USOO8426475B2

(12) United States Patent (10) Patent No.: US 8.426,475 B2 Weidner et al. (45) Date of Patent: Apr. 23, 2013

(54) TREATMENT OF CONNECTIVE TISSUE W W 28:8: A: 2.38 DISEASES OF THE SKN WO WO 2006/027579 A2 3, 2006 (75) Inventors: Morten Sloth Weidner, Virum (DK); OTHER PUBLICATIONS Hans Christian Wulf, Epsergaerde (DK) Pullen, Jr., R.; “Managing Subacute cutaneous lupus erythematosus' (73) Assignee: Astion Development A/S, Copenhagen Dermatology Nursing, Dec. 2001, pp. 1-3. O (DK) Freitas et al. "Chronic cutaneous Lupus erythematosus: Sudy of 290 patients'. An bras Dermatol, Rio de Janeiro, 2003, vol. 78(6), pp. 703-771.* (*) Notice: Subject to any disclaimer, the term of this Patent Abstract of Japan, 07258067 A, Oct. 9, 1995. patent is extended or adjusted under 35 Patent Abstracts of Japan, 07304647 A, Nov. 21, 1995. U.S.C. 154(b) by 1273 days. Patent Abstracts of Japan, 09 110674 A. Apr. 28, 1997. Patent Abstracts of Japan, 630 10716 A, Jan. 19, 1988. (21) Appl. No.: 11/402,255 Dawn Baramki BSN et al., “Modulation of T-cell function by (R)- and (S)-isomers of albuterol: Anti-inflammatory influences of (R)- (22) Filed: Apr. 12, 2006 isomers are negated in the presence of the (S)-isomers'. J. Allergy Clin. Immunol. 2002, 109(3):449-454. (65) Prior Publication Data Peter J. Barnes, “Effect of beta-agonists on inflammatory cells'. J. Allergy Clin. Immunol. 1999, 104(2 Pt 2):510-517. US 2006/0235048A1 Oct. 19, 2006 Richard Kalish et al., “Sensitization of mice to topically applied drugs: albuterol, chlorpheniramine, clonidine and nadolol. Contact (51) Int. Cl. Dermatitis, 1995, 35, pp. 76-82. AOIN3L/08 (2006.01) Karen E. McCrea et al., “Salmeterol, a long acting beta-adrenocep AOIN3L/00 (2006.01) tor agonist mediating cyclic AMP accumulation in a neuronal cell A6 IK3I/05 (2006.01) line', Br. J. Pharmacol. 1993, 110: 619-626. A6 IK3I/045 (2006.01) Philip J. Thompson et al., “Shrinking Lungs, Diaphragmatic Dys (52) U.S. Cl. function, and Systemic Lupus Erythematosus'', Am. Rev. Respir. USPC ...... 514/731: 514/738 Dis. 1985, 132(4):926-928. (58) Field of Classification Search ...... 514/731, Biochemical Modulation of Skin Reactions, pp. 10-11, edited by 514f738 Agis K. Kydonieus and John J. Wille, CRC Press LCC 2000. Rooks, Textbook of Dermatology, Chapter 65, pp. 56.2-56.4, vol. 3, See application file for complete search history. 7" edition, edited by Tony Bums et al., Blackwell Science, 2004. (56) References Cited Seong. H. Cho et al., “(S)-Albuterol Increased the Production of Histamine and IL-4 in Mast Cells'. Intl. Archives of Allergy & Immunol. 2001: 124:478-484, 2000. U.S. PATENT DOCUMENTS Dean Handley, PhD, “The asthma-like pharmacology and toxicology 4,088,756 A 5, 1978 Voorhees of (5)-isomers of beta agonists'. J. Allergy Clin Immunol. 1999, 4,284,623 A 8, 1981 Beck ...... 424,157.1 104(2 Pt 2):S69-S76 4,699,7774,574,129 A 10/19873, 1986 ZuponNair et etal. al. Clive P Phage PhD et al & 8Contrasting properties of albuterol 4,975,466 A 12/1990 Bottcher et al. stereoisomers'. J. Allergy Clin. Immunol. 1999, 104(2 Pt. 2):S31 4,980,159 A 12/1990 KOslo S41. 5,648,386 A 7, 1997 Resemann et al. L. J. Petersen et al., “The effect of salmeterol and salbutamol on 5,795,564. A 8, 1998 Aberg et al. mediator release and skin responses in immediate and late phase 5,919,827 A 7, 1999 Barberich et al. allergic cutaneous reactions'. Inflamm. Res. 48 (1999) 528-532. 92. A R388 AE al Joseph L. Rau PhD, “Introduction of a Single Isomer Beta Agonist'. 6,114,389 A 9/2000 Bouras ...... 514,574 Respiratory Care, Aug. 200, vol. 45, No. 8, pp. 962-966. 6,254,882 B1 7/2001 Jerussi (Continued) 6,267,972 B1 7/2001 Breton et al. 2003/02362986,437,165 B1*Al 12/20038/2002 MengMandala et al.et al...... 558,169 Primary Examiner — SreeniiPad Padmanabhan bh 2004/022O153 A1 11/2004 Jost-Price et al. Assistant Examiner — Kendra D Carter 2004/O220237 A1 11, 2004 Fu et al. (74) Attorney, Agent, or Firm — Foley & Lardner LLP 2004/0224876 A1 11/2004 Jost-Price et al. 2005/O130935 A1 6, 2005 Weidner 2005, 0192261 A1 9, 2005 Jost-Price et al. (57) ABSTRACT FOREIGN PATENT DOCUMENTS The present invention provides effective and safe medica ments for the treatment of connective tissue diseases of the W. wo, is: A 1492 skin, particularly with respect to the treatment of cutaneous WO WO 03/048122 A2 6, 2003 forms of Lupus Erythematous. The medicaments comprise as WO WOO3,088997 A2 10, 2003 the therapeutically active ingredient a beta adrenoceptor WO WOO3,0926 17 A2 11/2003 agonist. The invention furthermore relates to dermatological WO WOO3,O97073 A1 11, 2003 compositions without skin sensitization properties and which W. w888, A. 3.39. contain enantiomerically pure or enriched R-enantiomers of a WO WO 2005/004852 A1 1/2005 beta adrenoceptor agonist. WO WO 2005,102296 A2 4/2005 WO WO 2005/051293 A2 6/2005 5 Claims, No Drawings US 8,426.475 B2 Page 2

OTHER PUBLICATIONS Catherine D. Strader et al., “Identification of Two Serine Residues Catherine D. Strader et al. “Identification of Two Series Residues Involved in Agonist Activation of the B-Adrenergic Receptor'. The Involved in Agonist Activation of the B-Adrenergic Receptor'. The Journal of Biological Chemistry vol. 264, No. 23, Issue of Aug. 15. Journal of Biological Chemistry, vol. 264, No. 23, Aug. 15, 1989, pp. pp. 13572-13578, 1989. 13572-13578. Michelle L. Harris et al., “Autoimmunity in scleroderma: the origin, FJ Munoz Rodriguez et al., “Shrinking lungs syndrome in Systemic pathogenetic role, and clinical significance of autoantibodies'. Cur lupus erythematosus: improvement with inhaled beta-agonist Opin Rheumetol 15:778-784, 2003. therapy'. Lupus (1997) 6,412-414. D. Slattery et al., “Levalbuterol Hydrochloride'. Pediatric Pulmonol Israeli Office Action Patent Application No. 186491 dated Jan. 21. ogy 33:151-157 (2002). 2010. Michelle L. Harris et al., “Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies'. Curr Opin Reumatol 15: 778-784, 2003. * cited by examiner US 8,426,475 B2 1. 2 TREATMENT OF CONNECTIVE TISSUE beta-adrenoceptor agonist among other drug agents is pro DISEASES OF THE SKN posed to be administered as a secondary active drug agent. The patent application US2005192261 relates to topical FIELD OF THE INVENTION treatment with combinations of an antihistamine or an anti histamine analogue and a corticosteroid. The present invention relates to the field of pharmacologi The patent application WO05051293 relates to topical cal Science. There is provided novel principles of treating treatment with Ibudilast or a related compound. connective tissue diseases of the skin, particularly cutaneous The patent application US2004220153 relates to topical manifestations of Lupus Erythematosus in an individual by treatment with a selective serotonin reuptake inhibitors administering a beta-adrenoceptor agonist to the affected 10 (SSRI). skin areas of the individual. Furthermore, the invention is The patent application US2004224876 relates to topical directed to topically administrable compositions comprising treatment with a non-steroidal immunophilin-dependent a beta-adrenoceptor agonist in enantiomeric enriched or immunosuppressant (NSIDI) and an NSIDI enhancer (NSI pure form. 15 DIE). Notably, none of the above-mentioned patent application BACKGROUND OF THE INVENTION relates to the direct treatment of cutaneous forms of LE with a beta-adrenoceptor agonist, neither as the sole therapeuti There is no permanent cure for connective diseases of the cally agent nor as the primary therapeutically agent. skin, Such as cutaneous forms of Lupus Erythematosus. Furthermore, a number of treatment regimens have been Today, the treatment of connective diseases includes topical proposed for the treatment of systemic LE. In these treat treatment with strong steroids, sometimes in combination ments, the primary therapeutically effective drug agent even with anti-malarial drugs or systemic immuno-Suppressants. tually may be co-administered with a beta-adrenoceptor Unfortunately, the treatment with Such drug agents has seri agonist: ous side effects and cannot be applied for prolonged periods. 