iDilii0imiioimiii milouiiolioliiioirimrisiimiimiiii
`
`(12) United States Patent
`Angel et al.
`
`(1o) Patent No.:
`(45) Date of Patent:
`
`US 7,326,408 B2
`*Feb. 5, 2008
`
`(54) TOPICAL ACNE VULGARIS MEDICATION
`WITH A SUNSCREEN
`
`(75)
`
`Inventors: Arturo Angel, Santa Rosa, CA (US);
`David W. Osborne, Santa Rosa, CA
`(US); Gordon J. Dow, Santa Rosa, CA
`(US)
`
`(73) Assignee: Dow Pharmaceutical Sciences,
`Petaluma, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 11/823,385
`
`(22)
`
`Filed:
`
`Jun. 27, 2007
`
`(65)
`
`Prior Publication Data
`US 2007/0258919 Al
`Nov. 8, 2007
`
`Related U.S. Application Data
`(62) Division of application No. 11/393,981, filed on Mar.
`29, 2006, now Pat. No. 7,252,816.
`
`(51)
`
`Int. Cl.
`A61Q 17/04
`A61Q 17/00
`A61Q 19/04
`A61Q 19/00
`A61K 8/02
`(52) U.S. Cl.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`424/59; 424/60; 424/400;
`424/401
`(58) Field of Classification Search
`424/59,
`424/60, 400, 401; 514/859
`See application file for complete search history.
`
`5,017,366 A
`5/1991 Stiefel
`5,674,912 A
`10/1997 Martin
`5,679,374 A * 10/1997 Fanchon et al.
`6,153,176 A * 11/2000 Kaleta et al.
`6,217,852 B1
`4/2001 Gildenberg
`3/2002 Bonda
`6,355,261 B1
`8/2007 Angel et al.
`7,252,816 B1 *
`2005/0025727 Al
`2/2005 Lott
`2005/0089485 Al
`4/2005 Stiefel
`2005/0169948 Al
`8/2005 Bernstein
`
`OTHER PUBLICATIONS
`
`424/450
`424/60
`
`424/59
`
`Brisaert M, Investigation on the Photostability of a Tretinoin Lotion
`and Stabilization with Additives, Int. J. Pharm, 199(1):49 -57 (2000)
`(Abstract only).
`Cullen SI, Tretinoin- sunscreen Mixture in the Treatment of Acne
`Vulgaris, Cutis, 41(4):289 -291 (1988) (Abstract only).
`Cunliffe WJ, A Double -blind Investigation of the Potential Systemic
`Absorption of Isotretinoin, when Combined with ... , Acta Derm
`Venereol, 81(1):14 -17 (2001) (Abstract only).
`Eide B, Skin Cancer Awareness and Sun Protection Behaviors in
`College Students, J. Am. Acad. Dermatol., Abstract P1321 (Mar.
`2005).
`Kullawanijaya P, Photoprotection, J. Am. Acad. Dermatol., 52:937-
`958 (2005).
`Papageorgiou PP, Chloroxylenol and zinc oxide containing cream
`(Nels cream) vs. 5% benzoyl peroxide cream in ... , Clin. Exp.
`Dermatol., 25(1):16 -20 (2000) (Abstract only).
`Stiefel Laboratories, Inc., Rosac Cream with Sunscreens, Product
`Information (2004).
`Sirius Laboratories, Inc., Nicomide and Nicomide -T, Product Infor-
`mation (2003).
`Tan, JKL, A new formulation containing sunscreen (SPF -15) and
`1% Metronidazole (Rosalol Cream) in the treatment of Rosacea,
`Skin Therapy Letter, 6(8):1- 2(2001).
`Tan JK, Randomized placebo -controlled trial of metronidazole 1%
`cream with sunscreen SPF 15 in treatment of rosacea, J. Cutan.
`Med., Surg., 6(6):529 -534 (2002) (Abstract only).
`
`* cited by examiner
`Primary Examiner- Shelley A. Dodson
`(74) Attorney, Agent, or Firm -Howard Eisenberg, Esq.
`
`(57)
`
`ABSTRACT
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,969,516 A *
`4,505,896 A
`4,671,956 A
`4,959,213 A
`
`7/1976 Stoughton
`3/1985 Bernstein
`6/1987 Bouillon
`9/1990 Brod
`
`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.
`
`514/24
`
`21 Claims, No Drawings
`
`AMN 1042
`Amneal v. Almirall, LLC
`IPR2019-00207
`
`

