Increased compliance in the use of topical sunscreens is obtained by combining a topical sunscreen agent in a formulation containing an antibacterial medication such as azelaic acid or an antibiotic.

DESCRIPTION OF THE INVENTION

The present invention addresses a problem that has not been adequately addressed in the prior art and provides a solution to that problem that is distinct from the prior art. The present invention, in its several embodiments, provides a solution to the problem of how to increase compliance in the use of sunscreens, primarily in young people who typically receive a high proportion of their lifetime sun exposure before the age of 20 and who are notoriously non-compliant in the use of sunscreens, especially to the facial areas.

Although the prior art discloses compositions containing certain antibacterial compounds (erythromycin or sulfacetamide) in combination with a sunscreen, the sunscreens in these products are provided either to reduce phototoxic effects of an anti-acne medication or to reduce the sun-induced degradation of the medication. The sunscreens in these compositions were not directed to the problem of reducing facial sun exposure to the individual, except as mentioned to reduce harmful effects of the antibacterial compounds present in the composition. Accordingly, because the prior art is not concerned with the problem of protection from daily sun exposure in the adolescent and young adult populations, the prior art does not disclose sunscreens that are photostable to be combined with these antibacterial compounds.

In contrast, the present invention addresses the problem of lack of compliance in the use of sunscreens, which sunscreens are utilized to protect an individual from the harmful effects due to exposure to the sun. Therefore, certain embodiments utilize a photostable sunscreen agent, as described in more detail below.

The invention, in one embodiment, is a composition for the topical treatment of acne vulgaris. According to this embodiment of the invention, the composition contains one or more sunscreen agents, such as a photostable broad spectrum sunscreen agent, and one or more anti-acne vulgaris chemical agents selected from an antibiotic, like an antibiotic of the lincomycin family, such as lincomycin hydrochloride, lincomycin phosphate, clindamycin phosphate, and clindamycin hydrochloride, azelaic acid, and salicylic acid. Typically, the anti-acne vulgaris agent and the sunscreen agent are dissolved or suspended in a vehicle, such as water, alcohol, or propylene glycol. The composition of the invention is preferably used in single daily or multiple times daily application to the facial area. Preferably, application is once daily, preferably in the morning. The form of the drug product may be a gel, spray, foam, lotion or other dosage form that is cosmetically acceptable for use on the face and which is easily spreadable on the skin. It is preferred to apply the composition of the invention uniformly to all of the acne prone and sun exposed facial and neck areas to optimally treat acne and to reduce the incidence and severity of sunburn and chronic skin damage from solar radiation. The composition of the invention should be spread uniformly on the skin, such as by using the hands and fingers, to completely cover the intended areas of treatment. If the acne medication is used twice daily, the preferred times of application are morning and midday, that is during the hours of sunlight.

The invention is not intended to be used for "spot treatment" of individual acne lesions. Rather, the method of treatment of the invention involves application to broad areas of the face and neck.

In a preferred embodiment, the composition further contains an antioxidant. It has been unexpectedly discovered that combining an antioxidant in a composition containing an antibiotic of the lincomycin family such as clindamycin, and a sunscreen agent, such as a photostable broad spectrum sunscreen like zinc oxide, titanium oxide, or Tinosorb M provides a more stable composition with reduced degradation of the clindamycin during storage. A preferred antioxidant is sodium thiosulfate. Other suitable antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, ascorbic acid, ascorbyl palmitate, thiourea, acetylcysteine, dithiothreitol, cysteine hydrochloride, propyl gallate, and the tocopherols.

The invention, in another embodiment, is a method for topically treating acne vulgaris. Concomitantly, the skin is protected from exposure to the sun. According to this embodiment of the invention, a composition containing one or more sunscreen agents, such as a photostable broad spectrum sunscreen agent, and one or more anti-acne chemical agents, such as azelaic acid or salicylic acid, or an antibiotic like a member of the lincomycin family, such as lincomycin hydrochloride, lincomycin phosphate, clindamycin phosphate, and clindamycin hydrochloride, is applied to the skin of a subject suffering from or at risk of developing skin lesions due to acne vulgaris.