25 The patent application WO20030926.17 relates to the treat The present inventor has recognised the strong need for ment of an inflammatory skin disease. Such as Systemic Lupus therapeutic agents that can effectively alleviate the symptoms Erythematosus, by topically administering a steroid and a of cutaneous forms of Lupus Erythematosus (LE) without beta-adrenergic receptor ligand. exhibiting significant adverse effects. Quite Surprising, the The patent application US2003236298A1 (Atherogenics present inventor has found that the topical application of a 30 beta-adrenoceptor agonist effectively relieves the clinical Pharmaceuticals, Inc) relates to 1,3-bis-(substituted-phenyl)- manifestations in cutaneous forms of Lupus Erythematosus. 2-propen-1-ones that are inhibitors of the expression of Cutaneous forms of Lupus Erythematosus (Cutaneous VCAM-1 for the treatment of patients with a disease medi Lupus Erythematosus) encompass at least 10 to 15 different ated by VCAM-1, such as systemic Lupus Erythematosus. clinical presentations that usually can be divided into 3 cat 35 The patent applications US2005130935 and WO egories, including (1) acute cutaneous lupus erythematosus 2003097073 (Astion Development A/S) relate to combina (ACLE), (2) Subacute cutaneous lupus erythematosus tions of a beta-adrenoceptor agonist and an aminosugar for (SCLE), and (3) chronic cutaneous lupus erythematosus the treatment of inflammatory diseases, including systemic (CCLE). Some of the common types of cutaneous LE include Lupus Erythematosus. chronic cutaneous lupus erythematosus (CCLE) and various 40 The patent applications US20050176714 and sub-types thereof. WO2003104204 relate to pyridazine derivatives acting as Current evidence indicates that cutaneous Lupus Erythe phosphodiesterase IV inhibitors for the treatment of autoim matosus is a separate disease from systemic Lupus Erythe mune diseases, such as systemic Lupus Erythematosus. matosus and not just a benign variant of systemic LE in that Furthermore, unusual respiratory manifestations of sys the two diseases seems to be genetically different diseases 45 temic Lupus Erythematosus, “shrinking lungs' have been (Rooks, Textbook of Dermatology, chapter 65, page 56.2, treated with albuterol (Salbutamol) (Thompson PJ, Dhillon volume 3, 7" edition, edited by Tony Burns et al. Blackwell D P. Ledingham J. Turner-Warwick M. Shrinking lungs, dia Science, 2004). Systemic Lupus Erythematosus (SLE) is the phragmatic dysfunction, and systemic Lupus Erythematosus. most common connective tissue disease and is characterised Am Rey Respir Dis. 132(4), 926-8, 1985). by multi-organ inflammation, which most commonly affects 50 Topical administration of beta-adrenoceptor agonists has the skin, joints and vasculature. Almost any organ or system been shown to result in sensitization of the skin and allergic of the body, including the lungs, kidneys, heart or brain may reactions. For example, salbutamol (albuterol) has been be affected by the inflammation. reported to be a topical sensitizer that causes contact derma Beta-adreneroceptoragonists are traditionally used in the titis reactions when applied to the surface of the skin of treatment of respiratory diseases such as asthma, chronic 55 humans (in Biochemical Modulation of Skin Reactions, page bronchitis and nervous system injury. Beta-adrenoceptor 10-11, edited by Agis K. Kydonieus and John J. Wille, CRC agonists has also been found to interact with specific recep Press LCC 2000). tors on T-lymphocytes to mediate anti-inflammatory activi However, the present inventor has overcome this problem ties (Baramki D et al. Modulation of T-cell function by (R)- by providing topically administrable compositions only or and (S)-isomers of albuterol: anti-inflammatory influences of 60 mainly comprising the R-enantiomeric form of a beta (R)-isomers are negated in the presence of the (S)-isomer. J adrenoceptor agonist. Allergy Clin Immunol 2002 March; 109(3):449-54) and Bar Topically administrable compositions comprising an enan nes P. J. Effect of beta-agonists on inflammatory cells. J tiomerically pure beta-adrenoceptor agonist have been dis Allergy Clin Immunol 1999 August: 104(2 Pt 2):S10-S1)7. closed in the art: A number of drug agents and combinations thereof have 65 The patent application US2005192261 discloses topical been proposed for the treatment of various inflammatory compositions primarily comprising an antihistamine or an diseases including discoid Lupus Erythematosus, wherein a antihistamine analogue and a corticosteroid. US 8,426,475 B2 3 4 The patent application WO05051293 (COMBINATORX, The patent application JP 61-154201(TEIJIN LTD) dis INCORPORATED) discloses topical compositions primarily closes transdermal compositions comprising a B-stimulation comprising Ibudilast or related compounds. agent and a dissolution assistant agent. The patent application US2004220153 discloses topical The patent application.JP 06-048497 (Kao Corp) discloses compositions primarily comprising selective serotonin 5 a bathing agent composition containing a B-adrenergic stimu reuptake inhibitors (SSRI). lant, inorganic salt, an organic acid and an oily component. The patent application US2004224876 discloses topical The patent application U.S. Pat. No. 4,088,756 (The compositions primarily comprising a non-steroidal immuno Regents of the University of Michigan) relates to topically philin-dependent immunosuppressant (NSIDI) and an NSIDI applied compositions comprising at least one active com 10 pound selected from the groups C.1. B1, and B2-adrenergic enhancer (NSIDIE). agents and oral hypoglycemic agents. The patent application WO20030926.17 (COMBINA The patent application WO05102296A2 (HEPTAGEN TORX, INCORPORATED) discloses topical compositions LIMITED) relates to topically applied compositions com comprising a steroid and a beta-adrenergic receptor ligand. prising vitamin D or its analogue, cannabinoid or a cannab Topical compositions of a beta-adrenoceptor agonist are 15 inoid receptor agonist; and a beta-adrenoceptor agonist for proposed in several documents, but these fail to emphasise the the treatment of immuno-proliferative skin diseases. importance of administering the enantiomeric pure form: The The patent application WO20030926.17 (COMBINA patent application U.S. Pat. No. 4,574,129 (Bristol-Myers TORX, INCORPORATED) relates to topically applied com Company) discloses topical compositions comprising a positions comprising a steroid and a beta-adrenergic receptor beta-adrenoceptor agonist and vehicle materials for the agonist for the treatment of an inflammatory skin disease. treatment of topical anti-inflammatory effect in mammals. The patent application WO9519336 (IOVIS BIOMEDI The U.S. Pat. No. 4,699,777 (Schering Corporation) dis CAL AND PHARMACEUTICAL CONSULTANTS) relates closes transdermal compositions of albuterol further com to phenyl ethanolamine ethers acting as beta adrenergicago prising 5 to 50% of 1-dodecyl-azacycloheptan-2-one and 5 to nists that may be applied topically to skin. 50% of non-aqueous urea. 25 Notably, none of the above-mentioned patents and patent The U.S. Pat. No. 4,975,466 (Ciba-Geigy Corporation) applications disclose topically administrable compositions, discloses topical compositions based on Formoterol and wherein the beta-adrenoceptor agonist is the primary thera related compounds for use in the treatment of inflammatory peutical agent or the Sole therapeutical agent. skin diseases. The U.S. Pat. No. 4,980,159 (Bristol-Myers Squibb Com 30 SUMMARY OF THE INVENTION pany) discloses post-shave compositions (aqueous Solutions) comprising a beta-adrenoceptor agonist for pilomotor Surprisingly, the present inventor has found that beta effects. adrenoceptor agonists (in short “beta agonist”) have strong The U.S. Pat. No. 6,267.972 (Societe L'Oreal S.A) dis therapeutic potential in the treatment of cutaneous forms of closes cosmetic/pharmaceutical compositions for the treat 35 Lupus Erythematosus, even when applied as the Sole thera ment of cutaneous diseases and sensitive skin comprising an peutically active ingredient to a patient with cutaneous