`

`4
`
`US 7,326,408 B2
`
`1
`TOPICAL ACNE VULGARIS MEDICATION
`WITH A SUNSCREEN
`
`This application is a divisional application of pending
`U.S. patent application Ser. No. 11/393,981, filed on Mar.
`29, 2006 now U.S. Pat. No. 7,252,816.
`
`5
`
`FIELD OF THE INVENTION
`
`The invention pertains to the field of topically applied
`medications used to treat acne vulgaris.
`
`io
`
`BACKGROUND OF THE INVENTION
`
`15
`
`20
`
`It is well established that both acute and chronic sun
`exposure has general detrimental effects to the skin over
`time. Intervention with the use of sunscreens and sunblocks
`at a young age is advocated by dermatologists around the
`world. However compliance is minimal. Avoidance of sun
`exposure early in life is thought to be particularly important
`because the carcinogenic effects of the sun are cumulative
`and are manifested years after the exposure. For children,
`compliance is dependent primarily on the diligence of the
`parents. During the teenage years responsibility shifts to the
`individual, yet teenagers are notoriously noncompliant with
`the use of sunscreens. In fact the "sun exposed appearance"
`is regarded as desirable among teenagers generally. Sun-
`screen use for outdoor activities by adolescents and young
`adults is highly important for healthy skin, i.e., to minimize
`the risk of developing skin cancers and to reduce the
`premature signs of skin aging over time. Therefore, the
`public health need is great to improve and to facilitate the
`regular use of sunscreens among adolescents and young
`adults. It is particularly important to protect the facial area
`which receives intense and repeated sun exposure.
`Recent studies published by the American Academy of
`Dermatology highlight the lack of compliance of young
`adults and teenagers in the use of sunscreens. In a study
`entitled "New American Academy of Dermatology Survey 40
`Finds People Aware of the Dangers of the Sun, But Sun
`Protection Not Necessarily Practiced," Am. Acad. Dermatol.
`(Apr. 29, 2003), it was reported that, although 79% of
`surveyed parents and grandparents apply sunscreen to chil-
`dren when they play outdoors, this number drops to only 45
`34% for independent young people under the age of 25. In
`another study entitled, "New Study Finds High School
`Students Get Enough UV Exposure on an Average Day to
`Cause Sunburn ", Am. Acad. Dermatol. (Apr. 24, 2002), it
`was reported that, when high school students between the 50
`ages of 12 and 17 were provided with Ultraviolet B dosim-
`eters to wear on their wrists, UVB exposure that occurred
`during regular daily activities was sufficient to cause sun-
`burn in some students. Moreover, even though UVB expo-
`sure was less on cloudy days, the amount of UVB exposure 5s
`on these days was higher than expected and 80% of the sun's
`UV rays pass through the clouds. The study also estimated
`that almost 80% of a person's lifetime sun exposure occurs
`before the age of 18 Therefore, reducing the exposure of
`teenagers to harmful rays of the sun is extremely important.
`In another study entitled "Skin Cancer Awareness and Sun
`Protection Behaviors in College Students ", J. Acad. Derma -
`tol., Abstract P1321, page P107 (March 2005), it was
`reported that the majority of college students do not use
`sunscreen on a regular basis. In fact, fully 81% of college 65
`students surveyed reported that they never, rarely, or only
`sometimes use sunscreen.
`
`25
`
`30
`
`35
`
`60
`
`2
`In a recent article, Kullavanijaya, P, and Lim, HW, J. Am.
`Acad. Dermatol., 52:937 -958 (June 2005), incorporated
`herein by reference, review the various types of ultraviolet
`radiation, the harms that these rays can cause upon exposure
`to skin, and various types of sun protective agents that are
`applied to protect the skin. As disclosed by Kullavanijaya
`and Lim, most presently available sunscreen agents are
`effective primarily in blocking UVB rays and are photo -
`labile, that is they are degraded upon exposure to ultraviolet
`radiation. Many of the available sunscreens also induce
`adverse effects such as irritation, allergic contact reactions,
`photoallergy, and phototoxic effects.
`Newer sunscreen agents such as benzene 1,4 -di(3 -meth-
`(MEXORYL
`acid
`ylidene-l0- camphosulfonic
`SX ®,
`L'Oreal, Clichy, France) (described in U.S. Pat. No. 4,585,
`597, incorporated herein by reference), drometriazole trisi-
`loxane (MEXORYL XL ®, L'Oreal, Clichy, France) (de-
`scribed in U.S. Pat. No. 4,585,597), methylene -bis-
`(bisoctrizole,
`tetramethylbutylphenol
`benzotriazoyl
`TINOSORB M ®, Ciba Specialty Chemicals, Basel, Swit-
`zerland) (described in U.S. Pat. Nos. 5,869,030; 5,980,872;
`and 6,521,217, each of which is incorporated herein by
`reference), and bis- ethylhexyloxyphenol methoxyphenol tri-
`azine (anisotriazine, TINOSORB S ®, Ciba Specialty
`Chemicals) (described in U.S. Pat. Nos. 5,869,030; 5,980,
`872; and 6,521,217), as well as the inorganic sunscreen
`agents titanium oxide (TiO2) and zinc oxide (ZnO) are
`reported by Kullavanijaya and Lim to not share these
`disadvantages. These agents are broad spectrum UV absorb-
`ers, are photostable, and have not been found to cause the
`adverse effects associated with other sunscreen agents.
`Acne vulgaris, often referred to as "acne ", is a condition
`that is distinct from and is not related to acne rosacea. Acne
`vulgaris is a disorder of the pilosebaceous follicle. Common
`features of acne vulgaris include increased sebum produc-
`tion, follicular keratinization, colonization by Propionibac-
`teriunz acnes, and localized inflammation.
`Treatment for acne vulgaris is typically with one or more
`of a retinoid, such as tretinoin or isotretinoin, an antibiotic,
`such as clindamycin or erythromycin, or other medication
`such as azelaic acid, a sulfonamide, and antibacterials such
`as benzoyl peroxide. Retinoid compounds increase the sen-
`sitivity of skin to the sun and are often inactivated by
`ultraviolet light. Therefore, retinoid products are recom-
`mended to be used at night or together with a sunscreen.
`Sulfonamides likewise increase the sensitivity of skin to the
`sun and, therefore, may be combined with a sunscreen.
`Benzoyl peroxide is highly reactive and degrades upon
`exposure to the sun. Therefore, benzoyl peroxide may be
`combined with a physical sunscreen to inhibit this sun -
`induced degradation. Such problems have not been associ-
`ated with the use of antibiotics, such as those of the
`lincomycin family, or with azelaic acid or salicylic acid.
`Acne rosacea, often referred to simply as rosacea, is a
`separate distinct dermatological disorder, which is a chronic
`inflammatory skin disorder characterized by enhanced epi-
`dermal proliferation leading to erythema, typically with
`flushing, scaling, and thickening of the skin. Rosacea is
`often exacerbated by exposure to the sun. Therefore, treat-
`ment of rosacea often includes the use of sunscreens. In
`contrast to rosacea, acne vulgaris primarily affects young
`people, during the teenage years and sunscreens have no
`known beneficial role in treating acne vulgaris. In fact many
`sunscreens have been reported to be comedogenic, that is
`they have the potential to induce comedones which are the
`primary lesions of acne vulgaris.
`
`

