Octisalate

Homosalate

Homosalate is one of the most commonly used UVB filters in sunscreens in the US market. It belongs to the salicylate class and has a peak absorption of 306 nm. It is approved by the FDA for a maximum concentration of 15%. Along with other salicylates such as octisalate, it is a weak absorber and is often used in combination with other organic absorbers.

Octocrylene

Octocrylene is another widely used UVB filter. This molecule has the unique role in stabilizing avobenzone, the only long-range organic UVA filter available in the United States. Without octocrylene, avobenzone is degraded by 50% upon 1 hour of UV exposure, rendering the sunscreen less effective. Octocrylene has a thick, oily texture, and a peak absorption at 303 nm (range 290–360 nm).

Padimate O

Q50.2 Para-aminobenzoic acid (PABA) was one of the first chemical sunscreens to be widely available. However, its use in modern-day sunscreens has been limited for several reasons. This UVB filter required an alcoholic vehicle, it stained clothing, and it was associated with a number of adverse reactions, including subjective stinging and allergic contact dermatitis. Ester derivatives, mainly padimate O (octyl dimethyl PABA), became more popular with greater compatibility in a variety of cosmetic vehicles and a lower potential for staining or other adverse reactions. Despite being a potent UVB absorber, problems with PABA formulations have limited their use. Padimate O is the most potent FDA-approved UVB absorber. The decline in PABA use along with the demand for higher-SPF products led to the incorporation of multiple active ingredients in a single product to achieve the desired SPF.

Octinoxate (Octyl Methoxycinnamate)

Q50.2 The cinnamates largely replaced PABA derivatives as the next most potent UVB absorbers. Octinoxate (octyl methoxycinnamate, OMC) is the most frequently used sunscreen ingredient. As shown in Fig. 50.2, which illustrates absorbance curves on a logarithmic scale, OMC is an order of magnitude less potent than padimate O.

Octisalate (Octyl Salicylate)

Octyl salicylate is used to augment the UVB protection in a sunscreen. Salicylates are weak UVB absorbers and are generally used in combination with other UV sunscreens. Other salicylates need to be used in higher concentrations.

Ensulizole (Phenylbenzimidazole Sulfonic Acid)

Most chemical sunscreen ingredients are oils soluble in the oil phase of emulsion systems, accounting in part for the heavy, greasy esthetic properties of many of these products. Phenylbenzimidazole sulfonic acid is water soluble and used in products formulated to feel lighter and less oily, such as daily-use cosmetic moisturizers.

Oral 17β-Oestradiol

17β-oestradiol is the most potent oestrogen produced naturally by the body. When administered exogenously, it has poor bioavailability and is subject to rapid metabolism. It therefore needs to be esterified or micronised to become bioavailable to any significant extent. Oestradiol valerate refers to the addition of valeric acid as an ester modification. Oestradiol hemihydrate refers to microcrystalline oestradiol that contains two oestradiol molecules for every one water molecule [1]. Oestradiol hemihydrate and oestradiol valerate are considered dose equivalent with comparable pharmacokinetics [2].

Circulatory levels of 17β-oestradiol remain elevated for a longer period of time compared to other sex steroids [1]. This is due to the unique metabolism of oral 17β-oestradiol; after ingestion it is rapidly and extensively metabolised in the liver and gut to estrone and inactive estrone conjugates. These metabolites then enter the circulation in high concentrations and serve as a hormonally inert reservoir from which 17β-oestradiol is continuously reproduced after reconversion [1].

There are advantages and disadvantages to the oral route of oestradiol administration. Its use is practical, convenient, rapidly reversible and avoids skin barriers and irritation. However, the extensive gut and first pass liver metabolism of 17β-oestradiol means that higher doses are needed to achieve therapeutic tissue levels compared to the parental route and consequently supraphysiological levels of 17β-oestradiol entering the hepatic circulation can stimulate liver proteins. When using oral 17β-oestradiol serological testing for 17β-oestradiol levels are unreliable because estrone is the major circulatory metabolite.

Oral conjugated equine estrogens (CEE)

Transdermal patches

17β-oestradiol is a small lipophilic molecule and this characteristic has facilitated the development of transdermal delivery systems [4–7]. The first transdermal delivery system developed was the reservoir patch. This patch contained an oestradiol reservoir, an alcohol containing membrane and a backing layer. The alcohol containing membrane determined the rate of delivery of 17β-oestradiol into the skin [4,8]. This patch type was limited by a high frequency of skin reactions thought to be due the alcohol solvent [4,9]. Although these were available in different dosages, these patches could not be cut to adjust dosing.