LE. effective Substance Pantagonist amount of at least one beta Clinical data shownherein clearly demonstrate the significant adrenoceptor agonist together with an skin irritant. improvement of inflamed lesions after only 3 weeks treatment The patent application WO05102296 (HEPTAGEN LIM with topical Salbutamol to a patient suffering from Discoid ITED) discloses topical compositions comprising a combi 40 Lupus Erythematosus. In another patient diagnosed with nation of Vitamin D or an analogue, preform or derivative Sub-acute Cutaneous Lupus Erythematosus, complete remis thereof, a cannabinoid or cannabinoid receptoragonist, and a sion of the cutaneous symptoms was observed after 8 weeks beta-adrenoceptor agonist for the treatment of psoriasis. of treatment with topical Salbutamol. Notably, these patients The patent application WO03088997 (UNIVERSITEIT have had the diseases for several years, where treatment with UTRECHT HOLDING B.V) discloses topical compositions 45 strong corticosteroids had only little effect. of an antigen and a beta-adrenoceptoragonist for the induc Therefore, the present invention provides significant tion of tolerance to treat autoimmune diseases, delayed type improvements in the treatment of cutaneous forms of LE even hypersensitivity reactions and/or transplant rejection, and/or in patients that are not responding well to gluco-corticoster graft versus host reaction and/or allergic reactions. oids. The patent application US2003236298A1 (Atherogenics 50 The clinical data are very Surprising since cutaneous Lupus Pharmaceuticals, Inc) discloses topical compositions of 1,3- Erythematosus are very difficult to treat. bis-(Substituted-phenyl)-2-propen-1-ones inhibiting the Contrarily to existing therapeutic agents applied in the expression of VCAM-1. treatment of cutaneous Lupus Erythematosus, the beta The patent application US2005.130935A1 (Astion Devel adrenoceptoragonists according to the present invention have opment A/S) discloses combinations of beta-adrenoceptor 55 the advantage of not being likely to be associated with any agonist and an aminosugar for the treatment of inflammatory serious side effects, as these agonists are safe and well toler diseases. ated by the organism in pharmacologically relevant doses. The patent application.JP7304647 (KAOCORP) discloses Cutaneous forms of Lupus erythematosus are character compositions for massage comprising one or more com ised by patchy dermal lymphocytic infiltrates, where the pounds selected from (A): (i) a Xanthine derivative, (ii) a 60 majority of infiltrating lymphocytes are T-lymphocytes beta-adrenergic agent, (iii) an alpha-2 adrenergic activity expressing antigens. Without being limited to a particular inhibitor, and (iv) a bipyridine derivative; and (B) a scrubbing theory, the present findings of the novel use of beta-adreno agent. ceptoragonists can be extended to all skin diseases where the The patent application.JP9110674 (KAOCORP) discloses pathology, at least in part, involves expression of beta recep a bathing composition comprising a compound of the plant of 65 tors in leukocytes, such as in the T-lymphocyte. Typically, pepper family (e.g. Piper nigrum L. Piper longum L. Piper Such skin diseases presenting dermal lymphocytic infiltrates angustifolium), carbonate and an organic acid. include all kinds of connective tissue diseases. US 8,426,475 B2 5 6 Therefore, the present invention relates in a first aspect to a Thus, the invention is meant to be directed to the preven method for the treatment or prevention of cutaneous Lupus tion, alleviation and treatment of cutaneous manifestations in Erythematosus or another connective tissue disease affecting an individual Suffering from or diagnosed with a connective the skin in an individual. The method comprises administra tissue disease of the skin, such as cutaneous forms of Lupus tion to said individual of an effective amount of a therapeu Erythematosus. tically active ingredient in the form of a beta-adrenoceptor As used herein, the phrase "cutaneous forms of Lupus agonists, a stereoisomer thereof, an enantiomer thereof, a Erythematosus' and “cutaneous Lupus Erythematosus' are physiologically acceptable derivative thereof, and/or a phar meant to be interchangeable phrases encompassing various maceutically acceptable salt thereof. Preferably, the treat types of LE that have cutaneous manifestations of the disease ment is effected by mono-therapy, wherein no other therapeu 10 in the skin or mucosa of an individual. Such cutaneous forms tically effective ingredient is administered together with the of LE are typically characterised by the presence of the immu beta-adrenoceptoragonists. Furthermore, the administration noglobulins IgG, IgA and IgM and complements at the der is preferably effected by topical application to skin. mal-epidermal junction in skin lesions for 6 weeks or more The inventor has furthermore solved the problem with (Rooks, Textbook of Dermatology, chapter 65, pages 56.5 to topical sensitization of skin caused by beta-adrenoceptor 15 56.69, volume 3, 7" edition, edited by Tony Burns et al. agonists by selecting the particular enantiomer that is phar Blackwell Science, 2004). Some experts tend to categorise macologically active and which does not cause sensitization cutaneous forms of LE into three major types: (1) Acute reactions in skin. Cutaneous Lupus Erythematosus (ACLE), (2) Subacute Therefore, a second aspect of the invention relates to a Cutaneous Lupus Erythematosus (SCLE), and (3) Chronic topically administrable pharmaceutical composition com Cutaneous Lupus Erythematosus (CCLE). A major form of prising: CCLE is Discoid Lupus Erythematosus (DLE) exists together i) a therapeutically active ingredient in the form of enantio with many Sub-groups of cutaneous LE. Such as hypertrophic merically enriched or enantiomerically pure R-enantiomer LE (a form of DLE), Verrucous LE (a form of DLE), Tumid of a beta-adrenoceptor agonist, a physiologically accept LE. lupus panniculitis, disseminated DLE, Bullous SLE, able derivative thereof or a pharmaceutically acceptable 25 Telangietactic LE, Chilblain lupus, Childhood DLE, Lupus salt thereof, and Erythematosus Profundus and Mucosal DLE. The phrase ii) one or more dermatologically acceptable excipients or "cutaneous forms of Lupus Erythematosus' is also meant to carriers. encompass cutaneous manifestations of systemic LE. For The therapeutically active ingredient is preferably the sole example in connection with treating cutaneous manifesta therapeutically agent, or at least the primary therapeutically 30 tions in a Subject diagnosed with SLE. active ingredient included in the topically administrable com Therefore, in interesting embodiments of the present position. invention the treatment of cutaneous forms of Lupus Erythe Where it is desirable to employ additionally therapeuti matosus includes the treatment of Acute Cutaneous Lupus cally active ingredients in the methods, medicaments and Erythematosus, Subacute Cutaneous Lupus Erythematosus, topically administrable compositions of the invention, the 35 Chronic Cutaneous Lupus Erythematosus, cutaneous mani following therapeutically active ingredients are considered as festations of Systemic Lupus Erythematosus, and various less relevant or suitable for the treatment of connective tissue Sub-groups thereof. Such as Discoid Lupus Erythematosus, diseases of the skin and are rather excluded from such meth Hypertrophic Lupus Erythematosus, Verrucous Lupus ods, medicaments and compositions. Such a therapeutically Erythematosus, Tumid Lupus Erythematosus, Lupus Pan active ingredient may be selected from a steroid; Ibudilast or 40 niculitis, Disseminated Discoid Lupus Erythematosus, a related compound; a selective serotonin reuptake inhibitor Bullous Systemic Lupus Erythematosus, Telangietactic (SSRI); a non-steroidal immunophilin-dependent immuno Lupus Erythematosus, Chilblain lupus, Childhood Discoid Suppressant (NSIDI), an anti-histamine; or an aminosugar). Lupus Erythematosus, Lupus Erythematosus Profundus and/ Topically administrable compositions of this invention or Mucosal Discoid Lupus Erythematosus. have the significant advantage of being devoid of cutaneous 45 The terms "cutaneous manifestations and "cutaneous pre atrophy associated with treatment with topical gluco-corti sentations' are interchangeable terms, which refer to a patho costeroids, which have so far been the mainstay treatment of logical or clinical feature present in the skin or in the mucosa cutaneous Lupus Erythematosus. of an individual in risk of Suffering from, or diagnosed with a connective tissue disease of the skin. DETAILED DESCRIPTION OF THE INVENTION 50 Typical cutaneous manifestations (either pathologically or clinically) of cutaneous forms of Lupus Erythematosus The present inventor has recognised the beneficial effect of include the presence of a patchy dermal lymphocytic infil a beta agonist in treating connective tissue diseases, particu trates; liquefaction degeneration of the basal cell layer of the larly in the treatment of cutaneous forms of Lupus Erythema epidermis; oedema of the connective tissue below the epider tOSuS. 