The invention, in another embodiment, is a method for increasing the compliance by individuals such as teenagers and young adults, that is individuals between the ages of 10 and 25, such as between the ages of 13 and 20, and especially those individuals less than 20 years old, in the application of sunscreen, especially to the skin of the face. Adolescents and young adults are often susceptible to, or are suffering from, acne vulgaris and are highly motivated to apply medication faithfully to treat or to combat this condition. By combining a sunscreen, such as a photostable broad spectrum sunscreen agent, in a formulation containing an anti-acne vulgaris medication, such as azelaic acid or salicylic acid, or an antibiotic like an antibiotic of the lincomycin family, such as lincomycin hydrochloride, lincomycin phosphate, clindamycin phosphate, and clindamycin hydrochloride, such individuals will be concomitantly applying a sunscreen, even though such individuals would be less likely do so if the sunscreen were not combined with the anti-acne medication.

As used herein, the term "sunblock" refers to physical sunscreening agents that block exposure of the skin to ultraviolet light. As used herein, the term "sunscreen" or "sunscreen agent" refers to either a physical sunscreen (a sunblocking agent) or a chemical sunscreen. Thus, the term "sunscreen" is broader than the term "sunblock" and encompasses the term "sunblock". As used herein, the term "sunscreen formulation" refers to a formulation that contains a sunscreen and additional components.

As used herein, the terms "photostable sunscreen agent" and "photostable sunscreen formulations" refer to a sunscreen agent or to a formulation containing a sunscreen agent which agent or formulation absorbs ultraviolet radiation at a level that is 50% or higher of the UV absorbance of the agent or formulation prior to irradiation following exposure of a 0.5 ml sample per square centimeter (cm.sup.2) in a quartz petri dish of a formulation containing a sunscreen agent to irradiation of 200 watt-h/m.sup.2 from a xenon lamp source that correlates to the full spectrum of outdoor sunlight as specified in the International Standard for Outdoor Daylight. D65. The photostable sunscreen formulation may contain a sunscreen agent which is stable as it exists within the formulation but which is unstable inherently. Thus, a formulation is considered to be a photostable sunscreen formulation if it contains a sunscreen that is inherently unstable but is photostable, as defined above, when combined with one or more components present in the formulation.

Sunscreen agents and sunscreen formulations that are suitable for the present invention are photostable as defined above. It is preferred, however, that the photostable sunscreen agents and photostable sunscreen formulations that are used in accordance with the invention be even more stable than that defined above. In a preferred embodiment, the sunscreen agent or sunscreen formulation absorbs ultraviolet radiation at a level that is 75% or higher following the exposure to the xenon lamp source. This level of photostability is referred to herein as "75% photostability." It is most preferred that the sunscreen agents or sunscreen formulations absorb ultraviolet radiation at a level that is 90% or higher following exposure to the xenon lamp source, referred to herein as "90% photostability."

As used herein, a "broad spectrum sunscreen agent" is a chemical compound that absorbs or blocks exposure of both UVB (280 to 320 nm) and UVA (320 to 400 nm). A chemical compound is a broad spectrum sunscreen agent as defined herein if can be formulated to produce an SPF (Sun Protection Factor) of 5 to 10, as determined in accordance with the Testing Procedure specified in 21 C.F.R. Sec. 352.70-352.77 (Subpart D--Testing Procedures), and has a UV-A/UV-B ratio at least 0.75, or if can be formulated to produce an SPF of >10 to 15 and has a UV-A/UV-B ratio at least 0.50, or if it can be formulated to produce an SPF of >15 to 25 and has a UV-A/UV-B ratio at least 0.33, or if it can be formulated to produce an SPF of >25 and has a UV-A/UV-B ratio at least 0.25. The UV-A/UV-B ratio is calculated as the ratio between the areas defined by the UV-A and UV-B extinction capacity, as shown in the following formula wherein A=absorbance and .lamda.=wavelength:

.intg..times..function..lamda..times..times.d.lamda..intg..times..times.d.- lamda..intg..times..times..lamda..times.d.lamda..intg..times..times.d.lamd- a. ##EQU00001##

As used herein, "a broad spectrum sunscreen formulation" is a formulation that absorbs or blocks exposure of both UVB and UVA radiation according to the definition above for a broad spectrum sunscreen agent. Such a formulation may contain one or more broad spectrum sunscreen agents or may contain a multiplicity of sunscreen agents that individually are not broad spectrum agents but, when combined in a formulation, provide a broad spectrum sunscreen function.