The matrix patch was subsequently developed containing a more advanced technology where 17β-oestradiol is dispersed directly into a monolayered adhesive matrix without the need for a rate controlling membrane [4]. These patches are associated with fewer skin reactions because they do not contain alcohol solvent [8]. For each formula of matrix patch, the release rate of 17β-oestradiol is proportional to the surface area and therefore cutting the matrix patch provides a way of predictably reducing the dose [10].

Patches deliver a dose between 25 μg and 100 μg per day. However, the actual delivery rate may be different and there has been a wide range of 17β-oestradiol serum levels measured in women treated with the same patch [1,11]. When using a reservoir patch, serum 17β-oestradiol levels peak at 30 h and decrease thereafter declining markedly on day 3 due to low alcohol levels in the reservoir [1,12,13]. For this reason, reservoir patches much be changed every 3.5 days. In contrast, when using a matrix patch, serum 17β-oestradiol levels peak at 12 h and the diffusion rate of 17β-oestradiol then remains relatively constant over the next 7 days. Matrix patches are therefore effective for 7 days despite manufacturers recommending a patch change twice weekly [1]. Within 24 h after removal of patches, oestradiol levels return to baseline [1].

Transdermal gels

The application of gel products that contain an alcoholic base to solvate the skin results in rapid penetration of 17β-oestradiol into the stratum corneum [1,9]. There are two gel preparations available [1]. One preparation is a pump dispensing pack whereby one metred dose (1.25 g) supplies 0.75 mg 17β-oestradiol. The daily application of this gel leads to peak 17β-oestradiol levels within 3–5 days and after discontinuation of treatment 17β-oestradiol levels return to pre-treatment levels by 6 days [1]. The other gel preparation is available as single dose sachets that delivers either 0.5 mg or 1 mg 17β-oestradiol respectively. Daily application of this gel leads to peak 17β-oestradiol levels within 6 h and thereafter declines slowly [14]. The two gel formulations are considered bioequivalent [15].

Transdermal spray

The transdermal spray technology incorporates 17β-oestradiol, octisalate and alcohol into a unique drug delivery system [9]. Upon application to the underside of the forearm, 17β-oestradiol and octisalate form a reservoir depot underneath the skin [9]. Octisalate facilitates the slow diffusion of 17β-oestradiol through the skin layers into the dermis and then releases oestradiol into the microcirculation at a steady rate over 24 h before it declines [17].

The oestradiol transdermal spray is packaged in a metered dose pump and requires a daily application [9]. Dosing of one, two or three sprays is selected by the user to control symptoms. When pressed against the skin the applicator device controls the distance, angle and area of application, reducing the risk of variability in application technique [9]. Each metered dose pump can deliver up to 56 sprays of precisely 90 mcL which contains 1.53 mg of 17β-oestradiol [9].

Subcutaneous implant

Standard implant preparations contain 25 mg or 50 mg of 17β-oestradiol pellets which are replaced every 6 months and titrated according to circulating oestradiol levels and symptom response. Implants are inserted into the subcutaneous tissue in the lower abdomen, lower back or buttocks and represent a depot that releases 17β-oestradiol at an even and slow rate [1]. An implant that contains 25 mg of 17β-oestradiol pellets causes an oestradiol level of 330 pmol/L on average for 6 months [1,18].

Active Sunscreen Ingredients

Sunscreens have been traditionally divided into chemical absorbers and physical blockers, based on their mechanism of action. Chemical sunscreens are generally aromatic compounds conjugated with a carbonyl group.⁴ These chemicals absorb high-intensity UV rays, producing excitation to a higher-energy state. With return to the ground state, the result is conversion of the absorbed energy into longer, lower-energy wavelengths (such as infrared radiation, hence heat). Physical blockers reflect or scatter UVR. Microsized forms of physical blockers, also designated as inorganic particulates, also function in part by absorption. There are 55 UV filters approved for sunscreen products globally, but only 16 approved in the United States.

The most commonly used active sunscreen ingredients are listed in Table 50.3 by their US Adopted Name (USAN). Allowable ingredients are listed in the FDA monograph, as are appropriate concentrations for the various UV filters discussed in this chapter. Sunscreen nomenclature can be quite confusing. They may also be referred to by their chemical International Cosmetic Ingredient (INCI) name or by their trade name. Representative sunscreen chemical structures are shown in Fig. 50.1.

Sunscreen ingredients can also be classified by which portion of the UV spectrum they effectively absorb, as well as their role in a particular formulation with a combination of ingredients. The absorption spectrum of the most commonly used sunscreens is shown in Fig. 50.2. The most important sunscreen ingredients are discussed individually.

Ultraviolet B Sunscreens

Ultraviolet A Sunscreens

In the United States, there are only three UVA filters widely available and commonly used in sunscreen formulations. In the organic filter category, oxybenzone provides both UVB and short-range UVA protection. Avobenzone provides long-range UVA protection. In the inorganic category, zinc oxide provides UVA protection. Furthermore, the level and spectrum of UVA coverage depends on the particle size.

Physical Blockers

Despite popular belief that physical blockers only scatter UV light, both titanium dioxide (TiO₂) and zinc oxide work by absorbing and scattering UV light. Poor cosmetic acceptance limited the widespread use of TiO₂ and zinc oxide until microsized (‘nano-sized’) forms became available in the early 1990s. Also known as inorganic particulate sunscreens, these metal oxides are reactive and poorly soluble without coating and chemical treatment. Current studies indicate that these nanoparticles do not show significant skin penetration.⁷

Sunscreens Pending Approval

More sunscreen ingredients are available in Europe than in the United States. Several may soon become available via the TEA (material time and material extent application) approval process (Table 50.4). Providing both UVB and UVA protection, these absorbers also contribute to the photostability of formulations.

3.1 Drospirenone

Drospirenone (DRSP) is an anti-mineralocorticoid progestin derived from spirolactone [8–10]. Its basic structure consists of a 19-carbon chemical structure with two methylene groups, one of which is attached to C-6 and C-7 and the other to C-15 and C-16. DRSP is rapidly absorbed after oral intake and reaches a peak plasma level after 1 to 2 h. Its bioavailability is about 76% [1].

Due to its anti-mineralocorticoid action, this progestin has the property of controlling the angiotensinogen increase related to the ethinyl estradiol (EE) action when both molecules are combined in a contraceptive tablet. By preventing the transactivation of MR, the combination of DRSP with EE results in water and sodium excretion and a slight decrease in body weight as compared with classic oral contraceptive (OC) combining EE and levonorgestrel [11]. In postmenopausal women with mild hypertension, the combination of DRSP with natural estradiol in hormone therapy has been shown to induce a decrease in blood pressure [12,13].

DRSP also exerts an antiandrogenic action, lower than that of cyproterone acetate (CPA) but sufficient to be useful in women with acne when combined with EE which induces a high increase in sex hormone-binding globulin (SHBG). Therefore, in addition to contraception, the combination has been found to be useful in the treatment of premenstrual dysphoric disorder as well as in moderate acne [14,15]. Favorable effects on blood pressure and body mass index have been observed [16,17]. No negative impact on future fertility has been found with prior use of DRSP-containing COCs [18].

3.2 Dienogest

Dienogest has a 19-nortestosterone structure but with a 17alpha-cyanomethyl instead of a 17 ethinyl group [1,2]. It is metabolized by means of hydroxylation and aromatization [19,20]. Its pharmacokinetics make it suitable for oral administration, since it has a high oral bioavailability (>90%) and is rapidly absorbed, the peak level (t_max) is reached after 2 h and the elimination half-life is around 10 h [1]. It does not bind to SHBG; thus free serum levels of DNG tend to remain high, while free testosterone levels remain low [21]. Its antiandrogenic activity has been found to be 40% that of CPA which is the most potent antiandrogenic progestin [8]. Due to its high antiestrogenic effect on the endometrial tissue, this progestin also has the potential to be used in hormone replacement therapy (HRT) and also in the treatment of endometriosis [22].

Dienogest is now combined with estradiol valerate (E2V) instead of EE as an OC with a potential for better safety due to the replacement of EE with a weaker estrogen that has much less hepatic effect on liver estrogen-dependent proteins. However, large safety surveillance studies are still to be completed to demonstrate this potential benefit. A study on the contraceptive efficacy of this OC has generated an unadjusted Pearl index of 0.73 and an acceptable bleeding profile comparable to a LNG/EE second-generation pill [23].

3.3 Trimegestone

Trimegestone is a 19-norprogesterone derivative with strong progestational effect. TMG also possesses weak anti-androgenic and a modest anti-mineralocorticoid activity [24,25]. With regard to the progestational activity in vivo, TMG has been found to be the most potent of all progestins in the endometrial transformation test in the rabbit and counters the uterotrophic effect of estradiol (E2) in the immature mouse bioassay [26,27]. Results from preclinical studies have also demonstrated the limited effect of TMG on the GABA-ergic (γ-aminobutyric acid) system explaining the lack of unwanted mood effects in users [28].