55 mis; fibrinoid of the connective tissue below the epidermis; Accordingly, a first aspect of this invention relates to a atrophy of the dermis; keratotic plugging: thinning and pallor method for the treatment or prevention of a connective tissue of the epidermis with relative hyperkeratosis and plugging of disease of the skin, Such as cutaneous forms of Lupus Erythe the follicular mouth; thickening of the basement membrane matosus. The method comprises administration of a sufficient of the epidermis and sometimes Small vessels; premature amount of a beta agonist, a stereoisomer thereof, an enanti 60 elastotic degeneration of collagen in light exposed areas. omer thereof, a physiologically acceptable derivative thereof, A typical clinical feature is skin rash, chilblain-like lesions, and/or a pharmaceutically acceptable salt thereof to the alopecia in Scalp lesions, well-defined erythematous patches affected skin areas of an individual in need thereof. More which may contain scales, hyperkeratosis, telangiectasia, particularly, the beta agonist may in Some embodiments be nodular lesions, non-scarring papulosquamous lesions and the sole therapeutically active ingredient to be administered 65 annular polycyclic lesions. or at least be the primary/first therapeutically active ingredi The cutaneous manifestations may be limited to the skin, ent to be administered. Such as the skin of scalp, ears, nose, lips, arms, legs, fingers, US 8,426,475 B2 7 8 feet, toes, breast, and trunk. Furthermore, the cutaneous cutaneous disease mainly or only affecting the skin. manifestations may be found in the buccal mucosa, Such as Examples of connective tissue diseases of the skin include at lips and tongue and in the mucosa of Vulva and anus. least Scleroderma, Morphoea, Pseudoscleroderma, Occupa The term "DLE' defines a connective-tissue disease affect tional scleroderma, Graft-Versus-host disease, Eosinophilic ing only the skin, most frequently the skin in the face, neck 5 fasciitis, Connective tissue panniculitis, Systemic Sclerosis: and the scalp. DLE is characterised by well-defined red scaly Mixed connective tissue disease; Lichen sclerosus; Sclered patches of variable size (coin-shaped red bumps), which heal erma; Dermatomyositis; Rheumatoid disease: Still's disease: with atrophy, Scarring and pigmentary changes. As DLE Sjögrens syndrome and Rheumatic fever. lesions heal, they leave thickened, scarred areas of skin. When Still other related diseases where lymphocytic infiltrations the scalp is severely affected, there may be associated hair 10 are a pathological feature of the skin disease are Jessner's loss (alopecia). DLE is sometimes called chronic cutaneous lymphocytic infiltration, polymorphic light eruption (PLE), lupus erythematosus (CCLE). lymphocytic lymphoma, lymphocytoma cutis and Pemphig The term “SCLE' defines a specific subset of lupus and ous erythematosus. may be characterised as a non-scarring non-atrophy-produc The term “an individual in need thereof is meant to define ing photosensitive dermatosis. SCLE may occur in patients 15 a human or an animal, such as a mammal that is in need of with systemic Lupus Erythematosus (SLE), Sögren Syn treatment of a connective tissue disease of the skin. The term drome, and in patients with deficiency of the second compo “an individual” refers to an animal, and yet more typically a nent of complement (C2d). It may also be drug induced. Some mammal. The term "Mammal’ as used herein refers to any patients also have the lesions of DLE, and some may develop animal classified as a mammal, including humans, domestic small vessel vasculitis. Therefore, SCLE may be regarded as and farm animals, Zoo, sports, or pet animals. Such as dogs, a cutaneous disease categorised as an intermediate between horses, cats, cattle, etc. Preferably, the individual is a human, discoid Lupus Erythematosus and systemic Lupus Erythema a cat, a dog or a horse. tosus. SCLE may accompany other diseases or the treatment According to the invention, any cutaneous form of LE or of such diseases, such as in the course of PUVA treatment of other connective tissue diseases of the skin that affects both psoriasis, radiation therapy, or in connection with cancer, 25 humans and animals can be treated with a beta agonist. For Such as for example Hodgkin’s disease, cancers of the lung, example, the treatment, uses and medicaments described breast and liver. herein may be applied in the treatment of Lupoiddermatitis in The term “ACLE' defines a “butterfly rash'. The butterfly the dog and Hyperelastosis cutis in the horse. rash has an abrupt onset and can last for hours or days, and Beta-adrenoceptor agonist (Beta agonist) usually heals without Scarring. Typically, it is localized in the 30 According to the underlying principle of the present inven face, but it could occur anywhere on the body. Typically, it is tion, any drug agent or pharmacological tool exhibiting the present in patients diagnosed with SLE. Variations of this rash above-mentioned beta agonistic-activities may be applied in have been observed, including bullous formations or blisters. compositions, methods and uses as defined herein. Systemic Lupus Erythematosus (SLE) is regarded as a The term "beta-adrenoceptor agonist' or “beta agonist' distinct disease from the cutaneous forms of Lupus Erythe 35 is intended to mean any drug agent orpharmacological tool of matosus. Individuals diagnosed with SLE may have cutane inorganic, organic and biological nature with the ability to ous manifestations, such as cutaneous manifestations typi selectively or partially stimulatefactivate beta-adrenergic cally found in ACLE, SCLE and DLE. Some individuals may receptors. These receptors are G-protein coupled receptors suffer from Bullous systemic lupus erythematosus that shows widely distributed in animals and humans and activated by cutaneous manifestations. 