Examples of sunscreen agents that are broad spectrum photostable sunscreen agents include inorganic sunscreen agents such as titanium oxide and zinc oxide and tautomeric sunscreen agent compounds such as MEXORYL SX.RTM., MEXORYL XL.RTM., bisoctrizole, and anisotriazine.

As a way to improve the sunscreen usage of teenagers and young adults, this invention embodies a sunscreen, such as a photostable broad spectrum sunscreen, as a second active component along with a topical acne medication. Adolescents and young adults are very commonly afflicted with acne vulgaris and are generally motivated to use preventative topical medications to control acne and maintain their appearance in a positive way. Acne afflicts the face and neck areas primarily and these areas are also the skin areas with the greatest degree of chronic sun exposure.

Additionally patients being treated for acne are at additional risks from sun exposure due to the detrimental effect of sun exposure in combination with commonly used acne medications, both topical and oral. Thus, this invention piggybacks the use of a sunscreen, which is not perceived by teenagers and young adults to be important, on the use of a topical acne medication, which is perceived to be important. Any sunscreen or sun block combined with an antibacterial medication embodies this invention in its broad conception.

In accordance with a preferred embodiment of the invention, the sunscreen is a broad spectrum sunscreen agent or combination of agents. The broad spectrum sunscreen may an inorganic sunscreen agent, such as one or more of zinc oxide (ZnO), titanium oxide (TiO.sub.2), or ferric oxide (Fe.sub.2O.sub.3), which may be in a micronized form. These sunscreen are effective against exposure to UVA (ultraviolet-A) and UVB (ultraviolet-B) light. Alternatively, the sunscreen may be an organic sunscreening agent. An example of an organic sunscreen that is suitable for the invention is a benzotriazole sunscreen, such as methylene bis-benzotriazolyl tetramethylbutyl phenol (MBBT), marketed under the trade name TINOSORB.RTM. M (Ciba Specialty Chemicals, Inc., Basel, Switzerland). Other suitable but less preferred organic sunscreening agents include para-aminobenzoic acid (PABA) and derivatives, anthranilates, benzophenones, cinnamates including octylmethoxycinnamate, and salicylates. Other preferred organic sunscreen agents are a camphor derivative such as terephthalylidene dicamphor sulfonic acid, marketed under the trade name MEXORYL.RTM. SX (L'Oreal USA, New York N.Y.), and ibenzoylmethanes such as butyl methoxydibenzoylmethane (PARSOL.RTM. 1789, AVOBENZONE.RTM., Givaudon-Roure Corporation, Totowa, N.J.). A less preferred organic broad spectrum sunscreen agent is oxybenzone, also known as benzophenone, because of recent findings that oxybenzone is associated with a high incidence of skin irritation and is absorbed through the skin into the systemic circulation. The choice and concentration of sunscreens should be made in such a way to achieve a sun protection factor (SPF) of at least about 5, preferably at least about 10, and most preferably about 15 or more.

It is also preferred that the sunscreen agent or that the formulation of the invention containing a sunscreen agent be non-comedogenic. A sunscreen agent or formulation may be determined to be non-comedogenic by the following test.

The comedogenicity test is conducted using semi-occlusive patches on the backs of 20 human volunteers. Subjects exhibiting follicular hyperkeratosis (microcomedones) with a grade 0.5 to 1.0 are suitable for inclusion in the study. Microcomedones are graded on a scale of 0 to 3 with 0=none, 0.5=slight (tiny horny masses), 1=mild (small horny masses involving at least half of the follicles), 2=moderate (moderately sized horny masses over most of the field) and 3=severe (large globoid microcomedones over the entire field) based on follicular biopsy samples from the test area of the back. (Mills, Ohio, The follicular biopsy. In Serup J, Jemec GBE (eds) Handbook of Non-Invasive Methods and the Skin. CRC Press, Baca Raton, La. (1995)). Follicular biopsies are conducted at baseline (up to 45 days prior to study start) and at study end. If a subject has an irritation score of more than 1 at study end, a rest period is given until the initiation score is 1 or less, at which time the final follicular biopsy is performed.