`

`US 7,326,408 B2
`
`3
`The present invention is directed to methods of treating
`and preventing or inhibiting recurrences of acne vulgaris and
`addresses the significant need for increasing the compliance
`in the application of topical sunscreens in individuals suf-
`fering from or at risk of developing acne vulgaris, primarily s
`teenagers and other adolescents and young adults. In this
`way, chronic effects of overexposure to harmful rays of the
`sun, such as skin cancers, can be greatly reduced.
`
`DESCRIPTION OF THE INVENTION
`
`lo
`
`25
`
`20
`
`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 15
`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 sulfaceta-
`mide) 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 30
`compounds present
`composition. Accordingly,
`in the
`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 3s
`antibacterial compounds.
`In contrast, the present invention addresses the problem of
`lack of compliance in the use of sunscreens, which sun-
`screens are utilized to protect an individual from the harmful
`effects due to exposure to the sun. Therefore, certain 40
`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 45
`or more sunscreen agents, such as a photostable broad
`spectrum sunscreen agent, and one or more anti -acne vul-
`garis chemical agents selected from an antibiotic, like an
`antibiotic of the lincomycin family, such as lincomycin
`hydrochloride, lincomycin phosphate, clindamycin phos- so
`phate, 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 ss
`times daily application to the facial area. Preferably, appli-
`cation 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 60
`preferred to apply the composition of the invention uni-
`formly to all of the acne prone and sun exposed facial and
`neck areas to optimally treat acne and to reduce the inci-
`dence and severity of sunburn and chronic skin damage from
`solar radiation. The composition of the invention should be 65
`spread uniformly on the skin, such as by using the hands and
`fingers, to completely cover the intended areas of treatment.
`
`4
`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 treat-
`ment" 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 con-
`tains 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 degrada-
`tion of the clindamycin during storage. A preferred antioxi-
`dant is sodium thiosulfate. Other suitable antioxidants
`butylated
`include
`hydroxyanisole
`butylated
`(BHA),
`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 chemi-
`cal agents, such as azelaic acid or salicylic acid, or an
`antibiotic like a member of the lincomycin family, such as
`lincomycin hydrochloride, lincomycin phosphate, clinda-
`mycin 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 con-
`dition. 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, lin-
`comycin phosphate, clindamycin phosphate, and clindamy-
`cin 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 encom-
`passes the term "sunblock ". As used herein, the term "sun-
`screen 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 sun-
`screen agent or to a formulation containing a sunscreen
`agent which agent or formulation absorbs ultraviolet radia-
`tion at a level that is 50% or higher of the W absorbance
`of the agent or formulation prior to irradiation following
`exposure of a 0.5 ml sample per square centimeter (cm2) in
`
`