40 endogenous catecholamines, and which play important roles Therefore, the phrase “cutaneous manifestations of sys in regulating cardiac, Vascular, pulmonary, and metabolic temic Lupus Erythematosus' is meant to encompass that functions. Some patients diagnosed with Systemic Lupus Erythemato The beta agonist is preferably an organic molecule. SuS also have cutaneous disease, such as cutaneous manifes In one embodiment of the invention, the beta agonist of the tations similar to those found in patients diagnosed with 45 invention is a selective binding partner or at least a predomi ACLE, SCLE and DLE. nant binding partner for a beta-adrenergic receptor. As mentioned, the underlying pharmacodynamic principle In another embodiment of the invention, the beta agonist of this invention relates to enhancing the activity of beta of the invention may also exert binding capacity to other adrenergic receptors in the skin, where such beta-adrenergic families of receptors, such as C1, C2 B1 and B3-adrenergic receptors at least are expressed in leukocytes, such as in the 50 receptors, as long as the agonistic activity towards B-adren T-lymphocyte and wherein the agonistic activity of a beta ergic receptors is sufficient to obtain the desired effects agonist reduces the skin lesions. according to the invention. Thus, the beta agonist may Therefore, a beta agonist may be used in the treatment of exhibit unspecific binding to a beta-adrenergic receptor. all kinds of skin diseases where the lymphocytic infiltration in The beta-agonistic activity of a drug agent or pharmaco the epidermis, dermis, and/or mucosa is a pathological fea 55 logical tool towards beta-adrenergic receptors is easily con ture of the skin disease. firmed by methods known to the person skilled in the art. One Therefore, according to this invention another connective example is by testing the agonistic activity in a binding assay tissue disease of the skin may be treated with a beta agonist. using a ligand representing the beta-adrenergic receptors, The term “connective tissue diseases” refer to a heteroge such as the binding assay conducted by MDS Pharma Ser neous group of diseases, some hereditary, others acquired, 60 vices (Catalogue no. 204110 MDS Pharma Services Discov characterized by abnormal structure or function of one or ery, 2004-2005). The agonistic activity is determined by the more of the elements of connective tissue, i.e., collagen, measure of the concentration (nM) of the beta agonist elastin, or the mucopolysaccharides and wherein the skin can required to produce half maximal effect (ECs). The concen be affected. The phrase, “connective tissue diseases of the tration required should in general be less than 10.000 nM as skin' is meant to define a connective tissue disease that has 65 measured by the binding-based assay conducted by MDS cutaneous manifestations. Thus, the connective tissue disease Pharma Services or according to a similar binding-based may be a systemic disease where the skin is affected or a assay. The concentration resulting in ECso is preferably less US 8,426,475 B2 9 10 than 7000 nM, more preferably less than 5000 nm, such as alkheterocyclyl, and R and R may together form a 5 or 6 less than 4000, 3000, 2000, 1000, 800, 700, 600, 500, 400, membered carbon ring or a carbon ring with one nitrogen 300, 250, 200, 150, 100, 80, 60, 40, 20 or 10 nM. atom (N) in the ring. According to another alternative, the agonist activity of the The term “R” represents a radical selected from hydrido beta agonist of the invention may be determined by a cell (H), halogen (Br, Cl, Fl. I), C-alkyl, C-cycloalkyl, C assay described by McCrea and Hill SJ. (McCrea and Hill S alkenyl and C-alkynyl. J. Salmeterol, along-acting beta-adrenoceptoragonist medi The terms RandR" independently define a radical selected ating cyclic AMP accumulation in a neuronal cell line. Br. J from Co-alkyl, Cale-cycloalkyl, C2-alkenyl, C2-alkynyl, Pharmacol. 1993: 110:619-26.) In one embodiment of the C-alkoxyl, C2-alkaryl, C2-alkheterocyclyl, preferably 10 Co-alkyl, Cale-cycloalkyl, C2-alkenyl, C2-alkynyl and invention, the beta agonist of the invention has a relative Co-alkoxyl. The term "Ce-alkyl is meant to define Satu potency to a selective agonist, Such as formoterol or terbuta rated, straight-chained or branched alkyl radical containing line, between 0.01 and 1000, preferably between 0.1 and 500, from 1 to 6 carbon atoms, e.g. all alkyl radicals from methyl such as between 1 and 200 when tested in the above-men up to hexyl including all isomers thereof, e.g. iso-butenyl. tioned cell assay of McCrea and Hill SJ. 15 The term "Ce-alkenyl' defines unsaturated Straight According to still another alternative, the beta agonist of chained or branched alkylene radicals containing from 2 to 6 the invention has a relative potency to salbutamol of at least carbonatoms, e.g. 1- or 2-propenyl, 1-, 2- or 3-butenyl and the 0.01 and up to 1000 with respect to acting as a beta agonist in like and isomers thereof. the above-mentioned binding-based assay or cell assay. Pref "Ce-alkynyl' defines unsaturated chained or branched erably, the beta agonist has a relative potency to Salbutamol alkynyl radicals containing from 2 to 6 carbon atoms, e.g. ranging between 0.02 and 500, more preferably between 0.1 ethynyl, 1- or 1-propynyl, 1-, 2- or 3-butynyl and the like and and 100 when tested in the above-mentioned cell assay of isomers thereof. McCrea and Hill SJ. The term "Ce-alkoxyl means alkoxy radicals containing Currently, a number of beta agonists are available. Most of up to 6 and preferably up to 4 carbon atoms, e.g. methoxy, them have a structure related to catecholamines. Therefore, in 25 ethoxy, propoxy etc. one embodiment of the invention the beta agonist is selected The term "Ca-cycloalkyl means a cycloalkane having from the group of beta agonists that comprises, as part of from 4 to 7 carbon atoms, such as cyclobutane, cyclopentane their backbone structure, the following structural formula I: and cyclohexane. The term "Cza alkaryl” embraces aryl-substituted alkyl 30 radicals such as benzyl, diphenylmethyl, phenethyl, and diphenethyl having from 7 to 14 carbon atoms. The term “Cz-alkheterocyclyl designates an alkyl sub stituted heterocyclic group having from 7 to 14 carbon atoms X-- in addition to one or more heteroatoms, N. S. P. or O (e.g. y OH 35 3-furanylmethyl 2-furanylmethyl, 3-tetrahydrofuranylm Z ethyl, or 2 tetrahydrofuranylmethyl) Nonlimiting examples 2 R of heterocylics are pyrrolidinyl, tetrahydrofuryl, tetrahydro R3 r furanyl, pyranyl, purinyl, tetrahydropyranyl, piperazinyl, R2 piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl. 40 imidazolyl pyrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl. aziridinyl, furyl, furanyl, pyridyl, pyridinyl, The terms, Z, Y and X, are meant to define substituents of pyridazinyl, pyrimidinyl. the phenyl rings of structural formula I so as to define un The groups, C-alkyl, Cale-cycloalkyl, C2-alkenyl, substituted, mono-substituted, di-substituted or tri-substi C2-alkynyl, C-alkoxyl, C7-14 alkaryl, and C7-14 alkhet tuted phenyl ring, wherein Z. Y and X may be the same or 45 erocyclyl may optionally be mono or di-substituted with pri different. mary amino (NH), secondary amino (NHR'), tertiary amino According to the invention, the terms Z, X, and Y may (NR'R"), OH, cyano, nitro and halogen, wherein RandR" are independently designate radicals selected from hydrido (H), as defined herein. optionally substituted C-alkyl, C-cycloalkyl, C-alk The term “halogen defines bromine, chlorine, fluorine and enyl, C2-alkynyl, Co-alkoxyl, phenyl, C7-alkaryl, 50 iodine. Cz-alkheterocyclyl, acyl (OOR), cyano (CN), urea (NH The term "hydrido” designates a single hydrogenatom (H). CO. NH2), formamide (NH CO), trihalogen methyl, halo In one embodiment, the terms Z, X, and Y may indepen gen (Br, Cl, F, I), hydroxy (OH), hydroxy derivative (OR), dently designate radicals selected from hydrido (H), option primary amino (NH), secondary amino (NHR'), tertiary ally substituted C-alkyl, C-cycloalkyl, C-alkenyl, amino (NR'R"), carboxy (CO), carboxy derivative (CO R'), 55 C2-alkynyl, C-alkoxyl, phenyl, C7-14 alkaryl, C7-14 sulfonyl (HSO), sulfonyl derivative (R' SO) and sulfona alkheterocyclyl (OOR), cyano (CN), urea (NH CO mide (NH SO R'). Furthermore, two of the groups NH2), formamide (NH-CO), trihalogenmethyl, halogen selected from Z, X and Y may together form a 5 or 6 mem (Br, Cl, F, I), hydroxy (OH), hydroxy derivative (OR"), pri bered carbon ring or a carbon ring with one nitrogenatom (N) mary amino (NH), secondary amino (NHR'), tertiary amino in the ring, e.g. where Z and X, Y and X, or Y and Z together 60 (NR'R"), carboxy (CO), carboxy derivative (CO-R), sulfo forms a 5 or 6 membered carbon ring or a carbon ring with one nyl (HSO), sulfonyl derivative (R' SO) and sulfonamide nitrogen atom in the ring (a hetero ring). (NH SO R'), wherein R' and R" preferably designates The terms “R” and “R” refer to substituents of the amino Co-alkyl, C-alkenyl, C-alkynyl and C-alkoxyl. atom that are attached to carbon atom 2 (C) of structural In one further preferred embodiment, the phenyl ring of formula I. R and R may independently designate a radical 65 structural formula I defines un-substituted, mono-substituted selected from hydrido (H), C-alkyl, C-cycloalkyl, C or di-substituted phenyl ring, wherein Z and Y may be the alkenyl, C2-alkynyl, C-alkoxyl, C7-14 alkaryl, C7-14 same or different and X is hydrido (H). US 8,426,475 B2 11 12 Furthermore, in still further embodiments, the groups, Norbudrine (4-2-(Cyclobutylamino)-1-hydroxyethyl-1,2- Co-alkyl, C-cycloalkyl, C-alkenyl, C-alkynyl, C benzenediol); alkoxyl, C- alkaryl, and C-alkheterocyclyl may option Norepinephrine (Arterenol,4-(2-Amino-1-hydroxyethyl)-1, ally be mono-substituted with primary amino (NH), second 2-benzenediol): ary amino (NHR'), OH, cyano, nitro and halogen, wherein R' Orciprenaline (Metaproterenol, 5-1-Hydroxy-2-(1-methyl and R" are as defined herein, such as preferably wherein R' ethyl)aminoethyl-1,3-benzenediol): and R" preferably designates C-alkyl, C-cycloalkyl, Picumeterol (4-Amino-3,5-dichloro-6-2-(2pyridinyl) C2-alkenyl, C2-alkynyl and Co-alkoxyl. ethoxylhexylaminomethyl-benzenemethanol); The compounds of the present invention may contain one Pirbuterol (6-(1,1-Dimethylethyl)aminomethyl-3-hy or more asymmetric carbon atom. Therefore, the instant 10 droxy-2,6-pyridinedimethanol); invention may also include the individual diastereomers and Procaterol (8-Hydroxy-5-1-hydroxy-2-(1-methylethyl) enantiomers, which may be prepared or isolated by methods aminobutyl-2(1H)-quinolinone); known to those skilled in the art. For example, the carbon Protokylol (4-2-2-(1,3-Benzodioxol-5-yl)-1-methylethyl atom designated C represents an asymmetric carbon atom amino-1-hydroxyethyl-1,2-benzenediol); and compounds of structural formula I may be provided as a 15 racemate or as enantiomerically pure or enantiomerically Quinprenaline (8-Hydroxy-(1-methylethyl)aminome enriched 'R' or “S” forms. thyl-5-quinolinemethanol); Examples of beta agonists with a backbone structure Reproterol (7-3-2-(3,5-Dihydroxyphenyl)-2-hydroxy according to structural formula I are: ethylaminopropyl-3,7-dihydro-1,3-dimethyl-1H-pu Amiterol (4-Amino-(1-methylpropyl)aminomethylben rine-2,6-dione); Zenemethanol); Rimiterol (4-(Hydroxy-2-piperidinylmethyl)-1,2-benzene Bamethan ((Butylamino)methyl)-4-hydroxybenzenemetha diol); nol); Salbutamol, (Albuterol (1-(1,1-Dimethylethyl)aminome Bitolterol (4-2-(1,1-Dimethylethyl)amino-1-hydroxy thyl)-4-hydroxy-1,3-benzenedimethanol); ethyl-1,2-phenylene 4-methylbenzoate); 25 Salmefamol (4-Hydroxy--2-(4-methoxyphenyl)-1-meth Butaxamine (CL-1-(1,1-Dimethylethyl)aminoethyl-2,5- ylethylaminomethyl-1,3-benzenedimethanol): dimethoxybenzenemethanol); Salmeterol (4-Hydroxy-'-6-(4-phenylbutoxy)hexyl Carbuterol (5-2-(1,1-Dimethylethyl)amino-1-hydroxy aminomethyl-1,3-benzenedimethanol); ethyl-2-hydroxyphenylurea); Soterenol (N-2-Hydroxy-5-1-hydroxy-2-(methylethyl) Clenbuterol (4-Amino-3,5-dichloro-(1,1-Dimethylethyl) 30 aminoethylphenyl-methanesulfonamide); aminomethyl-benzenemethanol); Sulfonterol (O-(1,1-Dimethylethyl)aminomethyl)-4-hy Clorprenaline (2-Chloro-(1-methylethyl)aminomethyl droxy-3-(methylsulfonyl)methyl-benzenemethanol); benzenemethanol); Terbutaline (5-2-(1,1-Dimethylethyl)amino-1-hydroxy Colterol (4-2-(1,1-Dimethylethyl)amino-1-hydroxy ethyl-1,3-benzenediol); ethyl-1,2-benzenediol): 35 Tulobuterol (2-Chloro-(1,1-dimethylethylamino)methyl Deterenol (4-Hydroxy-(1-methylethyl)aminomethylben benzenemethanol); Zenemethanol); Zilpaterol (4,5,6,7-Tetrahydro-7-hydroxy-6-(1-methyl Dioxethedrin (4-2-(Ethylamino)-1-hydroxypropyl-1,2- ethyl)aminoimidazo[4,5,1-jk] 1 benzazepin-2(1H)-one); benzenediol); Zinterol (N-5-2-(1,1-Dimethyl-2-phenylethyl)amino)-1- Etafedrine (1-(Ethylmethylamino)ethylbenzenemethanol): 40 hydroxyethyl-2-hydroxyphenylmethanesulfonamide). Ethylnorepinephrine (2-Amino-1-(3,4-dihydroxyphenyl)-1- Therefore, some embodiments of the invention include a butanol); beta agonists that is a catecholamine derivative selected from Fenoterol (5-1-Hydroxy-2-[2-(4-hydroxyphenyl)-1-meth the group comprising Amiterol; Bamethan; Bitolterol; Butax ylethylaminoethyl-1,3-benzenediol): amine; Carbuterol, Cimaterol; Colterol; Clenbuterol; Clor Flerobuterol (C-(1,1-Dimethylethyl)aminomethyl-2- 45 prenaline; Colterol: Deterenol; Dioxethedrin; Etafedrine; fluorobenzenemethanol); Ethylnorepinephrine: Fenoterol; Flerobuterol; Formoterol: Formoterol (N-2-Hydroxy-5-1-hydroxy-2-[2-(4-methox Hexoprenaline; Indacaterol; Isoetarine; Isoproterenol (Iso yphenyl)-1-methylethylaminoethylphenylforma prenaline); Mabuterol; Medroxalol; Meluadrine; Nardeterol: mide); Norbudrine; Norepinephrine (Arterenol); Orciprenaline Hexoprenaline (4,4'-1,6-Hexanediylbisimino(1-hydroxy 50 (Metaproterenol); Picumeterol; Pirbuterol; Procaterol; Pro 2,1-ethanediyl)bis-1,2-benzenediol); tokylol; Quinprenaline: Reproterol: Rimiterol: Salbutamol Indacaterol (5-2-(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl) (Albuterol); Salmefamol; Salmeterol: Soterenol; Sulfonterol; amino-1-hydroxyethyl-8-hydroxy-2(1H)-quinolinone); Terbutaline: Tulobuterol; Zilpaterol; Zinterol; a stereoisomer Isoetarine (4-1-Hydroxy-2-(1-methylethyl)aminobutyl thereof; a physiologically acceptable derivative thereof; a 1,2-benzenediol); 55 pharmaceutically acceptable salt thereof, and mixtures Isoproterenol (Isoprenaline, (4-1-Hydroxy-2-(1-methyl thereof. ethyl)aminoethyl-1,2-benzenediol); Mabuterol Further examples of beta agonists include those, which as (4-Amino-3-chloro-(dimethylethylamino)methyl-5-(tri part of their backbone have a structure closely related to the fluoromethyl)benzene methanol): above-mentioned structural formula I, but where the asym Medroxalol (5-2-3-(1,3-Benzodioxol-5-yl)-1-methylpro 60 metric carbon atom (C) is missing: pylaminohydroxyethyl-2-hydroxybenzamide); Un-limited examples are: Meluadrine (2-Chloro-(1,1-dimethylethyl)aminomethyl Broxaterol (3-Bromo-(1,1-dimethylethyl)aminomethyl 4-hydroxybenzenemethanol); 5-isoxazolemethanol) Nardeterol (C-3-(1H-Benzimidazol-1-yl)-1,1-dimethyl Methoxyphenamine (2-Methoxy-N-dimethylbenzeneetha propylaminomethyl-2-fluoro-4-hydroxybenzen 65 namine) and; emethanol); Phenisonone (1-(3,4-Dihydroxyphenyl)-2-(1-methylethyl) 2-(Methylamino)-1-phenyl-1-propanol: amino-1-propanone). US 8,426,475 B2 13 14 Further examples of beta agonists also include those hav thereof, e.g. the sulphate or hydrochloride salt of salbutamol, ing a structure different from structural formula I: or an amino acid salt of Salbutamol. Such as a salt of salbuta Un-limited examples are: mol and an amino acid. Tretoquinol (Trimetoquinol, 1,2,3,4-Tetrahydro-1-(3,4,5- As mentioned the beta agonists may be provided as the trimethoxyphenyl)methyl-6.7-isoquinolinediol); and Stereoisomer thereof, the enantiomer thereof, the physiologi Sibenadet (4-Hydroxy-7-2-2-3-(2-phenylethoxy)propyl cally acceptable derivative thereof, and/or the pharmaceuti sulfonylethylaminoethyl-2(3H)-benzothiazolone). cally acceptable salts thereof. Additionally, a number of beta agonists are presently It will be appreciated by those skilled in the art that the known according to their Research Code: AR-C68397, CHF above-mentioned list of beta agonists may be modified at any 1035, QAB-149 (From Novartis/Skyepharma), GW-685698 10 of the functional groups in the compounds to provide physi (GSK), GW-159797 (GSK), AD-237 (Arakis, Vectura), HOKU-81, 678007 (GSK), 159802 (GSK), 642444 (GSK), ologically acceptable derivatives thereof. Of particular inter 159797 (GSK), 597901 (GSK), KUR-1246, KUL-721 1, est are derivatives formed by modification of the hydroxyl KUL-1248, AR-C89855, 5-1319 and TA-2005. groups or at the amino groups. It will be appreciated by those Accordingly, a beta agonists of this invention may be 15 skilled in the art that the physiologically acceptable deriva selected from the group comprising Amiterol; Bamethan; tives may be derivatized at more than one position. Bitolterol; Butaxamine; Carbuterol; Cimaterol; Colterol; By the term “physiologically acceptable derivatives Clenbuterol: Clorprenaline; Colterol: Deterenol; Dioxethe thereof is meant any physiologically acceptable ester, or salt drin; Etafedrine; Ethyinorepinephrine: Fenoterol; Fle of such ester, of a beta agonists of the invention which, upon robuterol; Formoterol: Hexoprenaline; Indacaterol: Isoetar administration to a human or animal, is capable of providing ine: Isoproterenol (Isoprenaline); Mabuterol; Medroxalol; (directly or indirectly) a beta agonists of the invention oran Meluadrine; Nardeterol: Norbudrine; Norepinephrine (Arter active metabolite or residue thereof. That is to say that the enol); Orciprenaline (Metaproterenol); Picumeterol; Pir physiologically acceptable derivative thereof is meant to buterol; Procaterol; Protokylol; Quinprenaline: Reproterol: define a prodrug of the beta agonist. Typical examples of Rimiterol: Salbutamol (Albuterol); Salmefamol; Salmeterol: 25 Suitable esters are formate, acetate, proprionate, and benzoy Soterenol; Sulfonterol; Terbutaline; Tulobuterol; Zilpaterol; late. Zinterol; Broxaterol; Methoxyphenamine; Phenisonone; Tre By the term “pharmaceutically acceptable salts' is meant toquinol (Trimetoquinol); Sibenadet; AR-C68397: CHF salts of a beta agonist that are derived from physiologically 1035; QAB-149; GW-685698 (GSK); GW-159797 (GSK); acceptable inorganic and organic acids and bases. Examples AD-237 (Arakis; Vektura); HOKU-81; 678007 (GSK); 30 of suitable acids include hydrochloric, hydrobromic, sulphu 159802 (GSK); 642444 (GSK); 159797 (GSK); 597901 ric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, (GSK); KUR-1246; KUL-7211; KUL-1248: AR-C89855; lactic, Salicylic, succinic, toluene-p-Sulphonic, tartaric, ace S-1319; TA-2005 or a stereoisomer thereof, an enantiomer tic, citric, methanesulphonic, formic, benzoic, malonic, naph thereof, a physiologically acceptable derivative thereof, and/ thalene-2-Sulphonic and benzenesulphonic acids. Further or a pharmaceutically acceptable salt thereof. 35 more, salts may be derived from natural amino acids, such as In interesting embodiments of the invention, the beta ago from an essential amino acid. nist has a Suitable log P value and a molecular size that are The beta agonist can be Supplied in the form of a pharma very well Suited and adaptable for topical application to skin. ceutically active salt, a prodrug, an isomer, a tautomer, a Therefore, a beta agonist of this invention preferable has a racemic mixture, or in any other chemical form or combina log Pvalue ranging between -4 to 4, preferable between -3.5 40 tion thereof that, under physiological conditions, still pro and 3.5, even more preferable between -3 and 3. Optimally, vides agonistic activity towards the beta-adrenergic recep the log P value ranges between -3.5 and 3, such as between tor. The present invention includes all possible diastereomers -3.5 and 2.5, such as between -3.5 and 2. Furthermore, the and enantiomers as well as their racemic and resolved, enan molecular weight of a beta agonist od thid invention should tiomerically pure forms. be less than 800 Dalton, preferable less than 700, 600 and 500 45 The enantiomeric forms may be of either the (R) or the (S) Dalton. Even more preferable less than 450 Dalton, such as configuration, or may be a mixture thereof. Thus, the beta less than 400 Dalton. Instill more preferred embodiments, the agonist according to the invention may be enantiomerically molecular weight is less than 300 Dalton, Such as ranging pure, or be stereoisomeric or diastereomeric mixtures. from about 136 to about 500 Dalton, from about 136 to 450 The term “stereoisomers thereof encompasses any iso Dalton, 136 to 400 Dalton. In even more preferred embodi 50 mers that possess identical constitution, but which differ in ments, the beta agonist has a molecular weight ranging from the arrangement of their atoms in space, such as enantiomers, 136 to about 350 Dalton, such as from 136 to 300 Dalton. diastereoisomers, and cis-trans isomers. Therefore, in more preferred embodiments, the beta ago In interesting embodiments of the invention, wherein the nist is a catecholamine derivative selected from the group beta agonist has an asymmetric carbon atom, the beta ago comprising Amiterol; Bamethan; Butaxamine; Carbuterol; 55 nist is Supplied as an enantiomeric pure or enantiomeric Cimaterol; Colterol; Clenbuterol: Clorprenaline; Colterol: enriched form. The term “enantiomeric enriched form’ Deterenol; Dioxethedrin; Etafedrine; Ethylnorepinephrine; encompasses mixtures of R and Senantiomers, where either Isoetarine; Isoproterenol (Isoprenaline); Mabuterol; Medrox the R or the Senantiomer is quantitatively present in excess of alol; Meluadrine; Norbudrine; Norepinephrine (Arterenol): either the S or R enantiomer, respectively. When they are Orciprenaline (Metaproterenol); Procaterol; Rimiterol: Salb 60 diastereoisomers, it is called diastereoselectivity and is quan utamol (Albuterol); Salmefamol; Salmeterol; Soterenol; Sul titatively expressed by the diastereoisomer excess. The enan fonterol; Terbutaline; Tulobuterol; a stereoisomer thereof, an tiomeric enriched form encompasses mixtures of the two enantiomer thereof, a physiologically acceptable derivative enantiomers, where the ratio of the Renantiomer to the S thereof, and/or a pharmaceutically acceptable salt thereof. enantiomer is ranging between 70:30 to 100:0, such as where In a currently interesting embodiment of the invention, the 65 at least 70% of the mixture is in the form of the Renantiomer, beta agonist is salbutamol or a physiologically acceptable such as at least 75%, 80%, 85%,90; or 95% is present in the derivative thereof, and/or a pharmaceutically acceptable salt form of the Renantiomer. US 8,426,475 B2 15 16 It is well known in the art that Rand Senantiomers often Salmefamol, Zilpaterol a physiologically acceptable deriva possess distinctive biological activities. Therefore, in inter tive thereof and/or a pharmaceutically acceptable salt. esting embodiments of the invention, where the beta agonist In a current interesting embodiment of the invention the is a catecholamine derivative with one asymmetric carbon beta agonist is R-salbutamol or a physiologically acceptable atom at C of structural formula I, the beta agonist is pro derivative thereof, and/or a pharmaceutically acceptable salt vided in the R-enantiomeric form because the inventor has thereof, such as the sulphate or hydrochloride salt of R-salb shown that the topical application of this enantiomer does not utamol or an amino acid salt of salbutamol. Such as a salt of cause adverse reactions, such as those reported for the corre salbutamol with an amino acid. R-salbutamol is also known sponding racemic mixture. Furthermore, the inventor has also as levo-salbutamol, R-albuterol or levalbuterol. proved that this enantiomer is effective in the topical treat 10 Other preferred beta agonists are R-terbutaline and RR ment of connective tissue diseases. Formoterol. Manner of Administration and Doses Therefore, in presently preferred embodiments of the A beta agonist of the invention may be administered to an invention, the beta agonist is provided as the enantiomer, individual through any route of administration resulting in which is pharmacologically active in the treatment of connec 15 either local presence of the agonist in skin or in mucous or tive tissue diseases and which further does not cause sensiti systemic presence of the agonist. Routes of administration for Zation of the skin after topical application to skin. According the various embodiments include, but are not limited to, topi to this invention, such embodiments include at least enantio cal, transdermal, nasal, and systemic administration (such as, merically pure or enantiomerically enriched R-enantiomer of intravenous, intramuscular, Subcutaneous, inhalation, rectal, beta agonists comprising in their backbone the spatial R buccal, vaginal, intraperitoneal, intraarticular, ophthalmic, configuration at C of structural formula I as depicted above. otic, or oral administration). As used herein, “systemic Such preferred embodiments of the invention comprises a administration” refers to all nondermal routes of administra beta agonist according to formula I, wherein the carbonatom tion, and specifically excludes topical routes of administra C of structural formula I designate an asymmetric carbon tion. atom with Substituents forming an R-configuration. 