• The PHA and bionic structure

Polyhydroxy acids and bionic acids are organic carboxylic acids, which possess two or more hydroxyl groups on an aliphatic or alicyclic molecular structure. When one of the hydroxyl groups occurs in the alpha position, the PHA is a polyhydroxy AHA Fig. 33.1; when an additional sugar is attached to the PHA structure, the molecule is a bionic acid (Fig. 33.1). Because they share the common AHA structure, PHAs and bionics have the ability to provide skin effects similar to traditional AHAs, such as glycolic acid.

Fig. 33.1 PHAs: gluconolactone and lactobionic acid

• Antioxidant and free radical scavenging effects of gluconolactone

The antioxidant properties of gluconolactone are evident in food and drug substances, in which gluconolactone has been shown to inhibit oxidation and help maintain product integrity Fig. 33.3.

Fig. 33.3 Antioxidant effects of PHAs: gluconolactone and lactobionic acid inhibit oxidative darkening of anthralin and hydroquinone and prevent oxidative browning of banana peels exposed to ambient conditions. Photos demonstrate the screening process

Bernstein et al demonstrated that gluconolactone provides free radical scavenging effects comparable to other well-known compounds such as ascorbic acid and alpha-tocopherol using an in vitro model of cutaneous photoaging. In this model, compounds are measured for their ability to prevent ultraviolet (UV) induced activation of an elastin promoter in skin via free radical scavenging activity. An increase in the expression of the elastin promoter causes an abnormal deposition of poorly structured elastic material in skin—the condition known as solar elastosis. Maximum protection by free radical scavengers occurs at a rate of approximately 50%; the other 50% is caused by direct UV damage to cells and cellular DNA. Results of the study indicated that gluconolactone provided up to 50% protection against UV radiation. This effect could not be explained by UV screening, and therefore was attributed to gluconolactone’s ability to chelate oxidation-promoting metals possibly via the direct free radical scavenging effects of gluconolactone.

• Clinical effects of gluconolactone

In vivo clinical studies of gluconolactone-containing formulations have demonstrated measurable benefits including antiaging and skin-firming effects that are comparable to commonly used AHAs (e.g. glycolic acid), with reduced irritation potential. In addition, significant antiaging benefits including reduced pigmentation and improved skin texture have been observed over a range of darker Fitzpatrick skin types (IV–VI) represented by a study population of African–Americans, Asians, and Hispanics.

Gluconolactone is well suited for adjunctive use with topical medications. It enhances epidermal cell turnover, which may in part help to explain the adjunctive benefits of PHAs in the treatment of acne. A vehicle-controlled, double-blind clinical study on mild to moderate acne demonstrated antiacne effects with less irritation of a 14% gluconolactone solution in comparison to a 5% benzoyl peroxide lotion. In addition, PHAs can be used to hydrate and condition skin during treatment with drying or irritating medications including topical retinoids, benzoyl peroxide, and azelaic acid. This benefit was demonstrated in a clinical study designed to evaluate the effects of standardized adjunctive use of a PHA cleanser plus PHA moisturizer in combination with 15% azelaic acid gel for the treatment of rosacea. Results indicated significantly greater improvements in global assessment and erythema relative to the azelaic acid treatment group that had not been standardized to adjunctive PHAs (P < 0.05). Compatibility of a 15% gluconolactone-containing cream (pH 3.3) in combination with daily use of tretinoin gel 0.1% has also been demonstrated.

Skin barrier strengthening effects of PHAs were evaluated in a vehicle-controlled, double-blind clinical study. Unlike AHAs (glycolic acid and lactic acid), antioxidant PHAs (i.e. gluconolactone) were shown to strengthen stratum corneum barrier function by reducing transepidermal water loss and erythema assessed via colorimetry following a chemical challenge. Clinically, this finding may help to explain data that revealed a lack of increased sun sensitivity with PHA use. The PHAs gluconolactone and glucoheptonolactone did not cause an increase in the formation of sunburn cells following exposure to UVB in the testing model employed by the Personal Care Products Council (formerly the Cosmetic, Toiletry, and Fragrance Association) and the Food and Drug Administration (FDA) Fig. 33.4.

Fig. 33.4 Sun sensitivity model: mean sunburn cell count (sunburn cell count per high power field)

• Antioxidant/chelation effects of lactobionic acid

Lactobionic acid is currently used in the pharmaceutical industry as a counterion (e.g. erythromycin lactobionate, calcium lactobionate) to minimize irritation. In addition, lactobionic acid is a key antioxidant chelator in organ transplant preservation solutions that are used to suppress tissue damage caused by hydroxyl radicals during organ storage and reperfusion. Lactobionic acid reportedly inhibits hydroxyl radical production by forming a complex with Fe(II).

The antioxidant properties of lactobionic acid have also been studied in food and drug substances, demonstrating the capacity to inhibit the oxidation of readily oxidizable drugs including anthralin and hydroquinone, as well as banana peels (see Fig. 33.3). Since oxidation and UV-induced free radicals are a cause of skin aging, the potent antioxidant benefits of lactobionic acid may play an important role in its antiaging effects.

• MMP inhibition effects of lactobionic acid

Investigative work in the field of organ preservation has revealed that lactobionate is a cryptic inhibitor of MMP enzymes obtained from human liver effluents during transplantation. Similar protective benefits in skin are desirable because MMPs are responsible for degrading the skin’s extracellular matrix and structural integrity. Accordingly, MMPs cause or contribute to wrinkle formation, skin laxity, and visible telangiectasia. Naturally occurring tissue inhibitors of MMPs protect the skin from degradation by these enzymes. Nonetheless, MMP activity in skin increases with UV exposure and advancing age, leading to the visual and morphologic signs of photodamage. Histology samples obtained from skin treated with 8% lactobionic acid after a period of 12 weeks have demonstrated reduced levels of MMP9 staining, thereby showing a preventive benefit in treating photoaged skin.

• Clinical effects of lactobionic acid

Lactobionic acid functions similarly to AHAs in providing antiaging and enhanced cell turnover effects. Lactobionic acid provides benefits to skin beyond traditional AHAs as a result of its unique chemical structure and molecular composition. Due to its multiple hydroxyl groups, lactobionic acid is a strong humectant, with the ability to attract and retain water better than common humectants including glycerin and sorbitol (see Fig. 33.2). It also forms a unique gel matrix during the drydown process as a result of its strong water retention properties.

PHA formulations of lactobionic acid in combination with gluconolactone are nonirritating Fig. 33.5. PHA/bionic combinations have also exhibited strong antiaging effects including marked improvements in skin clarity (260%, P < 0.05, n = 26) and notable skin plumping effects (9.7%, P < 0.05, n = 26).

Fig. 33.5 Results of a 14-day cumulative irritation patch test under occlusion of a combined 12% PHA/bionic formulation relative to a mild irritant (SLS solution) and a negative control (0.9% NaCl solution). The PHA/bionic formulation was nonirritating and scored equivalently to the negative control (saline)

A second independent study of lactobionic acid formulated in a simple cream base (8%, pH 3.8) was conducted to evaluate antiaging effects over a 12-week period in comparison to: (1) baseline condition on the face, and (2) an untreated control for forearm skin thickness measurements. Thirty-one female participants completed the study; statistically significant effects were evident at both 6 and 12 weeks (P < 0.05). Notably, skin clarity was improved by 100% and appearance of fine lines was reduced by 37%. Skin firmness and elasticity via the pinch recoil model increased by 14.5% at 12 weeks. Forearm skin thickness increased 7%, demonstrating a statistically significant response relative to baseline and the untreated control forearm. Histology specimens revealed an increase in viable epidermal thickness and dermal glycosaminoglycans, as well as reduced staining of MMP9 enzymes, demonstrating both preventive and corrective antiaging effects.