AU2015201750A1 - Improved methods and compositions for safe and effective treatment of erythema - Google Patents

Abstract

Improved methods and compositions for safe and effective treatment of erythema or a symptom associated with erythema in a subject are described. The methods involve topically applying to an affected skin area a topical composition comprising about 0.3% to about 10% by weight of brimonidine and a pharmaceutically acceptable carrier. 6361193_1 (GHMaers) P91331.AU.1 ONIAM Figure I. DaY 15 Dav 29 $3040 0- 3 6 9 Q 3 6 12 3 ie1 Time Poini (hour) -- 2-- 09iQD - 0 I nBID ----- 0.18%QD k elde- - l

Description

TITLE OF THE INVENTION Improved Methods and Compositions for Safe and Effective Treatment of Erythemna CROSS-REFERENCE TO RELATED APPLICATION 100011 This application is entitled to claim priority from U.S. Provisional PatentAplctoN. 6 1:!282, 754,l filed Ma ,rch 26, 20 10, the conte- nt of wh-ich is hereby incorporated by reference in its centre. Tis pplcatonis a divisional of..AU2Ol 11231543, the content of which is hereby incrpoate byref'ere nce in its entirety. BA CKGROU1_jND OF THE INVENTION 100021 Erythema is a skin condition characterized by redness of the Ski. It ccus with any skin injury, infetio, or inflammation. It can alo occur as a reaction to mnedications, illness or emotions, It can furher occur for raoscretyunknown. Erythemna is difficult to treat. Cu rrently available treatme.,nts for eryth-eim mnainly threat tlheneryn diseases an"d avoi'dknwtrges These treatments are of limitd effctieness, particuarly fR erteawhunon cause-s. [0003] Brmidne, a selective v2madrenergi gonist has benuse'd a-'s either a rnono-ther'apy or an adjunctie therapy to lowver inroua rsue(lop) in the traten fglaucomaf_ and o"cular hypertension (OHT) since its approval in 1996. The most common side effects associaed wit bri'mo-nidine therapy are dry mouthftgedosies edce midf hyper-emia, blurred vso and freign boysestin ypertension, palpitations and syncope have been reported bylss than 3% atintsin clinic al trials involvhigbiondn ophthlic treatmIrent. See M~iJunlo the haracySocetyof iscnsi, ay/June 2 00)1, at World Wide _ Web:. pswi .rg/ro esionl/parmco/rinonidie~pfand references therein Results from th dose= ranging study in patients itdh g lucoma o'r ocular h'Iypertnsion showed th-a although 10.5% (x~w) had6 hier. e ffica cy in the early phase of treatmnt, th AM5 (w/w) and 0.%(l)had smia effcacy after two weeks of treatment, and that 0.515 (w/w) had moesystemic and ocul ar Side effects than 0.2% (w/w). Sie, e.g. Wakters, Su yc pranlg,1996, 41: SI 9-S26)., O)phhli formultins containing 012%5 (w/w) brimonidine have been used fOr chronic brimlonidine has been only used frac therapy for the prvninofpoterivinacur press_-ure. spikes. In order to redue a vaey of ocuar and systemic sielfecs socatdwih h optamcapplicaion of=02%1 (w/w) brimonidine, ophthalmic formulti ons' 'onta'.'inin'g lower concentrations of brimonidine eg., 0.1 5% (ww) or 0.116 (w/w), have been siubseque ntly develop ed and used for chronic optamcapplications, 2 !00041 Brimonidine has been reported to be useful in treating erythema caused by rosacea. See, e.g.,U.S. Ser. No, 10/853,585 to Delovin et al. To ensure the safety and avoid unacceptable side effects, a previous clinical study used 0.2% (w/w) brimonidine tartrate as the "high" dosage for treating erythema. See US 2009/0061020 to Theobald et al. 100051 In the present invention, it has been surprisingly discovered that topical administration f brimonidine to a skin area affected by erythema or a related symptom resulted in significantly less systemic exposure to brimonidine than topical ophthalmic application of brimonidine. It has been found that although systemic exposure increased with the applied dose of brimonidine, statistical analysis showed hat the increase in systemic exposure (C.,,) was not dose proportional, e.g., the increase in the mnean .was much less than the increase in the dose. It has also been discovered that unlike the topical ophthalmic application of brimonidine, topical administration of higher than 0.2% (ww) brimondine to a skin area affected by erythema or a related symptom resulted in increased efficacy without observable loss of effectiveness over time No unacceptable drug related adverse events- wasobserved with the treatment of higher concentraion of brmonidine tested. 100061 Accordingly, a higher concentration of brimonidine, such as about 0.3% (w/w) to about 0% (w/w), can now be used in improved methods and compositions for safe and effective tratn f erth a or a ptom asociated therewith BRIEF SUMMARY Y OF T HE INVENTION [00071 In e general aspect embodies of the present invention relate to a method of providing a safe and ffective treatment of erythema or a symptom associated therewith in a subject. compstopicaly administering to a skin area affected by the erythema or the symptom a topical composition, which comprises about 03% to about 10% by weight brimonidine plpcsma profit having a mean g of about 54 % o a n a e brimoni dine and a pharmaceut cally acceptable earrer; (2) devising instructions for topically administering the topical composition to a skin area affected by the erythema or the symptom to obtain the safe and effective treatment, and 3 (3) providing the topical composition and the instructions in a unified package wherein the topical administration effects a serum or plasma profile of brimonidine having a mean Cnax of about 54 + 28 pg/mL or less and a mean AUC.

24 hr of about 568 + 277 pg.hr/mL or less. [0009] In another general aspect, embodiments of the present invention relate to a topical gel composition for providing a safe and effective treatment of crytherna or a symptom associated therewith in a subject. The topical gel composition comprises: about 0.3% (wlw) to about 10,0% (w/w) brimonidine; about 0.20% (w/w) to about 4.0% (w/w) geling agent; and about 5.0% (w/w) to about 30.0% (w/w) at least one polyol, wherein topical administration of the topical gel composition to a skin area affected by the erythema or the symptom effects a serum or plasma profile of brimonidine having a mean C. of about 54 28 pg'mL or less and a mean AUCoa4hr of about 568 ± 277 pg.hr/mL or less. [00101 in a preferred embodiment, the topical composition used in or encompassed by embodiments of the present invention comprises about 0.4% (w/w) to about 0.6% (v/w) brimonidine tartrate. 10011 I anoherpreferred embodiment, the erythema is erythemna of rosacea. [IN12J Ot e fees and advantages of the invention will apparnt fror the flowig discornudir the detailed description of the invention and its preferred embodiments and the appended claims. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 0131 The foregoing summary, as well as the following detailed description of the invention, be better understood when read in conjunction with the appended drawings. For the purpose o r t inn re s in the drawe o nts hich are presently prefrre. I shuldbe ndestod, oweerthat the invention is not lmtdby the drawings, [0014b n the drawings: 0 Figure 1 i rates composite success on Day 1, Day 15 and Day 29 after the initial treatment, usn last observation carried forward (LOCF) approach in the intent to treat (ITT) population; 100161 Figure 2 ustrates CEA success on Day 1, Day 15 and Day 29 after the initial treatment, using LOCF approach in the ITT population; and 00171 Figure 3 illustrates PSAS success on Day 1, Day 15 and Day 29 after the initial treatment using LOCF approach in the ITT population.

4 DETAILED DESCRIPTION OF THE INVENTION [00181 Various publications, articles and patents are cited or described in the background and throughout the specification, each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which have been included in the present specification is for the purpose of providing context for the present invention. Such discussion is not an admission that any or all of these matters form part of the prior art yih respect to any inventions disclosed or claimed. [00191 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains, Otherwise, certain terms used herein have the meanings as set in the specification. All patents. published patent applications and publications cited herein are incorporated by reference as if set forth fully herein. It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the"' include plural reference unless the context clearly dictates otherwise. 100201 As used herein, "erythema or a symptom associated therewith" is intended to encompass any type or classification of abnormal skin redness associated with or resulting from rosaceae.g erythema or a symptom associated therewith in a patient with rosacea. A major symptom of rosacea them which is a skin disorder that generally affects the cheeks, nose, chin, and forehead patent [00211 The term "erythema or a symptom associated therewith" encompasses different degrees or grades of erythema or a symptom associated therewith, from mild to severe. [0022] For example, erythema or a symptom associated therewith can be rated by a clinician based on Clininrs Erythema Assessment Score (CEA) on a scale from 0 to 4, with 0 being clear skin with no signs oferyt ;I being almost clear, slight redness; 2 being mild erythema, defte redness; 3 being moderate redness; and 4 being severe redness 100231 Erythema or a symptom associated therewith can also be rated by a patient based on Pat s S As m PSA, also called PSA-5 herein)on ca f 0 to 4, with being n redness I bei ery mild redness; 2 being mild redness; 3 being moderate redness and 4 being severe redness. [0024] In view of the present disclosure, a skin area that is affected by erythema or that is prone to be affected by erythema can be identified using any diagnostic signs or means known in the art, and can be treated by methods according to embodiments of the present invention.

5 100251 The efficacy of the treatment can be measured using method known in the art. For example, the efficacy can be measured by the grades of improvement as evaluated by CEA, PSA or the combination of CEA and PSA, and the duration of the improvement. [00261 As used herein, the term "brimonidine" refers to the compound (5bromo-quinoxalin-6 yI)-(4,5-dihydro- I H- imidazoli2-yl)-amine having the structure of formula (I): N Br NH N Formula (I) and any pharmaceutically acceptable salt of the compound, including, but not limited to, brimonidine tartrate. [0027] The phrase "pharmaceutically acceptable salt(s)", as used herein, means those salts of a compound of interest that are safe and effective for topical use in mammals and that possess the desired biological activity, Pharmaceutically acceptable salts include salts of acidic or basic groups presn t spei csharmaceutically acceptable ac d addition salts include, bu are notlimte to hdrohlrid, ydrob-rmJie. hydroiodide irt uft, bisulfatephosphate, acid phoshat, isn ioti ate actate latate sa iclate cirate tatra. antothenate, bitartrate, ascorate, uccinatealeate gentisinate fumarate, gluconate, giucaronate, saccharate, formate, benzoate glutamate, methanesufonate, ethanesu fonate, benensu I fonate, p-toluenesulfonate and pae'is-(2hydroxy naphthoate))salts. Certain compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable ase salts include, but are not limited to, aluminum, calciumlithiun, magnesium, potassium, zn, andietha amine alts, For a review on pharnaceutically acceptable salts see BERGE E AL.- 66 PHAv SC. -I9 (1977) incorporated heein by rferenc 10028! The term "topically administrable composition," a "topical composition," or a "topica ormulation s used herein: means any formulation or composition which is pharmaceutically and/or cosmetically acceptable for topical delivery of the specified compounds according to embodimnsof the inventi Exemplary forms of formulation that can be used for topic administration in embodimnents of the presentinvention include, but are no limited to, sprays mists aersols solutions, lotions, geis, creams, ointments, pastes, unguents, emulsions and suspensions.