25 The phrase “local presence of the agonist in skin or Thus, a beta agonist of this invention may be provided as mucous' is meant to include topical administration of the the enantiomeric form that has the spatial R-configuration at beta agonists to skin or mucous, such as mucous of the eye, C of structural formula I. Such a beta agonist may be enan buccal cavity, nasal cavity, or intestinal tract with the pre tiomerically pure or enantiomerically enriched R-enantiomer Sumption that systemic uptake of the beta agonists is limited of a beta agonist selected from Amiterol; Bamethan: 30 or nil. Thus, it is intended that less than 15% by weight, such Bitolterol; Butaxamine; Carbuterol; Cimaterol; Colterol; as less than 10%, 8%, 5% and 3% by weight, of the topically Clenbuterol: Clorprenaline; Colterol: Deterenol; Dioxethe administered agonist according to the invention may enter the drin; Etafedrine; Ethylnorepinephrine: Fenoterol; Inda blood stream or be recovered in urine and faeces. caterol: Isoproterenol (Isoprenaline); Mabuterol; Melu The phrases 'systemic presence of the agonist' and “sys adrine; Nardeterol; Norbudrine; Norepinephrine (Arterenol): 35 temic administration' are interchangeable terms and are Orciprenaline (Metaproterenol); Picumeterol; Pirbuterol: meant to include any form of administration of the beta Quinprenaline; Reproterol: Salbutamol (Albuterol); Salme agonists resulting in the entrance of the agonist into the blood terol, Soterenol; Sulfonterol; Terbutaline; Tulobuterol; stream. Therefore, the agonist may be administered by the Zinterol; a physiologically acceptable derivative thereof and/ per-oral, transdermal, transmucosal or the parenteral route. or a pharmaceutically acceptable salt thereof. In Such 40 In a currently interesting embodiment of the invention, the embodiments R of structural formula I designate hydrido beta agonist is intended for the local treatment of the skin and only. is to be administered topically, Such as to the skin an indi In other embodiments, where R designates a radical vidual. The treatment is preferentially accomplished by topi selected from the group consisting of halogen, C-alkyl, cal application of a beta agonist as defined herein to the Co-cycloalkyl, C2-alkenyland C2-alkynyl, the beta-ago 45 affected skin areas for the local treatment of the skin. In such nist may be provided in two diastereomeric forms both having embodiments, the systemic absorption following the topical the spatial R-configuration at C such as the RR or RS dias application should be limited or nil. tereomer of Ethylnorepinephrine, Flerobuterol, Formoterol, The potency of beta-adrenergic agonists varies signifi Hexoprenaline, Isoetarine, Medroxalol, 2-(Methylamino)-1- cantly for which reason the sufficient clinically relevant dose phenyl-1-propanol, Procaterol, Protokylol, Rimiterol, 50 to be applied as well as the necessary dosage regimen to be Salmefamol and Zilpaterol a physiologically acceptable applied may vary significantly. derivative thereof and/or a pharmaceutically acceptable salt, In the case of systemic administration, the daily total dose wherein the R in RS refer to the asymmetric carbon C1 of would typically be in the range of 0.000001-5 mg/(kg body structural formula I. It should be understood that such dias weight) depending on the duration of the treatment, the phar tereomers can be provided as the diastereomeric pure RS or 55 maceutical formulation of the beta agonist and the bioavail RR isomer or as the diastereomeric enriched RS or RR iso ability following per-oral administration, transdermal, trans C. mucosal or parenteral administration. The skilled person will Therefore, the term “R-enantiomers of beta agonist' is appreciate that the total daily dose may be divided into one or meant to include any beta agonists comprising in their back more doses, such as two doses per day or three doses per day. bone the R-enantiomer configuration of structural formula I, 60 In case of topical administration, the daily dose of the despite the fact that they have an additional chiral centre. beta-adrenergic agonist is defined according to the concen Thus, an R-enantiomers of a beta agonist encompasses RR tration of the beta-adrenergic agonist in the topically admin and RS enantiomers, where the first mentioned R refer to the istrable composition. The concentration of the beta-adren chiral centre of the carbon atom C1 of structural formula I, ergic agonist is typically in the range of 0.0001-50.0% (w/w) such as Ethylnorepinephrine, Flerobuterol, Formoterol, 65 depending on the duration of the treatment, the type of for Hexoprenaline, Isoetarine, Medroxalol, 2-(Methylamino)-1- mulation and the number of times that the topical composi phenyl-1-propanol, Procaterol, Protokylol, Rimiterol, tion is to be applied daily. US 8,426,475 B2 17 18 As mentioned in a current interesting embodiment of the invention, the beta agonist is R-salbutamol or a pharmaceu II tically acceptable salt thereofand the effective total daily dose with respect to R-salbutamol to be administered systemically 2 e is between 0.05 mg to 10 mg, preferably between 1-2.5 mg. 5 Concerning, topically administrable R-salbutamol or a phar X Sa Sa 1 10H maceutically acceptable salt thereof, the preferred concentra Z tion with respect to R-salbutamol is between 0.01-10.0% 2 R (w/w), preferably between 0.05-5.0% (w/w). R3 In considering administering a beta agonist, either as the 10 R racemic mixture or as the R-enantiomer, topically to skin, a topically administrable composition should preferably com prise the beta agonistinian amount ranging between 0.01 and wherein the terms Z. Y. X, R. R. R. R. R" are as defined 10% by weight, preferably between 0.05 and 7% by weight, above with respect to structural formula I; and wherein the such as between 0.05 and 6% by weight, 0.05 and 5.5% by 15 composition further comprises one or more dermatologically weight, 0.05 and 5% by weight, 0.05 and 4.5% by weight, acceptable excipient or carrier. 0.05 and 4% by weight, 0.05 and 3.5% by weight, such as 0.05 Specifically, such a topically administrable composition and 3% by weight. In still more preferable embodiments of comprises as the therapeutically active ingredient a beta the invention, the dermatological formulation should com adrenoceptoragonist according to formula II or a physiologi prise a beta agonist in an amount ranging between 0.2 and 20 cally acceptable derivative thereof or a pharmaceutically 7% by weight, preferably between 0.2 and 6.5% by weight, acceptable salt thereof, wherein the carbon atom at C desig such as between 0.2 and 6% by weight, 0.2 and 5.5% by weight, 0.2 and 5% by weight, 0.2 and 4.5% by weight, 0.2 nate an asymmetric carbon having R-configuration and and 4% by weight, 0.2 and 3.5% by weight, such as 0.2 and wherein the terms Z. Y. X, R. R. R. R. R" are as defined 3% by weight. In further preferable embodiments of the 25 above. invention, the dermatological formulation should comprise a Such an R-enantiomer (provided as enantiomerically pure beta agonist in an amount ranging between 0.2 and 2.5% by or as enantiomerically enriched) is preferably selected from weight, such as about 0.5%. 1, 1.5, and 2% by weight. the group consisting of enantiomerically pure or enantiomeri Topically Administrable Compositions cally enriched R-enantiomer of Amiterol, Bamethan, As mentioned, the safe administration of a beta agonist 30 Bitolterol, Butaxa mine, Carbuterol, Cimaterol, Colterol, may require the administration of an enantiomer or a diaste Clenbuterol, Clorprenaline, Colterol, Deterenol, Dioxethe reomer, which does not cause sensitization of skin and still drin, Etafedrine, Ethylnorepinephrine, Fenoterol, Inda possesses beta-adrenergic receptor agonistic activity. caterol, Isoproterenol, Mabuterol, Meluadrine, Nardeterol, Therefore, still another aspect of the invention relates to a Norbudrine, Norepinephrine, Orciprenaline, Picumeterol, dermatological/topical administrable pharmaceutical com- 35 Pirbuterol, Quinprenaline, Reproterol, Salbutamol, Salme position comprising an R enantiomer of a catecholamine terol, