Encapsulated salicylic acid for acne treatment

The structure is based on the hydrophobic polymeric matrix of sub-micron spheres that controls the adhesion and release of an anti-acne agent, salicylic acid (SA). The sub-micron spheres adhere to the epidermis, gradually disassociating, while:

•  enhancing deposition onto skin as compared to commercial products to enhance efficacy,
•  maintaining a consistent skin pH of 4.5 to 5.0 that does not irritate the skin, and
•  maintaining a skin friendly performance effective to treat acne.

The amount of active ingredient (SA), which was deposited onto the skin, was found to be three times higher in SalSphere SA 30 in a body wash, as compared to the free formula. The SalSphere SA 30 used in a body wash maintained a skin-friendly pH of 5.0 that is suitable for sensitive skin. All tested human volunteers reported SalSphere SA 30 makes the skin clearer, smoother, is gentler, non-itchy, nonirritating, and an overall cleaner product. Further studies also indicated that over 70% of the tested subjects displayed increased efficacy, reduced shine including a faster recovery in reducing excess sebum content on skin upon usage of the SalSphere SA 30 in a body wash.

Acne vulgaris (also known as acne) is a form of skin disease, which affects the porous intrusions of the follicularsebaceous unit. Acne is the most common skin disorder in the United States afflicting 40 to 50 million Americans.1 The primary source in the development of acne begins with the human sebum (a naturally produced oil within the sebaceous gland), which causes a plug/cap to form within the pores of the epidermis. As the inside components (dead skin particles, oils, etc.) begin to saturate and congest the pores, it becomes a hospitable environment for pathogenic bacteria2 (known as Propionibacterium acnes), to trigger an inflammatory cytokine response. Once inflammation of the sebaceous gland becomes prevalent, signs of comedones, papules, pustules, along with occasional nodules appear onto the outer surface of the skin.

Salicylic acid (SA): properties, mode of action and challenges

While there is a multitude of effective ingredients for preventing, and/or treating the infectious components of acne,3-5 SA has been widely accepted as an anti-acne agent, due to its high efficacy. SA is one of the safest and most effective treatments, particularly for patients with mild to moderate acne. Concentrations of SA ranging from 0.5% to 10% have been recommended for acne, but the maximum strength allowed in non-prescription acne products, in the United States, is up to 2% by the FDA Final Acne Monograph. SA acts by peeling decayed skin layers and unclogging the follicles, which results in a skin cycle renewal. The mechanism of action for SA is disruption of intercellular adhesions and inhibiting an inflammatory cascade associated with acne formation. However, the challenge in utilising SA as an anti-acne medication is poor solubility in water (0.2 g/100 mL at 20°C), which is below the required 0.5%-2.0% concentration for effective formulation. Therefore, the challenge becomes to successfully dissolve SA into a water-based anti-acne emulsion, while delivering it effectively to reduce irritation.

Sub-micron technology for acne treatment

One commonly observed obstacle is the delivery of SA as a non-clear topical application. Through the attempts to deliver free SA to the skin surface using a rinse-off application such as body wash, much of the product is lost and/or becomes inactive and, in turn, becomes ineffective when treating acne. It has only recently been demonstrated that the distance between corneocytes (surface skin cells), in the stratum corneum (outer layer of the skin) are within the nanoscale (13 nm, across five 3-5 nm areas between the sheets of the intercellular lipids). Thus, for effective deposition of the SA, sub-micron spheres are ideal. Therefore, the primary goal in delivering SA is to stabilise the compound in an applicable complex, which can efficiently be deposited onto the skin, and specifically to the pimples or comedones. Another commonly encountered issue, when administering SA, is in the stability of the acid when mixed into solution. As previously stated, SA has poor solubility in aqueous solvents, while soluble in various organic solvents and harsh surfactants. The primary issue, concerning the available methods in the market, is that the organic solvents used to aide in delivering SA cause irritation, dryness, as well as possible burning of the skin. The stability of the acid depends on its soluble nature in solution. While SA, in a free form solution, is lipophilic (hydrophobic), it can be properly encapsulated and suspended in aqueous solution by being confining to the encapsulated sub-micron spheres.

SalSphere SA 30

SalSphere SA 30 (now referred to as ‘SA 30’) employs a unique delivery system designed to slowly release SA over time from small vesicles called submicron spheres6,7 (Fig. 1). These tiny, hydrophobic spheres encase the SA and suspend it in an aqueous medium via a hydrophilic outer shell. Once applied to skin, the charge moiety anchors the sphere for deposition while the hydrophobic matrix gradually breaks down and releases the SA in a controlled manner, over time (Fig. 2). This technology allows for the utilisation of a pre-manufactured blend of SA to enable suspension in a clear base. SA 30 is a water-based clear product (Fig. 3a) that is easily incorporated into an aqueous face wash or gel (Fig. 3b). This feature eliminates the need to pre-dissolve the SA in solvents, alcohol, or surfactants that can harm and/or cause additional irritation to skin that would already be inflamed.

Method of manufacture

The SA 30 spheres are prepared by high shear homogenisation in the aqueous phase as described in the patent.7 The SA 30 spheres are inherently more stable than structured vehicles such as lipospheres. Moreover, it has a lower risk of reaction to be delivered with the vehicle than emulsion systems due to a solid inert matrix material. The way to monitor the leakage of SA is by pH. The suspension has a constant pH of 5. Reduced pH indicates leakage of SA.

Materials and methods
Clinical study of deposition of SA 30

Facial wash containing SA 30

See Table 1. The final formula is a clear solution (Fig. 3b) and has a skin friendly pH of 5.05.

Application procedure

Using the extraction apparatus (circular bulb 15.5 cm2 in area), the applied are as were marked. Approximately 0.3 g of the body wash was applied to each sample area, rubbed for 15 seconds and rinsed-off. After 15 minutes, each application area was rinsed with 4.5 mL of ethanol (1.5 mL of ethanol rinse for 30 seconds, extraction repeated a total of three times) and collected for HPLC analysis of SA.

Skin study: skin pH post application

Skin pH is typically used as a criterion to predict the possible irritation capability in a product. A pH range of 4.5 to 5.0 is considered safe for normal skin. Volunteers washed their forearms with two different cleansers. The cleanser used on one arm contained a commercial formula using Free (nonencapsulated) SA while the cleanser on the other arm contained SA 30 both at a 2% final concentration of active ingredient SA. The pH of the skin was tested with a Hanna, HI99181 skin pH meter following application and rinse-off of the washes on the forearms.

Consumer perception tests

Sensation test

Subjects were blindly tested using three formulas:

•  SA 30 in body wash
•  Free SA in body wash
•  Commercial market product containing 2% SA.

Sensations were observed both prior to, and after, adding water to the applied sample area.

Deposition test

Subjects were treated with an “artificial sebum” formula onto the arm. After five minutes, the three samples: SA 30 in body wash, free SA in body wash, and market product containing 2% SA were applied to each spot. After an additional five minutes, the test area was washed with water. The following criteria were used to test the consumer perception of the product:

•  softness of product
•  cleansing effect
•  gentle sensation
•  irritability
•  smoothness
•  residue on skin
•  shiny, oily feeling
•  itchiness
•  skin dryness
•  heaviness of product.

Results

Deposition of SA 30

Clinical studies show that SA 30 is most effective method for enhanced deposition of SA over time as compared to the controls (Fig. 4). The level of SA deposited onto skin from SA 30 is 1.158±0.28% vs. 0.38±0.11% for the free. The per cent active ingredient, SA, deposited onto the skin was three times higher for the SA 30, in sulfate free body wash, application as compared to the 2% free SA. Deposition of SA onto skin is key for longer lasting benefits from the product. Deposition is required for long lasting contact of SA with the skin. Usually, in a rinse-off application, the contact time is 30-60 seconds before it is washed off. The technology enables to benefit from incorporating SA for several hours after the rinse-off.

Skin-friendly pH: slow release of SA

The results show a final skin pH that minimally deviates from the normal skin pH of 5 when using the SA 30, whereas the free formula displays a pH drop into a range that could potentially cause irritation (Fig. 5). Thus, the structure of SA 30 provides a slow/timely release of SA, in its most potent form, over time. Delivering the acid in this controlled, slow manner determined by changes in skin pH allows the skin to re-balance its pH shortly upon coming into contact with the acid.

Consumer perception

All tested human volunteers reported SA 30 (in a sulfate-free body wash) to be a clearer, smoother, more gentle, non-itchy, non-irritating, and cleaner product when compared to the free formula, or even conventional products on the market. Further studies also indicated that over 70% of the tested subjects displayed a significant reduction in the “artificial sebum” in the SA 30 formula versus the free SA and commercial product.

Conclusion

The SA 30 is a clear, water-based solution that is non-itchy and non-irritating. Consumers found improved sensations of smoothness, and cleanliness when applying the SA 30 formula versus the free SA. The SA 30 (in body wash) is also effective in significantly enhancing deposition, of the active ingredient (SA), onto sebum, which would result in a faster recovery. Thus, sub-micron technology-based encapsulation of hydrophobic/lipophilic SA has shown to be extremely beneficial for maintaining a friendly skin with consistent skin pH of 5, enhancing deposition onto skin while being consumer/skin friendly. The ultimate benefits of the SalSphere SA 30 is that a clear, smooth product can be used for reduction of spots, fine wrinkles etc.

References

1 Imahiyerobo-Ip JI, Dinulos JG. Changing the topography of acne with topical medications. Curr Opin Pediatr 2011; 23 (1): 121-5. 2 Gribbon EM, Cunliffe WJ, Holland KT. Interaction of Propionibacterium acnes with skin lipids in vitro. J Gen Microbiol 1993; 139: 1745-51. 3 Zaenglein AL. Making the case for early treatment of acne. Clin Pediatr (Phila) 2010; 49 (1): 54-9. 4 Lolis MS, Bowe WP, Shalita AR. Acne and systemic disease. Med Clin North Am 2009; 93 (6): 1161-81. 5 Bowe WP, Shalita AR. Effective over-the-counter acne treatments. Semin Cutan Med Surg 2008; 27 (3): 170-6. 6 Shefer A, Shefer S. Multi component controlled delivery system for soap bars. US Pat. 6825161, Nov 30, 2004. 7 Shefer A, Shefer S, Compositions and method for targeted controlled delivery of active ingredients and sensory markers onto hair, skin, and fabric. US Pat. 6979440, Dec 27, 2005.