6 [00291 The term "topically administrable composition" as used herein, also encompasses locally applied and locally acting formulations such as formulations for use with implants, injections, or patches. 100301 The choice of topically administrable composition will depend on several factors, including, but not limited to, the nature of the symptoms to be treated or prevented, the physiochemical characteristics of the particular compound to be administered and of other excipients present, their stability in the formulation, the aesthetics of any given formulation, available manufacturing equipment, and cost constraints. [00311 As used herein, the term "composition" is intended to encompass a product comprising the specified ingredient in the specified amount, as well as any product which results, directly or indirectly, from combinations of the specified ingredient in the specified amount. 100321 As used herein, the term "subject" means any animal, preferably a mammal, most preerably a human, to whom will be or has been administered compounds or topical formulations according to embodiments of the invention. Preferably, a subject is in need of, or has been the obectof ob ervationexperiment of, treatment or prevention of erythema or a symptom associated therewith. 100331 As used herein, the term "instructions" when used in the context of a packaged product includes a publication, a recording, a diagram or any other medium of expression which can be used t communicate the usefulness of the packaged product for its designated use, The instructions can, for example, be affixed to or included within a container for the packaged product. 100341 As used herein, the terry "treatment" or "treating" refers to an amelioration, prophylais or reversal of erythema or a symptom associated therewith, for example, by lessening or delaying the onset of the redness of the skin affected by the erythema or the symptom. 100351 As used heren, a "afe and effctive amoun of brssa means the amount of brimo-nidine that isefctv-o treat erythemna or ao Symptom associated the.rewith, without causing unacceptable drug related adverse events, when administered to a subject. 10036] As used hein the phrase "nacceptable drug rated advrs events," "unacceptable advere drug events, d "unacptable adverse drug action," shal all mean harm or undesired outcome associated with or caused by a proposed use of a drug, and the harm or undesired outcome reaches such a severity that a regulatory agency deems the drug unacceptable for the proposed use, 100371 It has been discovered in the present invention that topical administration of a safe and effective amount of brimonidine, such as a topical composition comprising about 0.3% to about 10% by weight of brimonidine, to a skin area affected by erythema or a symptom associated 7 therewith, provides effective treatment of erythema or a symptom associated therewith, without causing unacceptable drug related adverse events. For example, it was discovered that topical administration of a topical composition comprising increasing concentration of brimonidine to a skin area affected by erythema or a symptom associated therewith resulted in a clear dosage responsive increase in the efficacy and an increase in the systemic exposure. However, statistical analysis showed that the increase in systemic exposure (Cm) was not dose proportional, e.g, the increase in mean C.iwas much less than the increase in dose. It has also been discovered that, unlike the topical ophthalmic application, topical administration to an affected skin area a higher concentration of brimonidine resulted in increased efficacy without observable loss of efficacy over time. No unacceptable adverse event was observed with the treatment of higher concentration of brimonidine tested. Topical skin treatments of erythema or a symptom associated therewith with all concentrations and regimens tested resulted in significantly lower systemic exposure to brimonidine than the treatment with eye drops applied as recommended in the label of the ophthalmic products. [00381 Such superior clinical activities of the higher concentrations of brimonidine, e.g., about 0.3% to about 10% by weight, have not been previously reported. The present discovery is surprising and unexpected, particularly in view of the previously reported efficacy and safety profiles of brimonidine in ophthalmic applications, where a significant loss of effectiveness over time was seen with the brimonidine 0.5% (w/w) formulation and the chronic use of much lower concentrations of brimonidine, e.g, 0.1% or 0.15% by weight, is preferred, because the lower concentrations provide improved tolerability while maintaining lOP lowering efficacy. [00391 Accordingly, in one general aspect, embodiments of the present invention relate to a method of providing a safe and effective treatment of erythema or a symptom associated therewith in a subject, comprising topically administering to a skin area affected by the erythema or the symptom a topical composition comprising about 0.3% to about 10% by weight brimonidine and a pharmaceutically acceptable carrier, wherein the topical administration effects a serum or plasma profile of brimonidine having a mean C. of about 54 ± 28 pg/mL or less and a mean AUCo.2 4 of about 568 i 277 pg.hr/mL or less. The mean C%, and the mean AUCo- 24 hr correspond to the serum or plasma profile of brimonidine after ophthalmic treatment with 0.2% (w/w) brimonidine tartrate eye drops as recommended in the label of the ophthalmic product. [00401 According to an embodiment of the present invention, upon topically administering the topical formulation to the affected skin area, the onset of noticeable effect, i.e., at least 1-rade improvement of the erythema or the symptom, is first observed. The noticeable effect is then progressed to maximum improvement, which includes 2-grade of improvement of the erythema or 319m 1 GHM ) P1MAMW Alt 1 SOAM 8 the symptom that lasts for a sustained period of time. The maximum improvement then declines to noticeable effect, which then disappears. The grades of improvement of the erythema or the symptom can be evaluated by Clinician's Erythema Assessment Score (CEA) a Patient's Self Assessment (PSA), or a combination of CEA and PSA [0041] According to an embodiment of the present invention, the topical administration of a topical composition comprising about 03% (w/w) to about 10% (w/w) brimonidine to a skin area affected by erythema or a symptom associated therewith results in significantly more effective treatment of the erythema and the symptom than a vehicle control for reduction of facial erythema associated with rosacea as measured by a 12 hour success profile evaluated on both CEA and PSA scales, without causing any unacceptable adverse effect. [00421 In one embodiment, the 12 hour success profile comprises at least ]-grade improvement of the erythema or the symptomn [0043! According to another embodiment of the present invention, the topical administration of a topical composition comprising about 0.3% (w/w) to about 10% (w/w) brimonidine to a ski area affected by erythema or a symptom associated therewith resulted in significantly more reduction facial erytherma associated witb rosacea compared to a vehicle control as measured by a 12 hour success pro evauad on both CEA and PSA scales, without causing any unacceptable adver effect 100441 In an embodiment of the present invention, the 12 hour success profile comprises a noticeable effect of 1-grade improvement of the erythema or the symptom and about I hour to about 8 hous of a >graim enf the erythema or the symptom. According to embodiments of the reset inenton, he 2grae imroveentlasts, for example, at least about 6 hours, atles about 5 hour , st about 4 houat east about 3 hours, at least about 2r house or at least about I hor deedn)o h Plied dose, thle particular subject, the severity and complication o f erythema being treated, etc. 0045 In d embodient, the 12 hour success profile comprises a noticeable effect of 1-rade pro nt io hema or the symptom and about 2 hours to about 7 hours of a 2-grade improvement of the erythema or the symptom. [0046 another preferred embodiment, the 12 hour success profile comprises a noticeable ) effect of grade improvement of the erythena or the symptom and about 3 hours to about 6 hours of a 2-grade improvement of the erythema or the symptom.

9 100471 In yet another preferred embodiment, the 12 hour success profile comprises a noticeable effect of 1 -grade improvement of the erythema or the symptom and about 2 hours to about 5 hours of a 2-grade improvement of the erythema or the symptom. 10048] In a preferred embodiment, the erythema is erythema of rosacea. 100491 In an embodiment of the present invention, the topically administrable composition comprises about 0.3%, 05% 1.0%, 1 5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.%, 7.0%, 7.5%, 8.0%, 8.5%. 9.0%, 9,5% or 10 0%, by weight of brimonidine, such as brimonidine tartrate 100501 In another embodiment of the present invention, the topically administrable composition comprises about 0.4%, about 0,45%, about 0.5%, about 0.55% or about 0.6%, by weight of brimnidnesuch as brimonidine tartrate. 100511 In a preferred embodiment, the topical composition comprises about 0.5% by weight of brimonidine, such as about 0.5% by weight of brimonidine tartrate. [0052] To treat or prevent erythema or a symptom associated therewith, in view of the present disclosure, the topialyae posions the invention can be topically applied dirctly to the affected area in any conventional mnner known in the art, e~g. by dropper, applicator stick, or coton swab as a mist ia an aerosol applicator, via an intradermal or trasernlptchrb simply spreading a formulation of the invention onto the affected area wit fingers, a sponge, a pad, or wipes. Generally, the amount of a topical formulation of the invention apped t the Acted skin area ranges from about 0.000 1 g/cm 2 of skin surface area to about 0.05 g/c, preferably, 0.002 g/en to about 0.005 g/cn 2 of skin srface area. Typically, one to four applcations per day are recommended during the term of treatment, 100531 According to a preferred embodiment of the present invention, the topical composition is topically applied to the affcte skn area once daily. [00541 Methods of the pri sent ivnoncan be used in conjunction with one or more other treatments and medications fo erythema or a symptom- associated tewith uch as the medications used to trat the underlying disease thtcauses erte aatihistami'nnes t oto itching, atibiotics, Ccoictroids, intravenous imuolbuis ctanpe , c [0055Y The other medicanment or treatmen can be adiitrdto tesubjectsiulanoul wih, or in a sequence and within a time interval of the administration of brimonidine, such that th active ng s or agents can act together to treat or prevent erythema and symptoms associated therewith, For example, the other medicament or atment and brimonidine can be administered in 10 the same or separate formulations at the same or different times, ie., before or after. Any suitable route of administration can be employed to deliver the additional treatment or medication. [00561 Another aspect of the invention relates to a packaged product for providing a safe and effective treatment of erythema or a symptom associated therewith in a subject, The method comprises: (1) obtaining a topical composition comprising about 0.3% to about 10% by weight brimonidine and a pharmaceutically acceptable carrier; (2) devising instructions for topically administering the topical composition to a skin area affected by the erythema or the symptom to obtain the safe and effective treatment; and (3) providing the topical composition and the instructions in a unified package, wherein the topical administration effects a serum or plasma profile of brimonidine having a mean CT of about 54 + 28 pg/mL or less and a mean AUCo.

2 4 h of about 568 .277 pg,hr/mL or less. 100571 In one embodiment of the invention, the topical composition is contained within one suitable container, such as a dropper, ajar, or a tube with a suitable small orifice size, such as an extended tip tube, made of any pharmaceutically suitable material. The topical formulations according to embodiments of the invention can be filled and packaged into a plastic squeeze bottle or tubc. Suitable container-closure systems for packaging a topical formulations of the invention are commercially available for example, from Wheaton Plastic Products, 1101 Wheaton Avenue, Millville, N. 08332. Optionally, an applicator can be provided in or attached to the container, or separately from the container 100581 In one embodiment of the invention, the instructions are, for example, a pamphlet or package label The instructions explain how to administer topical formulations of the invention, in an amount and for a period of time sufficient to provide a safe and effective treatment of erythema or a symptom associated therewith. Preferably, the instructions include, for example, the dosage and administration instructions the topical formulations composition, the clinical pharmacology, drug resi stance, pharmacokinetics, absorption, bioavailability, and contra indications. [00591 Another aspect of the present invention relates to a topical gel composition for providig a safe and effective treatment of erythema or a symptom associated therewith in a subject. The topical gel composition comprises: about 0.3% (w/w) to about 10.0% (w/w) brimonidine; about 0.20% (w/w) to about 4,0% (w/w) gelling agent; and about 5.0% (w/w) to about 30.0% (w/w) at least one polyol, S1I wherein the topical administration of the topical gel composition to a skin area affected by the erythema or the symptom effects a serum or plasma profile of brimonidine having a mean C. of about 54 + 28 pg/nL or less and a mean AUC: 24 h of about 568 ± 277 pg.hr/mL or less. 100601 The topically administrable composition are prepared by mixing a pharmaceutically acceptable carrier with the safe and effective amount of brimonidine according to known methods in the art, for example, methods provided by standard reference texts such as, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 1672-1673, 866-885(Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K.; et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), both of which are hereby incorporated herein by reference, 100611 Inl a preferred embodiment, the topical gel composition comprises about 0.4% to about 0.6% by weight of brironidine, more preferably, 0.5% by weight of brimonidine tartrate. 100621 Suitable gelling agents known in the art, including those used in the two-phase or single phase gel systems, can be used in the present invention, Some examples of suitable gelling agents are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517518 (Alfonso R. Gennaro ed. 19th ed. 1995), which is hereby incorporated herein by reference. The gelling agents used in embodiments of the present invention, includebut are not limited to, one or mre hydophilic and hydroacohoic gelling agents used in the cosmetic and pharmaceutical industries. Preferably, the hydrophilic or hydroalcoholic gelling agent comprises "CAROPOL@" (B± Goodrich. Cleveland, Ohio), "HYPAN@" (Kingston Technologies, Dayton, NJ) "NATROSOL@" (Aqualon, Wilmington, Del.), "KLUCEL@" (Aqualon, Wilmington, Del.), or "STABILEZE"(ISP Technologies, Wayne N.). The preferred compositional weight percent range for "CA RBOPOL" is between about 0.5% to about 2%, while the preferred weight percent rangeor NT&SO® n "KLUCEL®W" is between about 0.5%; to about 4%0 The preferred compositioal wegtpercent range' tbr, both "H YP1A N® and "RTABI_ LE ZE®." is btwe 0,5%1 to aboutS 4%,Oter preered gellig agents inclde hdoytycluoe ells uMEM decadiene crosspoiymer, PYM/MA coplymer, glycerineplacyae or a comb-."ination teef 100631 Examps of careers that can be used in the present uintion include, but are no limited to Carbomer 910, 934P, 940, 941, 980 and 1342 and Carbopol@ 974P and Carbopol® 980. Preferably, the carbomer s Carbomer 934P or Carbopol@ 974P, and Caropol@ 980. ) 0064 According to embodiments ofth present invention, the amount of the carbomer in the composition is about 0 5%v 0%, 0.7%, 0 8%, 0,85%, 0.95% 1.05%, 1.15%, 1.25%, 1.35%, 1 .45% 1.5%, .6%, 1 % 1 8% 9% or 2.0% (w/w).

12 [00651 Polyol gel formulations with various ingredients solubilized therein have been used to minimize irritation when applied to the skin of a subject, while ensuring bioavailahilitv of the active agent in the formulation. See Ofher Ill et al, "Gels and Jellies," pp. 1327-1344 of Encyclopedia o Pharmaceutical Technolog, vol. 3 (ed. by Swarbrick, et al, pub. by Marel Dekker, 2002); or Pena, "Gel Dosage Forms: Theory, Formulation, and Processing," pp. 381-388 of Topical Drug Delivery Formulations, (ed. by Osborne et al., pub, by Marcel Dekker, Inc., 1990). Polyols in gel formulations can serve one or more functions such as solubilizing agents, moisturizers, emollients, skin humectant skin-penetration agents, etc. Suitable polyols that can be used in embodiments of the present invention include, but are not limited to, glycerine, propylene glycol, dipropylene glycoL hexylene glycol, butylene glycol, and liquid polyethylene glycols, such as polyethylene glycol 200 to 600, [0066] According to embodiments of the present invention, the amount of the total polyols in the composition is about 5.0% to 30.0% (w/w) for example, about 5.0%, 5.5%, 6.0%, 6.5%, 7.0% 75%, 8,0%, 8,5%, 9.0%. 95%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0% 145%,15.0%, 17%, 20%, 25% or 30% (w/w). 100671 Preferably, the topical gel composition comprises a first polyol and a second polyol, such as propylene glycol and glycerine, respectively. 10068] According to embodiments of the present invention, the amount of each of the first and second polyols in the composition is independently about 4 to 15%, such as 4.5% to 6.5% (w/w, for example 4.5%, 5.0%, 5.5%, 6.0% or 6.5% (w/w) [00691 The pH of the topica formulations of the invention are preferably within a pyiolgicalyacceptable pH, eg, tw i th e range of about 4 to about 8, preferably, of about 6 t about7.5, an-d more preferably about 4,5 to 6.5. To stabiize the p1-I, preferably, an effective amount fomuatonin an amun f ro bot .5 to about I wegtpecent- of hefomulation. 100701 The topical decomposition of the present invention can include one or more other ingredients, such as a protetiv agent tic et, a adsorbent apseative, an antioxid a surfactant a skin-penetration agent local anesthetics analgesics etc. 1007I In a preferred embodint, a topical gel composition according to embodiments of the invention further comprises water disperseibl form of titanium dioxide (TiO2) preferably at an amount that is sufficient to mask the color of brimonidine or another colored ingredient in the formulation, but would not cause irritation to the skin. TiO2 may cause mild irritation and reddening to the eyes thus eye contact with the TiO 2- containing topically administrable composition should 13 be avoided. Titanium dioxide imparts a whiteness to the topically administrable composition and helps to increase the opacity and reduce the transparency of the composition. Titanium dioxide absorbs, reflects, or scatters light (including ultraviolet radiation in light), which can help protect products from deterioration. Titanium dioxide can also be used as a sunscreen to protect the user from the harmful effects of ultraviolet radiation that is part of sunlight. [0072] According to embodiments of the present invention, the amount of water dispersible form of titanium dioxide in the composition is about 0,04 to 0.2%, such as 0.04%, 0.0425%, 00525% 0.0625%, 0,0725% 00825%, 0.09%, 0 10%, 0. 15%, or 0.20% (w/w) [0073J Suitable preservatives include, but are not limited to quatenary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; parabens such as rethylparaben, ethyl paraben, propylparaben and butylparaben; aniacteia estrs fo xmlseso arhdoyezoic acid; and othe-r anti-mnicrobi a aents, such as' c'hilorhexidine, correobnicadpolym-yxinW, and phenoxyethanol. Preferably, the preservatve' is seecedfom thle gru ossin fsdu enzoate, phenoxyeanoyl, benzyl alcohol, m-ehyprbnimdolinlue and d izolidin--yl1ra 100741 In Adiio to bimonidine, the tpclyamnsrbecomposition according to embodiments of- the ivnoncan opioally incud one or more other pharmaceuticaly active ingredients, includig, but notlmteqo mediJcations used ton~ treat thonderlying isease that Causes ryM nt isanes to control tc antiritics, cor icosterods, iavenous 100751 This invention will be bettr undersood by reference to the non-limitng examples that flow, but those skilled in the art wil readily appreciate that the only re o the invention as described moere fuly in the climns wvhic h f- ollo thereafter. ExaM IcI Gel Topica l Formulations 100761 This example ilustraes gel topical formulations that can be use: d in the present inv'-ention. [00771 A first group of gel formulatons is descrbe In TWal I blw., ,v Ingredients % (w/w) % ( % (w/w) ionidine tart ate 0.3 - 0,6% 0.6 - i% 3 - 0% Methylparaben NF 0.15% 0.20% 010% Propylparaben NF O003% 002% 0 04% 14 Hydroxyethyleellulose NF 1 0% 1.25% 1.5% Butylene glycol 1,3 3.0% 6.0% 18 0% Glycerine 2,0% 4.0% 12 0% Disodium Edetate USP 0 05% 0.05% 0,05% Purified Water USP QS QS QS TOTAL 100% 100% 100% 100-781 The p- of the formulation is adjusted to about 4.5 to 70. 100791 A second group of gel formulations is descrbed in Table 2 below Table 2 Ingredients % (W/W) % (W/W) % (W/W) Brimonidine tartrate 0.3 - 0.6% 0.6 3.0% 3.0 10% Methylparaben 020% 0. 20% 0.20% Propylparaben 005% 0,05% 0,05% KLUCEL@ 20% 2,5% 1 0% Propylene glycol 3% 6% 15% Glycerine iJSP 3% 6% 15% 10% Titanium dioxide 0.5% 0,6% 0,7% Purified Water, USP QS QS QS TOTAL 100% 100% 100% [0080] The ingredients are mixed together and aqueous sodium hydroxide is slowly added to the mixture until a pH of about 4.5 to 6.5 is reached and the gel is formed. 100811 A third group of gel formulations is described in Table 3 below. Table 3 Ingredient % (wiw % (w/w) % (ww Brmonidine tartrate 0.3 06% 0.6 -30% 3.0 10% Carboner1934P 1 25% 1.0% 5% Metylparaben02% 0.15% 020% Phenoxyethanoi 0.4% 0.35% 0,4% Glycerol 5,5% 0% 5% Kowet titanic urn dioxide 0.0625% 0.0725% 0.0825% Propylene glycol 5.5% 10% 15% Dl W ater QS QS QS TOTAL 100% 100% 00% lflh I '_ F'SR VI SF2. O~AQ.

15 {0082] The ingredients are mixed together and aqueous sodium hydroxide is slowly added to the mixture until a pH of about 4.5 to 6.5 is reached and the gel is formed. [0083] A fourth group of gel formulations is described in Table 4 below. Table 4 Ingredients % (W/W) % (w/W) % (W/W) Brimonidine tartrate 0.3 - 0,6% 0.6 - 30% 3.0 - 10% Methylparaben 0.15% 0.125% 0,1% Propylparaben 0,05% 0.05% 0.06% Carbopol@ 980 1,0% 0.8% 1 .5% Glycerin 5.5% 10% 15% 10% Titanium dioxide 0.575% 0.675% 0.775% Polyethylene glycol 4.5% 8% 12% Water QS QS QS TOTAL 100% 100% 100% 100841 The ingredients are mixed together and stirred. Triethanolanine is added until a pH of about 5. to 7.0 is attained. Examde2 mparate B aiabity and Pharmacokineties Study of Brimonidine Compositins [00 Th is study was a randomized, evaluator-blnded intra-ind ividual comparative phrnackietc tuy f riondie are,optamcsuin (0.2%) and topical gel (0,07%' n o capped under maximal use condions fr 29 days in subjects moderate severe eythema asociatedwith roscea. MaOr entance crieri incude clinical diagnosis ere f e oated with rosaeaCE so o ev rOklig t-suec om i opal to o i c xosre o t with brirnonidine tnartat ophthalmic slto02%wsperformned. 100861 A total of& 102 subjects were randomized: 24, 26, 25, and 27 subjects in 0,5%, Gel Q, 0. 8% Ge lBID, 0.1 8%el QOD, and (050 Gel BID. respectively. On the Day I viit one drop of' bimnidine taae ophthalmic solution 0.2% was administered toch eye e very S hoursover a 24 h our period. After a 2-d ay wvash-out period. one gram of topica gel, (0.07%- , 01 8%, .0 of brmoi inertrate) was applied once (QD) or twice daily (BID) t o thi e face of subj ect s for 4 weeks.

16 [00871 Blood samples for complete PK profiling were taken during the 244hour ocular treatment (study Day 1) and during the first day of topical application (study Day 4), fifteen days of topical application (study Day 18) and after the last topical application up to 72 hours post-dose (study Day 32). Additional blood samples were collected before application (Day 10, Day 24). Brimonidine plasma concentrations were determined by using a validated LC-N4SIMS method with a lower limit of quantification (LOQ) of 10 pg/mL. [00881 The PK parameters for brimonidine were calculated using standard non-compartmenta method and Cma, AUCo-24,r were analyzed statistically using log-transformed data. For both the differences between times administration routes and between treatment groups, the limits of the intervals were back-transformed into exponential to obtain 90% confidence intervals (90% CI) of the ratios of geometric means on the original scale, The statistical analysis was performed using al C.( LQ values being replaced by the LOQ) and using only quantifiable AUC2 4 hr, [0089J PK results demonstrated that: (I) Ocular treatment: Administration of brimonidine tartrate 0.2% by ophthalmic route resumed in quantifiable exposure (10 pg/mL) in all patients receiving TID treatment. The phamakietic (PK) pameters of the ophthalmic solution have a ean C of 54 * 28 pg/m range: 16 134 pg/mL) and a mean AUCo- 2 h of 568 + 277 pg,hr/mL (range: 124 - 1490 pg.hr/ml) consistent with the known data of brimonidine tartrate 0.2% (w/vw) ophthalmic solution eg NDA :2 1-262, 02% Brironidine Purite Multiple dose TID, C 65 t 38 pg/mL. 2 Topical treatments: Daily topical application of brimonidine Gel for 29 days resulted ( 10 pg/rL) systemic exposure in 24%, 48%, 68% and 75% of subjects receiving brimonidie Gel 0.07 % BID, 0.18 % QD, 0 8 % BID or 0.5% QD, respectively At the end of the the SD) C8 ere 1 9 17 + 20 i0 pg/nI, 25 24 Quniibe v11) e,1 83 0 1y1 216 pghrm frbrmniie e 0,07% / BiD 0,18 % QD, 0.18 BID o 0.%QD,repcily [0090] The effect of muliple dose of brimonid ine gel on P K profile (Time effect:Day 4 Day 18/Day 32 as assessed for each topical treatment groups. Systemic exposures of the first day of topical application were comparable to those observed after 29 days topical applications in al treatment groups, thus suggesting that thereis no drug accumulationhroughout the treatment duration (i.e. 4 weeks) whatever the dose and the dose regimen. Whatever the dose and dose 17 regimen tested, the Ocular/Topical ratios calculated over the entire topical treatment period (Day 4, Day 18 and Day 32) was significantly lower than 1. 100911 After topical application of brimonidine gel, systemic exposure increases with applied dose. However, statistical analysis showed that systemic exposure (C,,a,) is not dose proportional, The mean C, increased lower than dose proportionality. [00921 The topical systemic exposure (expressed as C. or AUCo2) from the skin treatment was compared to the one obtained aRer ocular treatment. See Table 5, [00931 Table 5: statistical comparison of the ocular and topical treatments Parameter CD07805/47 Gel CD07805/47 Gel CD07805/47 Gel CDO70S547 Gel 0.5% QD 0 18% BID 0.P% QD 0.07% BlD Estimate (90% CI) Estimate (90% CI) Estimate (90% CI) Es!imate (90% C I)_ Cmax Ratio between Topical Administration Visi and Day I (Ophthalmic administration . Day 4/Day 1 03 (0.,0.3) 0.3 (0.2, 0.3) 0.2( 0.2,0 3) 02(02,0.2) Day 18/Day 1 0.6 (0.5, 0.7) 03 (0.3, 0o4) 0.2 ( 0.203) 0.2 (0.2,02) Day 32/Day 1 0.4 (0.3, 0.4) 0.3 (0.3,0.4) 0.3 (0.23) 0,2 (0.2, 03) Quantifiable AUC 0

.