Although TMG is a potent progestin with a good antiovulatory action, it has not been developed as a contraceptive so far. Preclinical studies in the rat have demonstrated inhibition of ovulation and anti-estrogenic activity in the uterus [24]. The contraceptive potential of using TMG via a transdermal system has been explored, but so far no clinical trial has been published [29].

3.4 Nestorone

Nestorone (16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione) is a 19-norprogesterone derivative with a high progestational activity which may be attributed to the absence of the 19-methyl radical and the addition of the 16-methylene substitute, which promotes binding to and transactivation of the PR [5,30]. Other factors which contribute to its high specificity include its lack of binding to the AR [31,32] with no binding to SHBG [29]. NES binds to GR but does not exert glucocorticoid activity in in vivo assays at the doses required for its contraceptive efficacy [30]. NES is inactive orally but highly potent when administered parenterally [33,34].

NES has been shown to exert a high contraceptive activity when administered via different nonoral delivery routes, such as vaginal rings, implants and transdermal systems. As NES has the highest antiovulatory action among existing progestins, a very low dose could be used and delivered from non oral delivery systems.

A vaginal ring containing NES/EE releasing low doses of NES (150 mcg) and EE (15 mcg) is undergoing development as a contraceptive at the Population Council [35,36]. At present, the ring is in its final stages of development. Second-generation vaginal rings, which include a design delivering NES with E2, the natural estrogen, instead of EE, are in the early developmental stage.

The contraceptive potential of NES delivered via the transdermal route has also been studied. The first study testing NES transdermal gel found it to be effective in suppressing ovulation in a high percentage of women [37]. In a 3-month multicenter study carried out among 150 cycling women, NES gel was applied transdermally in three different doses of 0.3, 0.6 and 1.2 mg. The level of ovulation suppression reached 53%, 64% and 83% in the three dose groups, respectively [37,38]. Based on these promising results, higher doses of NES were combined with low doses of E2, and preliminary results indicate a high antiovulatory efficacy.

Similarly, the Metered Dose Transdermal System (MDTS), which is in the initial stages of development, is a fast drying liquid formulation used in a nonocclusive spray containing NES dosed via a precisely engineered system delivering the drug to the skin surface [39]. NES is combined with a safe skin penetration enhancer — octisalate, which forms a reservoir within the skin wherein the drug is slowly absorbed into the circulation over a duration of several hours. A pharmacokinetic trial of this new transdermal delivery system has demonstrated the feasibility of achieving serum levels of NES sufficient to block ovulation and hence provide effective contraception. A spray formulation incorporating both NES and an estrogen, either E2 or EE, is undergoing clinical trials.

NES has been tested in the form of a single implant releasing 100 mcg of NES per day administered to lactating women in a 2-year study [40]. No pregnancies were reported in 2195 women-months of exposure, and implant users demonstrated significantly less irregular bleeding compared to copper-T IUD users. This progestin also has the advantage of being safe for infants as NES is not active orally and is quickly destroyed in the gastrointestinal tract. Massai et al. [40] followed the growth of infants who were breastfed by mothers receiving an implant of NES and found no difference in infant growth and development as compared with those who were breastfed by mothers using the IUD.

3.5 Nomegestrol acetate

Nomegestrol acetate is a 19-norprogesterone derivative which is also characterized by the absence of a methyl group at the 19 position [41]. NOMAc is a potent antigonadotropic agent in women, exerts a high progestational action although lower than NES and TMG, and has also shown some antiandrogenic effect in animal models [42]. It does not exert any androgenic, estrogenic or glucocorticoid activities and has been shown to be neutral on carbohydrate and lipid metabolism [43].

NOMAc has been tested for its contraceptive action in the form of oral pills and subdermal implants. Clinical trials with Uniplant, a single silastic capsule containing NOMAc, has shown efficacy in preventing pregnancy [44,45]. Its mechanism of action has been attributed to a high antigonadotropic activity leading to blockade of ovulation and prevention of follicular growth, as well as changes in the cervical mucus, endometrial vascularization and endometrial architecture [45,46]. At an oral dose of 1.25 mg/day, NOMAc has been shown to suppress ovulation, while at higher doses of 2.5 or 5 mg/day, full suppression of both ovulation and follicular development is seen [47]. A new OC has been developed recently combining NOMAc and E2 showing a high contraceptive efficacy and good bleeding control [48]. As for the new combination of DNG and E2V, these new contraceptives have the potential for a better safety than EE-based OCs due to the substitution of EE with a natural estrogen with less impact on the synthesis of estrogen-dependent liver proteins. However, large safety surveillance studies are still to be done after the new E2-based combinations are available, hoping that preferential prescribing and biased results will be avoided.