`

`US 7,326,408 B2
`
`5
`a quartz petri dish of a formulation containing a sunscreen
`agent to irradiation of 200 watt-h/m2 from a xenon lamp
`source that correlates to the full spectrum of outdoor sun-
`light 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 com-
`bined with one or more components present in the formu-
`lation.
`Sunscreen agents and sunscreen formulations that are
`suitable for the present invention are photostable as defined
`above. It is preferred, however, that the photostable sun-
`screen 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 ultra-
`violet radiation at a level that is 75% or higher following the
`exposure to the xenon lamp source. This level of photosta-
`bility is referred to herein as "75% photostability." It is most
`preferred that the sunscreen agents or sunscreen formula-
`tions 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 Protec-
`tion 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 k= wavelength:
`
`A(À)dA/
`
`A
`
`I:0
`
`00
`
`320
`
`dl
`
`dA
`
`As used herein, "a broad spectrum sunscreen formula-
`tion" 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 formu-
`lation 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 com-
`bined 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 ®,
`MEXORYL XL *, 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
`
`6
`component along with a topical acne medication. Adoles-
`cents and young adults are very commonly afflicted with
`acne vulgaris and are generally motivated to use preventa-
`tive topical medications to control acne and maintain their
`5 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 addi-
`tional risks from sun exposure due to the detrimental effect
`to 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.
`15 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 inven-
`tion, the sunscreen is a broad spectrum sunscreen agent or
`combination of agents. The broad spectrum sunscreen may
`20 an inorganic sunscreen agent, such as one or more of zinc
`oxide (ZnO), titanium oxide (Ti02), or ferric oxide (Fe2O3),
`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
`25 organic sunscreening agent. An example of an organic
`sunscreen that is suitable for the invention is a benzotriazole
`sunscreen, such as methylene bis- benzotriazolyl tetrameth-
`ylbutyl phenol (MBBT), marketed under the trade name
`TINOSORB® M (Ciba Specialty Chemicals, Inc., Basel,
`30 Switzerland). Other suitable but less preferred organic sun -
`screening agents include para- aminobenzoic acid (PABA)
`and derivatives, anthranilates, benzophenones, cinnamates
`including octylmethoxycinnamate, and salicylates. Other
`preferred organic sunscreen agents are a camphor derivative
`35 such as terephthalylidene dicamphor sulfonic acid, marketed
`under the trade name MEXORYL® SX (L'Oreal USA, New
`York N.Y.), and ibenzoylmethanes such as butyl methoxy-
`dibenzoylmethane (PARSOL® 1789, AVOBENZONE ®,
`Givaudon -Roure Corporation, Totowa, N.J.). A less pre -
`40 ferred organic broad spectrum sunscreen agent is oxyben-
`zone, also known as benzophenone, because of recent find-
`ings 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 sun -
`45 screens 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
`50 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- occlu-
`sive patches on the backs of 20 human volunteers. Subjects
`exhibiting follicular hyperkeratosis (microcomedones) with
`55 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), 2mod-
`erate (moderately sized horny masses over most of the field)
`to 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
`65 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
`
`

`

`US 7,326,408 B2
`
`7
`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 infiltra-
`tion, 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 medi-
`cation retains at least 75% of its activity following exposure
`of the medication in a 0.5 ml sample per square centimeter
`(cm') in a quartz petri dish of a formulation containing the
`acne medication agent to irradiation of 200 watt-h/m2 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 includ-
`ing erythromycin, azithromycin, clarithromycin, tilmicosin,
`and tylosin, and lincomycin -type antibiotics such as clinda-
`mycin hydrochloride, clindamycin phosphate, lincomycin
`phosphate, or lincomycin hydrochloride. Additional topical
`anti -acne active ingredients may be contained in the com-
`position 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 medi-
`cations, such as ROSAC® 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, medica-
`tions that degrade due to sun exposure or that result in injury
`to an individual upon exposure to the sun, such as sulfona-
`mides and tetracycline, are expressly excluded from the
`scope of the present invention.
`Additionally, certain skin care compounds, such as ben -
`zoyl 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 inven-
`tion.
`
`20
`
`8
`The amount and concentration of sunscreen in the com-
`position 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
`5 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
`io 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
`15 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 -
`25 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
`30 and chemical incompatibilities wherein one active ingredi-
`ent 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
`35 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° 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
`40 period of time at this temperature. Making such formula-
`tions 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
`45 capable of causing skin irritation. Therefore, if a potentially
`irritating anti -acne medication is included in the composi-
`tion 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
`50 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
`55 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
`60 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 par