Semi-occlusive patches with 0.1 ml of test product are applied 3 times per week and left in place for 48-72 hours before reapplication to the same site for a 4 week period. Assessments of irritation are made on a 6-point scale with 0=no sign of irritation, 0.5=barely perceptible redness, 1=slight redness, 2=noticeable erythema with slight infiltration, 3=erythema with marked edema, or 4=erythema with edema and blistering. A negative control which is a non-occlusive patch without any test material is applied. The average microdomedone scores for the negative control and the test material are calculated separately by dividing the total of the score by the number of test subjects. A test material is judged to be non-comedogenic if the average score is not more than 0.5 units higher than the negative control.

The acne medication that is useful in the present invention is azelaic acid or salicylic acid, or an antibiotic. The acne medication of the present invention is preferably one that is photostable and that does not increase sensitivity of the skin to sun exposure. As used herein, the terms "photostable" in reference to the acne medication means that the acne medication retains at least 75% of its activity following exposure of the medication in a 0.5 ml sample per square centimeter (cm.sup.2) in a quartz petri dish of a formulation containing the acne medication agent to irradiation of 200 watt-hi/m.sup.2 from a xenon lamp source that correlates to the full spectrum of outdoor sunlight as specified in the International Standard for Outdoor Daylight. D65.

Preferred antibiotics include macrolide antibiotic including erythromycin, azithromycin, clarithromycin, tilmicosin, and tylosin, and lincomycin-type antibiotics such as clindamycyin hydrochloride, clindamycin phosphate, lincomycin phosphate, or lincomycin hydrochloride. Additional topical anti-acne active ingredients may be contained in the composition of the invention if desired in combination with the salicylic acid, azelaic acid, or antibacterial compound. Such additional topical anti-acne active ingredients include but are not limited to one or more additional antibiotics, salicylic acid, azelaic acid, niacinamide, urea peroxide, and retinoids such as tretinoin, adapalene and tazarotene.

Preferably, the topical acne medication is photostable and does not increase the incidence of adverse reactions to sun exposure, such as occurs commonly with sulfonamides and tetracycline. In topical compositions containing such medications, such as ROSAC.RTM. Cream (Stiefel Laboratories, Inc., Coral Gables, Fla.), a sunscreen is included to prevent the deleterious effects of the sun's radiation in combination with a sulfonamide. This is in contrast to the present invention in which a sunscreen is utilized for its effect in preventing damage to an individual caused by exposure to the sun and in which the anti-acne medication in the composition is not degraded by the sun and does not induce adverse effects to an individual when exposed to the sun. Therefore, medications that degrade due to sun exposure or that result in injury to an individual upon exposure to the sun, such as sulfonamides and tetracycline, are expressly excluded from the scope of the present invention.

Additionally, certain skin care compounds, such as benzoyl peroxide, are reactive and degrade due to exposure to sun. For that reason, these compounds may be combined in a composition with a sun filter. See Bouillon, et al, U.S. Pat. No. 4,671,956. Compositions containing benzoyl peroxide are expressly excluded from the scope of the present invention.

The amount and concentration of sunscreen in the composition will vary depending on the particular sunscreen present but is an amount and concentration which is effective to protect an individual from the UV radiation. Similarly, the amount and concentration of the anti-acne medication will vary depending on the particular anti-acne medication in the composition but is an amount that is effective to treat, prevent, or reduce the symptoms of acne vulgaris.

For an optimally effective sunscreen formulation, two or more active sunscreen ingredients may be combined in a composition in order to attain both the breadth of sunscreen protection (UVB and UVA) as well as to achieve sufficient SPF. There are a great many sunscreen ingredients listed in the FDA's OTC monograph of approved sunscreen active ingredients in addition to the sunscreens that are described herein. However, as described above, it is preferred that the composition of the invention contain a broad spectrum sunscreen effective against both UVA and UVB. It is further preferred that the sunscreen is photostable.