PABA derivatives

Although PABA is an effective UV-B absorber, it is rarely used in sunscreens because of its potential to cause allergic contact dermatitis and photoallergic dermatitis.²⁷ It is also known to stain clothing. PABA derivatives, such as padimate O, are less effective than PABA at filtering UV radiation, but they are also less likely to cause hypersensitivity reactions or stain clothing.³¹

Cinnamates

As their name implies, cinnamates are derivatives of cinnamon. They are chemically related to balsam of Peru and cocoa leaves, and individuals who are sensitized to these items may cross-react to sunscreens that contain cinnamates.²² Because cinnamates are comprised of polar oils, sunscreens that contain cinnamates may leave a greasy sensation on the skin when applied.³² Octinoxate, a cinnamate, is currently the most commonly used UV-B filter in the United States.²⁷ A weak absorber of UV-B radiation, octinoxate is frequently combined with other UV filters in sunscreens to achieve adequate sun protection. Cinoxate is another cinnamate derivative that is rarely used in modern sunscreen formulations.

Salicylates

Salicylates are photostable agents with high substantivity; as a result, they are frequently incorporated into water-resistant products and combined with photolabile UV-A filters, such as avobenzone.^24,31 Octisalate, homosalate, and trolamine salicylate are commonly found in sunscreens. Trolamine salicylate is also often used in hair products as a UV filter.³³

Octocrylene

Octocrylene lacks substantivity, but it is frequently used with the UV-A filter, avobenzone, as a photostabilizer.³⁴

Ensulizole

As a water-soluble agent, ensulizole is commonly used as a component in cosmetic moisturizers.³¹

Protection from UV-B has historically been the focus of sunscreen development. However, as the role of UV-A radiation in photocarcinogenesis, photoimmunosuppression, and photoaging has been better understood, UV-A filters have increasingly been incorporated into commercial sunscreens. UV-A is classified as either UV-A-2 (320–340 nm) or UV-A-1 (340–400 nm) depending on wavelength, and these filters vary in their absorptive properties along the UV-A spectrum. The UV-A filter agents are summarized in Table 1.

Benzophenones

Oxybenzone, sulisobenzone, and dioxybenzone are UV-A filters that are commonly incorporated into sunscreens. Of these, oxybenzone is the most commonly used.³¹ Although these agents primarily offer protection in the UV-A-2 range, a second protective band is found in the UV-B range.²² Oxybenzone is the most common cause of contact photoallergy among sunscreens, however, and its use in sunscreens is limited by its allergic properties and by its photolability.³⁵

Avobenzone

Avobenzone is currently the only filter approved by the Food and Drug Administration (FDA) and has a peak absorbance in the UV-A-1 spectrum.²⁷ Although avobenzone has a broad absorbance spectrum, its use has historically been limited by its photolability. Today, avobenzone is frequently incorporated into sunscreens with more photostable agents, such as octocrylene, salicylates, and oxybenzone. The results of recent studies have suggested that combining avobenzone with octocrylene provides the most effective UV-A protection available in the United States.³⁶

Meradimate

Meradimate's absorption spectrum lies within the UV-A-2 range. Overall, it is a weak UV-A filter and is rarely used.²⁴

Ecamsule

Ecamsule is a recently approved sunscreen agent in the United States. Compared with other agents, ecamsule is a photostable and efficient UV-A filter.³⁷

Inorganic sunscreens, such as zinc oxide and titanium dioxide, provide protection in the UV-A and UV-B ranges, but overall they tend to be less efficient at filtering UV radiation than the newer organic agents.³¹ Inorganic sunscreens have historically tended to be cosmetically unappealing; they may leave a whitish discoloration on the skin, stain clothing, and be comedogenic.^25,31 Micronized formulations are now more commonly used; because particle size has decreased, these newer formulations are able to protect against shorter UV wavelengths.³⁷

The agents discussed previously differ in their UV protective wavelengths, and a combination of several filters is often required to achieve the desired level of protection. In addition, there are several broad-spectrum UV-A and UV-B filters available outside of the United States. Bisoctrizole (absorption peaks: 303 nm and 344 nm) and bemotrizinol (absorption peaks: 305 nm and 360 nm) are examples of 2 broad-spectrum agents available in Europe that are currently undergoing approval in the United States.³⁸