2 or Ratio between Topical Administration Visit and Day I (Ophthalmic administration) Day 4/Day 1 0.6 (0.4,00.7) j A (0.3,0.5) O. ( 02,04) 0.1 (0J,0.3)* Day Day ay 1 0.7 (0.6, 0.9) 0.5 (0.4, 0.6) 0.3 (0.2,0,4) 0 5 (0.20.8) Day 32/Day 1 0.5 (0A,0.7) 0.5 (0.4,0.6) 03 (02,04) 0.4(0.3,0.7" (a) shoId he takwn with care due to the imited number of quantifiable A U24 (2 to V.A.: Day4 frt topical administration; Day 18 4 15th topical administration; Day 32-4 29th and last topical adm/n/strat/on 100941 In all the dosages and dose regimens tested the Ocular/Topical ratios calculated over the entire duration of the topical treatment period (Day 4, Day 18 and Day 32) were significantly lower than 1. The C, mean ratio was 0.2 for 0.07 % BID group, ranged from 0.2 to 0.3 for 0.18 % QD and BID groups and ranged from 0.3 to 06 for 0.5 %o QD group. For C, the upper limit of the 90 %o confidence interval did not include 0.8 whatever the dose and dose regimen tested. The highest ratio was observed in the 0.5 %2 QD group (mean ratio 0.6, 90 % CI [05-0.7])after 15 days of application, but not confirmed at the end of the 29-day of topical treatment (mean ratio 0.4, 90 %; Cl [0.3-0.4]). The same tendency was observed with the quantifiable AUCo 4 The clinical study results demonstrated that the systemic exposure obtained after topical treatment with all concentrations and regimens tested in the study is significantly lower compared to the systemic exposure obtained with the eye drops applied as recommended in the label of the ophthalmic products. 100951 In conclusion, quantifiable PK profiles (at least Ca) were observed in all treatment groups. It has been found that although systemic exposure increased with the applied dose of 836193Q (GHFMflas) P913313%tS SOMfAM 18 brimonidine, statistial analysis showed that the increase in systemic exposure (Cmn) was not dose proportional, e.g., the increase in the mean Cm, was much less than he increase in the dose. No evidence for systemic accumulation was observed, [0096] All evaluated concentrations and regimens were well tolerate and safe. No clinically meaningful reductions in mean lOP, vital signs or routine laboratory parameters were observed wih any of the topicalgel treatment groups. Increasing drug concentration or regimen had no effect on the incidence of related cardiac/vascular AEs. There is no identifiable relationship between any PK parameter and the incidence or severity of any AEs related to the topical gel. There were no SAIs reported during the treatment period with the topical gel for skin application (DAY 4 through study completion). Two SAEs were reported during the ophthalmic solution treatment period (DAYS -3) in two subjects, with one SAE (Acute Hypotensive Event) considered related to the ophthalmic solution. Both subjects with SAEs were discontinued from the study prior to any exposure to the topical gel. 100971 The study results demonstrated that the systemic exposure obtained after topical treatment of the affected skin areas with all concentrations of brimonidine and regimens tested is significa-ntl lower compared to the systemic exposure obtained with the eye drops (0.2% by weig brimonidine tartrate) applied as recommended inthe labelof the ophthalmic products. 0098 Basd on res fn this comparative bioailabilit and pharmacokinetics stud, c atis of brimonidire higher than 0.2% (w/w) can be used for topical administration to an affected skin area for safe and effective treatment of a skin disorder. Example 3 Clinical Study on the Effectiveness and Safety of Brimonidine Tartrate Gel Composition composition containing 0.5% b rimoni dine tartrate (Gel 0.5%) applied topically once daily (QD) and a topical gelomposition containing 0.18% brimonidine tartrate (Gel 018%) applied topically once daily (QD) or twice daily (BID) compared toVehicle Gel applied topically once daily (QD) or twice dily (BID), tafeedskJira of su~bjects with mnoderate to severe facialerteasoctd with rosacea, ) 00100 Major entrance crite ia included clinical diagnosis of moderate to severe facial erythema associated with Rosacea, CPA score 23 and PSA-5 score 3, presence of no more than 2 facial lesions, and IOP level at least 10 mmHg. M: s*: 19 "3 A'. NRI> 19 1001011 Qualified subjects were randomized in a 1:1:1:1:1 ratio (block size of 5) to one of the five treatment arms (0.5% QD, 0 18% BiD 0.18% QD, Vehicle BID, Vehicle QD). 1001021 A total of 269 subjects from 17 cynical sites were randomized to Topical Gel or Vehicle Gel: 53, 54, 54, 53, and 55 subjects in the 0.5% QD, 0.18% BID, 0,18% QD, Vehicle BID, and Vehicle QD arms, respectively All 269 subjects were included in the ITT and Safety population, and 237 subjects were included in the PP population. 1001031 CEA and PSA evaluation data were collected at each clinic visit at Hours 3. 6. 9, and 12 after study drug application. Data collected at 30 minutes after study drug application comprised the secondary endpoints of CEA Initial Effect and PSA Initial Effect. Subject-reported efficacy data were collected at clinic visits and on non-clinic days during the treatment period. Safety were assessed throughout the study, 1001041 The primary endpoint, Composite Success, is defined as a 2-grade improvement on both CEA nP -measured at Hours 3, 6, 9 and 12 on Day 29 aft r Staisical analysis was peromed to compare each active treatmnt(0.5% QO, 0.18%1 BID and QD) vs. the corresponding Vehicle; Q co Vehicle BID, respectively. Additional analyses fo'r Composite- Sucics on early treatment visits Day I15 an.-d DyI -were performied, to:frte investigate the early treatment effect. 1001051 Maximal drug effct peaked bewen apoitey3 to 6 hours aftrdosig. On D_'ay 29, statistically significant, differ-ence bewe .%QD vs. eil QD was observed (pc0O ). Consistently, the Same superiority of 0.5% QD vs. Vehicle QD wsobse rved on Day If- ;(p)<OOO)0l adDay l (p00 ") The sttstical resuls basd on the ITT population (LOC Fapproach) wr confirmlned in the population point (PP) populaton and three sestvt nlss(i~e. imputing missing data by assigning failure, success, and avrgedt, respectively). [001061 Aks shown in ig. I, superior itreatmewnt effect was clearl demj .onstrate ,d in 0%Q.D, followed by 0.18 131 and Q1. Consistently, 0.511 QD:, sllhowevd stogandobs effIect as measured by Composite Success throughout the 12 hour duration, stating on Day I and comntned till Day '29. Thrfr,no evidence of tachyphylaxls was observed. The magnitude of the trament effecs were gf-eneral simla between 0. 18%; BID and 0.1 8% QD. The lower vehce effec in the Vehicle QOL regimen resulted i n bette,,r stisial dtW1Outcome for" 018%' Q) -vs. Veh i Cle QO [001071 In addition to the analysis on Composite Successwhc is dfndjointly by two independent static asesetCEA-Sucess nd PSA-5 Succe ,ss wraloanaly ,zed individually. The wmagiudes of the CEA-Succes (Figure, 2) and, PSA-5 (Fgr )Success were greater in all 20 treatment groups compared to Composite Success but the pattern of the relative effects was same as observed in Composite Success. Consistently, 0.5% QD showed the greatest effect for CEBA Success and PSA-5 Success; 0 18% QD and BID showed numerically better effect compared to Vehicle QD and BID, respectively. 1001081 The conclusion based on Composite Success, CEA-Success and PSA-5 Success was supported by PSA-5 Diary data (i.e. the subjects' daily recording of their facial redness) during the study, [001091 The overall incidence of related adverse events (AEs) for the study was low. The number of related AEswas comparable between the treatment groups, and there was no significant difference in incidence of related adverse events between active and vehicle treatment arms. There was no significant increase in the number or severity of systemic or topical related AEs with increase in ge concentration or application frequency. No severe related AEs were reported durir the study There were no reported systemic cardiac AEs considered related to the study medication. Nocase of related facial fishing led to study discontinuation or interruption of daily treatment. 100110 No cl iically meaningfu abnormal trends or shifts were observed in mean blood pressure (systolic and diastolic) or heart rate for any of the treatment groups during the treatment phase (Da 1, 15, and 29) or at the end of the folow-up period, and there was no observable difference in mean blood pressure or heart rate changes between active and vehicle arms. Increasing drug concentrate or application frquency had no effect on the incidence of isolated vital sign abnormalities Ther Sno reported adverse events of acute hypotension, bradycardia, or syncope during the study This clinical study demonstrated that Gel 0,5% QD possessed superior efficacy compared to the corresponding vehicle and Gel 0.18 % QD and BID treatments evaluated in the study (primary endpointm pote Success defined as a 2-grade improvement on both CEA and PSA5 at Hours 6 9 and 12 on Day 29) The primary outcome was supported by the secondary endpoints No unacceptable drug related adverse event was observed Safety and tolerbilityof Gel 0,5% QD favorable No evidence of tachyphylaxis or rebound was found in the study 100111 Unlike ophthalmic applications f brimo ine, where the onic use of lower cncentrto fbionidie eg. 0.1 (w prvde ipove toeabiity whe maintaining ccentrations of brimonidine provide significantly improved clinical efficacy in treating erythema or related symptoms, while not causing any observable change in patient safety and tolerability as compared to lower concentrations of brimonidine.

21 100112] It will be appreciated by those skilled in the art that changes could be made to the embodinents described above without departing from the broad inventive concept thereof, It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims, 1001131 It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. [00114] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e, to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims (20)

1. A method of providing a safe and effective treatment of erytherna or a symptom associated therewith in a subject, comprising topically administering to a skin area affected by the erythema or the symptom a topical composition comprising about 0.3% to about 10% by weight brimonidine and a pharmaceutically acceptable carrier, wherein the topical administration effects a serum or plasma profile of brimonidine having a mean C, o f about t 5 4 - 28 pgr/rn L or less and a me an A U C 0 . 24 o of about 568 t 277 pg.hr/mL or less,

2. The method of claim 1, wherein the erythema is erythema of rosacea.

3. The method of claim 1, further comprising administering to the subject at least one additional treatment and medication for erythema or the symptom associated therewith.

4. The method of claim 1, wherein the topical composition is administered to the skin area once daily.

5. The method of claim 1, wherein the topical administration of the topical composition to the skin area resulted in significantly more reduction of facial erythema associated with rosacea compared to a vehicle control as measured by a 12 hour success profile evaluated on both CEA and PSA scales, wherein the 12 hour success profile comprises a noticeable effect of I -grade improvement of the erythema or the symptom and about I hour to about 8 hours of a 2-grade improvement of the erythema or the symptom.

6. The method of claim 5, wherein the 12 hour success profile comprises a noticeable effect of 1 grade improvement of the erythema or the symptom and about 3 hours to about 6 hours of a 2 grade improvement of the erythema or the symptom.

7. The method of claim 1, wherein the topical composition further comprises about 0.20% (w/w) to about 4.0% (w/w) gelling agent; and about 5.0% (w/w) to about 30.0% (w/w) at least one polyol.

8. The method of claim 7, wherein the topical composition comprises about 0.4% to about 0.6% by weight of brimonidine tartrate.

9. The method of claim 8, wherein the topical composition comprises about 0.5% by weight of brimonidine tartrate.

10. The method of claim 7, where the topical composition comprises about 0.50% (w/w) to about 2.0% (w/w) carbomer.

11. The method of claim 10, wherein the carbomer is selected from the group consisting of carbomer 934P, Carbopol@ 974P, and Carbopol@ 980,

12. The method of claim 7, wherein the topical composition further comprises about 0.04% to about 23 0.08% (w/w) water dispersible form of titanium dioxide.

13. The method of claim 7, wherein the topical composition further comprises a preservative selected from the group consisting of sodium benzoate, phenoxyethanol, benzyl alcohol, methylparaben, imidazolidinyl urea and diazolidinyl urea.

14. The method of claim 7, wherein the topical composition comprises at least one of glycerin and propylene glycol.

15. A method of producing a packaged product for providing a safe and effective treatment of erythema or a symptom associated therewith in a subject, comprising: (1) obtaining a topical composition comprising about 0.3% to about 10% by weight brimonid ine and a pharmaceutically acceptable carrier; (2) devising instructions for topically administering the topical composition to a skin area affected by the erythema or the symptom to obtain the safe and effective treatment, and (3) providing the topical composition and the instructions in a unified package, wherein the topical administration effects a serum or plasma profile of brimonidine having a mean C , of about 54 + 28 pg n L or less and a mean A U Co.24hr of about 568 a 277 pg.hrimL or less.

16. A topical gel composition for providing a safe and effective treatment of erythema or a symptom associated therewith in a subject, comprising: about 0.3% (w/w) to about 10.0% (w/w) brimonidine; about 0.20% (w/w) to about 4.0% (w/w) gelling agent; and about 5,0% (w/w) to about 30.0% (w/w) at least one polyol, wherein the topical administration of the topical gel composition to a skin area affected by the erythema or the symptom effects a serum or plasma profile of brimonidine having a mean C. of about 54 28 pg/mL or less and a mean AUCO.24hr of about 568 277 pg.hr/mL or ess.

17. The topical gel composition of claim 16, comprising about 0.4% to about 0.6% by weight of brimonidine,

18. The topical gel composition of claim 16, comprising about 05% by weight of brimonidine tartrate.

19. The topical gel composition of claim 16, comprising about 0.50% (w/w) to about 2.0% (w/w) carbomer,

20. The topical gel composition of claim 16, comprising at least one of glycerin and propylene glycol.