Despite its widespread use as an anti-acne agent, SA presents the noted problems of skin irritation and formulation difficulties. In fact, approximately 60% of patients
Use of Salicylic Acid for Acne Treatment 47 relying on anti-acne medications report high levels of side effects including skin dryness and even a flare up in acne with low levels of efficacy due to the keratolytic activity of SA7 resulting from a use level of up to 2%.8 Thus, there exists a poignant need for a technology to provide SA in a form with which it is easy to formulate and will result in reduced side effects.
The secondary challenge of formulating with SA originates from the fact that it is poorly soluble in water (2 g/L at 20ºC) and has a pKa of 2.97. As a result of its low solubility, formulators often must use organic solvents or harsh surfactants in order to suspend the SA in finished products. However, most of the organic solvents are not approved by the Personal Care Products Council (PCPC) and the use of surfactants, such as Polysorbate 80, can exacerbate irritation. As a result, SA should be incorporated in a skin-friendly medium that will deliver it via a water-based acne emulsion in an effective manner to eliminate irritation.
The issue of low pH has traditionally been addressed through addition of a base such as sodium hydroxide (NaOH) to bring the product to a pH that is more tolerable on the skin. The resulting reaction of the NaOH and SA, however, forms a salt (sodium salicylate) that is minimally effective in treating acne and significantly reduces the exfoliating effect of SA.9 Therefore, an encapsulation system for SA should not only provide a skin-friendly solution that will lower irritation, but should also isolate the acid from a final product formulation to a degree that the formulation maintains a pH of 4.5 to 5.5 without necessary additions of a base. Further, this system should not chemically alter the salicylic acid, but should deliver it to the skin in pure form in order to achieve the highest efficacy possible. A trio of possible encapsulation systems is discussed in detail below.
Liposomes: Phospholipids are widely used as delivery systems due to the fact that they are comprised of a special class of phosphate lipids (phosphatidylcholine (PC), sphingomyelin (SM) and other phospholipids10) that resemble the lipid layer surrounding cells that facilitate penetration. The lipid component of phospholipids is hydrophobic and non-polar, while the phosphate component is hydrophilic.
When mixed with hydrophobic and hydrophilic ingredients, liposomes will arrange in a micelle structure around these ingredients with the lipid ends of the micelle surrounding the hydrophobic ingredients and the phosphate ends surrounding the hydrophilic ingredients. They are currently available in the market for use with SA.
Encapsulation of SA in liposome systems has major drawbacks,11,12 including a limited shelf-life stability, formulation issues,13 and low loading of the SA. The shelf life stability of liposomes in a formulation depends on the interaction of the liposomes with the other base ingredients and the ability of the liposome lipid bi- or multi-layer structure to maintain its physical integrity in the product base. If this structural integrity is not maintained, agglomeration of the liposomes can occur resulting in a significant increase in particle size and formulation instability. In addition, liposomes have the inherent limitation in formulating where procedures as well as raw materials must be considered carefully in order to avoid adverse effects, such as shifts in pH, which could have detrimental effects on their stability.
Cyclodextrins: Cyclodextrins are obtained from the enzymatic degradation of starch. These molecules are composed of polysaccharides and possess an inner radius of 0.5-0.85 nm that can host cosmetic functional ingredients. The outer faces of this complex are hydrophilic, while the cavity is hydrophobic. The cavity is where a cosmetic active is surrounded, thereby protecting these actives from thermal, chemical, and mechanical degradation, retarding loss via evaporation and retaining poorly water-soluble actives. There is a commercial formula of SA that is solubilized in cyclodextrin complexes for anti-acne applications. The claims are enhancement of exfoliation and suitable for acne treatments.
While promising, both liposome and cyclodextrin technology do not fully address the issues presented herein relating to the balance between efficacy and skin-friendly attributes. Sufficient data does not exist on the effect of these delivery systems on skin pH nor on release kinetics and how these kinetics impact performance of the SA. Basically, the formulation comprising of the technology does not result in skin friendly pH upon topical application. The adhesion from a rinse-off is not guaranteed due to lack of suitable anchoring complexes. Slow gradual release is not validated and confirmed by published data. Thus, there is a need for an intelligently engineered delivery system that solves all of these issues.
Sub-micron Technology: A hydrophobic sub-micron technology employs a unique delivery system designed to encapsulate SA, and slowly release it over several hours from small vesicles called sub-micron spheres (Figure 1). These tiny (0.1 μm in diameter), hydrophobic (lipid matrix) spheres encase SA and suspend it in an aqueous medium via a hydrophilic outer shell that possesses a cationic charge. Once applied to skin, the charge moiety on the shell anchors the sphere for deposition while the hydrophobic matrix gradually dissolves into lipid architecture of skin, releasing the functional ingredient in a controlled manner over time.14,15
Figure 1. Structure of sub-micron spheres.
Use of Salicylic Acid for Acne Treatment 49 Overcoming Solubility and Compatibility Issues: The hydrophobic sub-micron technology encapsulates SA at loadings up to 30% without any phase separation or discoloration and maintenance of assay levels, particle size, pH, and color under accelerated aging conditions of three months at 42°C. As discussed earlier, the encapsulation causes no chemical alteration to the acid. Rather, the hydrophobic spheres enrobe the SA and suspend it in a water-based medium in shells that are composed of inert materials. The outer portion of these shells is treated with a cationic polymer that, in addition to contributing to better skin adhesion via electrostatic attraction, helps to suspend the shells in an aqueous medium via ionic interactions.
Therefore, the formulator does not need to utilize additional solvents or surfactants in order to suspend the acid in their products. The sub-micron technology is easily incorporated under either rotary mixing or homogenization, depending on the viscosity of the formula. Once diluted down to the active level of 0.5–2.0% in a final OTC (or 6% for Rx) anti-acne treatment, the sub-micron technology lends minimal opacity, which results in an additional benefit of being able to formulate largely translucent rinse-off products (Figure 2B). Because the SA is encased in a hydrophobic vehicle, it is largely isolated from the rest of the formula. As a result, formulations using this technology can be created at pH ranges of 4.5–5.5. This alleviates the formulator’s dilemma of having to limit their ingredient choices or having to use extra suspension or dissolution agents for the SA. Seeing a reduction of pH in a final product would indicate the release of free SA into the medium. When testing a commercial face wash product containing SA, acidic pH of 3.12-3.76 was observed, while the sub-micron technology in face wash, at the same level of SA as the commercial product, exhibited a pH of 5.7. Thus, the technology has the ability to maintain a skin-friendly pH in formulations.
Figure 2. Sub-micron technology as (A) raw material and (B) in a facial cleanser at 2% SA.
Reducing Skin Toxicity and Addressing Issues for Sensitive Skin: The second issue discussed, and not addressed by earlier delivery systems, is the low skin pH that is related to using a product loaded at effective levels of SA. As mentioned, an alkaline ingredient is commonly used to raise the pH of the formula that reduces the efficacy of the SA as it is neutralized. The sub-micron technology approaches skin-friendly pH in a different manner. The technology releases on skin through a gradual dissolution of the hydrophobic components of the sub-micron shell into lipid architecture of skin. This dissolution delivers the encased ingredients to the skin in a slow-release pattern, which allows the skin pH to re-balance itself and not decrease to a degree that might cause irritation to occur. Solving this sensitivity issue leads to a third benefit which is an extended efficacy in the activity of the SA.
The controlled release pattern ensures a continual dose of the acid, in a controlled manner, for an average of 6–8 hours. The technology maintains a constant advantage over free SA in terms of overall percentage that is retained on skin for this period.
There is always more SA present on the skin that aids in a more pronounced reduction of acne when compared to free. This advantage is discussed in more detail in a subsequent section of this chapter.
When testing skin-friendly pH on skin, two different body wash formulations were prepared: 1) 2% free SA and 2) 6.67% of technology which yields 2% salicylic acid.
Volunteers washed their forearms with cleansers containing either the technology or free SA. The pH was tested with a Hanna, HI99181 pH meter. The sub-micron technology has the distinct advantage of providing the functional ingredient in a formula at skin-friendly pH of 5.
Figure 3. Skin pH after treatment with sub-micron technology comprising of SA.
Use of Salicylic Acid for Acne Treatment 51 The results show a final skin pH that is ~ 5 upon using the technology, while the free displays a reduced pH which may lead to potential irritation (Figure 3).
Improving Performance and Compliance: It has been shown that sustaining the release of SA on the skin reduces percutaneous absorption and thus limits side effects. During most attempts to deliver free SA to the skin surface using a rinse-off application such as body wash over 99% of SA is lost, reducing deposition on skin.
Therefore, the primary goal in delivering SA is to stabilize the compound in an applicable complex, which can efficiently be deposited onto the skin, and specifically to the pimples or comedones. Traditional rinse-off products deposit a low amount of SA on skin.2 Therefore, sub-micron technology was developed to deposit SA and control its release rate on skin for a longer period of time.
Because
the technology delivers the SA to the skin gradually, the acid remains at an increased activity level over free SA (Figure 4).Clinical Deposition Test of SA (Rinse-off): The ability of the sub-micron technology comprised of SA to provide enhanced deposition of SA on skin was studied in vivo by skin extraction using an extraction apparatus (circular bulb 15.5 cm2 in area). A measured amount of the product, approximately 0.25 grams, was applied to the target area. The samples were left on the target site for one minute.
The applied area was rinsed with 100 mL of water and tapped dry with a paper towel.
A 3 mL disposable syringe was filled with 1.5 mL of ethanol, and the ethanol was placed into the skin extraction apparatus and carefully inverted over the application area, tightly holding the bulb in place and swiveled for 30 seconds. The ethanol Figure 4. Longevity of SA from sub-micron technology vs. free over a six- hour period.
fraction was collected into a labeled glass jar. The extraction step was repeated a total of three times per marked area on the test subject’s arm, as depicted in Figure 5..
Figure 6 shows the sub-micron technology resulted in threefold higher deposition of SA onto skin vs. free. In a separate study, all tested human volunteers (n = 12)
Figure 5. Skin Extractions for validation of controlled release of SA.
Figure 6. Enhanced deposition of SA after treatment with 2 % SA from free vs. sub-micron technology from a body wash.
Use of Salicylic Acid for Acne Treatment 53 reported the sub-micron technology in sulfate-free body wash as clear, smooth, gentle, non-itchy, non-irritating, and clean. Additionally, more than 70% of the volunteers displayed significant reduction in artificial sebum using the sub-micron technology formula in a facial cleanser vs. a commercial product (data not shown).
Formulations With Sa And Encapsulation Technologies
The following are practical ways in which to formulate with sub-micron technology comprised of SA for effective acne treatment. To begin, below is a lotion formulation wherein the pH of the final mixture is 3.51. Note that this pH is very acidic, and thus may lead to irritation on the skin.
Cyclodextrin Technology: A clear water-soluble spray comprised of moisturizing agents in addition to cyclodextrin enabled encapsulation of SA was made as shown below. The adjusted pH of the finished product was in the range of 3.8-4.2.
Formula of Free SA in Lotion
Phase INCI W/W %
A
Butyrospermum Parkii (Shea Butter) Fruit 16.5
Cetearyl Alcohol and Ceteth-20 Phosphate 8
Octadecyl Alcohol 2.8
Partially Hydrogenated Oil 6.8
1-Hexadecano 2
B
Water (aqua) 58.9
Glycerin 2
C Salicylic Acid 2
D Phenoxyethanol/ Ethylhexlglycerin 1
Total 100
Mixing instructions:
1. Combine Phase A ingredients and heat at 75°C until melted.
2. Combine and mix Phase B, then slowly add to Phase A ingredients. Continue heating and mixing.
3. Mix until homogenous.
4. Add Phase C ingredients to mixture after cooling to 40°C.
5. Add Phase D ingredients and mix until homogenous.
pH of final mixture=3.51
Hydrophobic Sub-micron Technology: A sub-micron technology that addresses multiple benefits over formulating with the functional ingredient alone bears out significant advancements.16 A few examples will follow. Hydrophobic sub-micron technology comprised of SA can be readily formulated into a body wash, facial cleanser, gel, alcohol-free toner, or body cream. The advantage of formulating with
technology include: the ability to process at low temperatures, stable emulsion appearance, a product performance superior to controls, and skin-friendly pH.
Foaming issues, especially during mixing, may occur, but can be resolved with a number of anti-foam agents available commercially, though incompatibility with anionic, carbomer-containing bases may be a disadvantage.
Formula of Cyclodextrin Encapsulated SA in Moisturizing Clear Gel**
Phase Raw Material/ INCI Name W/W %
A
Deionized Water 76.55
Phenoxyethanol, Methylparaben, Butylparaben,
Ethylparaben, Propylparaben 0.3
Glycereth-26 2.5
B Carageenan 0.5
C Hydroxypropyl Cyclodextrin (and) Salicylic Acid 12.5 D Glycerin, Urea, Saccharide Hydrolysate, Magnesium
Aspartate, Glycine, Alanine, Creatine 2
E Deionized Water 1
Imidazolidinyl Urea 0.25
F 1 % Soln. Water (aqua) (and) HA 4
G Sodium Chloride (25 % Soln.) 0.4
H Triethanolamine, 99 % q.s.*
* to adjust pH 100
Mixing instructions:
1. Heat Phase A to 75°C on overhead mixer at medium/high speed.
2. Slowly add Phase B to Phase A and mix until completely hydrated.
3. Cool combined Phase A and Phase B to 40°C and add Phase C at medium/low speed.
4. Add Phase D to vessel at medium/low speed and cool to 35°C.
5. Add premixed Phase E to vessel at medium/low speed and cool to 25°C.
6. At 25°C, add Phase F and Phase G to final mixture in order of addition at medium/low speed.
7. Adjust pH to 3.8-4.2 using Phase H.
pH of Final Mixture: 3.8-4.2
**Referenced in EW Flick, Cosmetic and Toiletry Formulations, Beauty Aids, 2001, 2 ed., Vol. 8, Section 6, Page 48.
Use of Salicylic Acid for Acne Treatment 55