inflammatory and non-inflammatory lesions after 12 weeks of treatment

Mean percentage reductions in the inflammatory and non-intlammatory lesion counts were statistically significant in the APS treatment group compared with the CL group.

Study results demonstrated the superiority of APS over CL in the treatment of facial acne. APS was shown to be superior to CL in percentage reduction in inflammatory and noninflammatory lesions, as well as the global improvement scores.

Conclusion

APS was found to be more efficacious than CL in the treatment of facial acne vulgaris.

Comparison of clinical efficacies of sodium ascorbyl phosphate, retinol and their combination in acne treatment¹⁶

In this cross, double- blind study, 30 subjects having facial acne of grade ll-lll, with ten to fifty inflammatory lesions were included in the study. The subjects were randomly assigned to use 5% sodium ascorbyl phosphate (SAP) with a control base cream, 0.25 retinol cream with a control base lotion, and 5% SAP lotion along with 0.2% retinol separately.

Subjects using retinol cream were advised to use it during the night time for the same period.

For the combination treatment group, subjects were assigned 5% SAP lotion twice daily and 0.2% retinol cream once daily.

Figure. 15: Percentage reduction of lesions in each treatment group

Acne vulgaris treated with 5% SAP was not significantly different from that of 0.2% retinol at baseline following 4 to 8 weeks of application.

The combination treatment significantly reduced inflammatory lesions, compared with 5% SAP and 0.2% retinol following 8 weeks of treatment.

Conclusion

The combination treatment of 5% SAP and 0.2% retinol was most effective in reducing inflammatory lesions because it incorporated the synergistic effects on lipid peroxidation and the sebaceous glands function, in addition to the enhancement of SAP permeability by the desquamation of the stratum corneum influenced by retinol, keratin plug removal and the anti-inflammatory effect of retinol. The synergistic effect of these two active ingredients results in a potent remedy for acne vulgaris.

Post Procedure Inflammation

Effect of vitamin C on postoperative C02 laser resurfacing erythema⁹

Post-operative erythema of several months duration is a universal and problematic side effect of cutaneous carbon dioxide (C02) laser resurfacing. The following study was conducted to determine the effectiveness of two formulations of topical vitamin C (L-ascorbic acid) in reducing the degree and duration of erythema post-C02, laser resurfacing.

At 13 to 42 days post-operatively (mean: 23.5 days) one-half of each patient's face was randomly selected for application of topical vitamin C (L-ascorbic acid) serum (11 patients) or cream (10 patients) once daily for a period of 8 weeks. Patients applied a bland emollient on the control side.

In each group 8 out of 10 patients displayed a greater reduction in erythema with topical vitamin C (L-ascorbic acid), compared with the control half.

The average difference in the erythema readings at baseline, compared with those obtained at week 8, was 3.86 for the facial half treated with vitamin C (L-ascorbic acid) cream and 2.53 for the control facial half. Similarly these readings were 3.06 and 2.56 with vitamin C (L-ascorbic acid) serum and control, respectively.

Figure. 16: Decrease in erythema

Application of vitamin C (L-ascorbic acid) results in a more rapid resolution of erythema, compared to bland emollient, when topical therapy is initiated 2 or more weeks after laser resurfacing procedure.

Conclusion

Topical vitamin C (L-ascorbic acid), when used in an appropriate vehicle and when initiated 2 or more weeks post-operatively, may decrease the degree and duration of erythema after cutaneous C02 laser resurfacing.

VC 15: An Ideal Formulation of Topical Vitamin C

VC 15 is the first vitamin C serum in India.lt contains L-ascorbic acid at a concentration of 15%. It is a stable formulation with a pH of 2.7. VC 15 promises to be non-irritating and non-comedogenic. It is available in a bottle of 15 ml along with a dropper.

Table 2: VC 15 - an ideal formulation of Vitamin C

VC 15: An Outline of its Use

Indications

VC 15 is indicated for the following:

Photodamaged/aging skin (prevention and cure)
- Dry skin
- Dull complexion, tough texture Fine
- lines and deep wrinkles
- Age spots
Melasma/hyperpigmentation
Acne and acne scars
Post-procedure inflammation

Dosage and Administration

VC 15 should be used once daily in the morning. The user should be instructed as follows: Before application, ensure that the skin area to be treated and your hands are thoroughly clean. Apply the serum before using any sunscreen and/or make-up. Use within one month after opening the bottle.

Some people may experience a slight tingling or stinging sensation after application of the serum, but this effect diminishes with continuous use.

Excess application of VC 15 will not provide quicker or better results. So. please use only the recommended dosage.

Contraindications

VC 15 is contraindicated in patients having a history ot hypersensitivity to vitamin C or any of the ingredients in the formulation.

Warnings and Precautions

VC 15 is meant for external use only. Avoid direct contact with the eyes or mucous membranes. Use within 1 month after opening the bottle. Store between 15-30°C. Keep the dropper tightly screwed on when not in use.

Due to the high concentration of L-ascorbic acid, there may be a temporary tingling or stinging sensation after applying the product. If this occurs, avoid using the product on the most sensitive facial areas including the sides of the nose and around the eyes.

Discontinue use of the product only if it has turned dark brown.

Undesirable Effects

The only adverse effects reported are mild and typically resolve in the first 2 months of therapy. These minor adverse effects included stinging (55%)

erythema (24%). and dry skin (< 1%).¹²

VC 15: Place in Therapy

On the basis ol a solid foundation of in vivo, in vitro and animal model data, it can be stated that vitamin C alleviates oxidative stress on the skin. Along with its antioxidant property it also has photoprotective, depigmenting and anti-inflammatory properties. Vitamin C also provides the additional advantages of replenishing vitamin E and stimulating dermal collagen synthesis, a major target in chronic photoaging.

A significant body of scientific research supports the use and valuable role of topical vitamin C in the treatment and prevention of photodamaged/aging skin. Topically applied vitamin C is also useful for lightening hyper-pigmentation due to its depigmenting property. Due to its documented anti-inflammatory properties, it is useful in treating inflammatory acne and post-procedure inflammation. By promoting collagen synthesis, topical vitamin C improves fine lines and wrinkles. In addition to these uses, topical vitamin C can be used as an adjunct to sunscreen for photoprotection.

Table 3: Properties supporting clinical uses of topical vitamin C

Because of the diverse biologic effects of Ihis compound topical vitamin C has become a useful part of the dermatologist's armamentarium.

References

1. Burke KE. Interaction of vitamins C and E os better cosmeceuticals. Dermatologic Therapy 2007; 20:314-21.
2. Farris PK. Topical Vitamin C: A Useful Agent for Treating Photoaging and Other Derma tologic Conditions. Dermatol Surg 2005; 31:814-18.
3. Colven RM.. Pinnell SR. Topical Vitamin C in aging. Clin Dermatol 1996; 14:227-34.
4. Phillips CL, Combs SB, Pinnell SR. Effects of ascorbic acid on proliferation and collagen synthesis in relation to donor age of human dermal fibroblasts. J Invest Dermatol 1994;103:228-32.
5. Davidson JM, Luvalle PA, Zoia O, et al. Ascorbate differentially regulates elastin and collagen biosynthesis in vascular smooth muscle cells and skin fibroblasts by pretranslational mechanisms. J Biol Chem 1997; 272:345-52.
6. Humbert PG, Haftek M, Creidi P et al. Topical ascorbic acid in photoaged skin. Clinical topographical and ultrastructural evaluation: Double-blind study vs. placebo. Exp Dermatol 2003; 12:237-44.
7. Darr D, Combs S, Dunsten S et al. Topical vitamin C protects porcine skin from ultra violet radiation-induced damage. Br J Dermatol 1992; 127:247-53.
8. Carcamo JM, Pedraza A, Borquez-Ojeda O, Golde DS. Vitamin C suppresses TNF alpha-induced NF-kappa B activation by inhibiting I kappa B alpha phosphorylation. Biochem 2002; 41:12995- 30002.
9. Alster T, West TB. Effect of vitamin C on postoperative C02 laser resurfacing erythema. Dermatol Surg 1998; 24:331-34.
10. Espinal-Perez L, Moncada B, Castanedo-Cazares R A double-blind randomized trial of 5% ascorbic acid vs 4% hydroquinone in melasma. Int J Dermatol 2004; 43:604-7.
11. Pinnell SR et al. Topical L-ascorbic acid: percutaneous absorption studies. Dermatol Surg 2001 Feb;27(2):137-42.
12. Traikovich SS. Use of topical ascorbic acid and its effects on photodamaged skin topography. Arch Otolaryngol Head Neck Surg 1999;125:1091 -8.
13. Fitzpatrick Richard E. and Rostan Elizabeth F. Double-Blind, Half-Face Study Com paring Topical Vitamin C and Vehicle for Rejuvenation of Photodamage. Dermatol Surg 2002:28:231-236.
14. Woolery-LIoyd H, Baumann L, Ikeno H. Sodium L-ascorbyl-2-phosphate 5% lotion for the treatment of acne vulgaris: a randomized, double-blind, controlled trial. J Cosmet Dermatol. 2010 Mar;9(l):22-7.
15. Hiroshi Ikeno, Kitaro Ohmori, Shunji Yunoki. Takeshi Nishikawa. Open study comparing 5% sodium L-ascorbyl-2-phosphate lotion versus 1 % clindamycin phosphate lotion for acne vulgaris. Cosmetic Derm 2006; 19(1): 43-48.
16. Ruamrak C, Lourith N, Natakankitkul S. Comparison of clinical efficacies of sodium ascorbyl phosphate, retinol and their combination in acne treatment. Int J Cosmet Sci. 2009Feb;31(l):41-6.
17. Lupo MR Antioxidants and vitamins in cosmetics. Clinics in Dermatology 2001; 19:467-473.
18. Data on file, Cipla Ltd.