Further, there are a multitude of anti-acne ingredients that may be used in the topical treatment and prevention of acne. The anti-acne ingredients, such as salicylic acid, azelaic acid or an antibiotic, may be used singly in the formulation of the invention or in combination with one or more other anti-acne ingredients, such as those listed above. One important factor in utilizing the compositions and methods of the present invention is the selection of anti-acne ingredients and sunscreen ingredients that are compatible with and that are stable within the selected vehicle. There can be physical and chemical incompatibilities wherein one active ingredient adversely affects another or the vehicle. The present invention involves stable formulations in which each active ingredient is compatible within the formulation. This means that the formulation is physically and chemically stable, that is the physical properties of viscosity, odor, and color of the formulation remain substantially unchanged upon storage for a period of 12 months at 25.degree. C. and there is no more than a 10% loss of any active ingredient (sunscreen agent or anti-acne medication) when the formulation is stored for this period of time at this temperature. Making such formulations is described herein, and methods for the manufacture and testing of such formulations for stability are known to those skilled in the art.

Many anti-acne medications and many sunscreens are capable of causing skin irritation. Therefore, if a potentially irritating anti-acne medication is included in the composition of the invention, it is preferred that a non-irritating sunscreen or one with a low irritation potential, such as titanium dioxide, be included. Likewise, if a potentially irritating sunscreen is included in the composition, it is preferred that the anti-acne medication in the composition not be irritating or be only mildly irritating.

An additional benefit of the invention to persons suffering from acne is sun protection, and avoidance of exacerbating the condition when using a product based on this invention. As a result of using the combined product, patients exposed to the sun may be effectively treated by the anti-acne component and be protected from sun exposure.

As previously stated, individuals in the typical acne age group is generally not motivated to use sunscreen products, yet are highly motivated to use products to prevent, treat, and manage their acne. Acne patients under the care of physicians are most commonly given multiple medications as part of their over all treatment regimen. Often, patient compliance is a problem in managing such patients because the young patients do not consider protection from the sun to be of great importance even though they typically place great importance on treating their acne. According to the invention, the sunscreen is combined in the same formulation as the anti-acne medication. This results in an increased compliance for the use of sunscreen products because the patients are motivated to use the anti-acne medication which is in combination with the sunscreen.

The formulation is preferably a semi-solid dosage form, but it may be a liquid including a spray, also. Among the most preferred semi-solid dosage forms, gels are the most preferred, followed by foams, lotions, and creams. Foams, lotions, and creams preferably have a low ratio of oil phase, if present, to water phase. Cosmetic elegance and spreadability of the vehicle are important aspects of this invention in order to obtain patient compliance and uniform and complete application of the sunscreen component to the skin.

By increasing the routine use of sunscreens by adolescents and young adults, multiple health benefits are obtained, including: An effective method of having adolescents regularly use sunscreens on exposed facial areas, Reduced long-term risk of skin cancer, Minimization of the visible signs of skin aging, Preventing the photo-exacerbation of acne that occurs with sun-exposed acne patients, thus obtaining improved efficacy with the anti-acne component of the combination, and Establishing the habit in these young people of protecting the skin from daily sun exposure and of being responsible for the maintenance of healthy skin.
 

Claim 1 of 42 Claims

1. A photostable, chemically stable, and physically stable formulation for topical application to the skin for treating acne vulgaris and protecting skin from harmful effects of chronic exposure to the sun comprising a vehicle, one or more sunscreen agents dissolved or suspended in the vehicle, which sunscreen agent is selected from the group consisting of titanium dioxide, zinc oxide, bisoctrizole, anisotriazine, para-aminobenzoic acid (PABA) and derivatives, anthranilates, benzophenones, cinnamates, salicylates, camphor derivatives, benzene 1,4-di(3-methylidene-10-camphosulfonic) acid, drometriazole trisiloxane, and dibenzoylmethanes, and an antibiotic medication of the macrolide or lincomycin family that is effective in treating or reducing the signs of acne vulgaris, which antibiotic medication is dissolved or suspended in the vehicle.

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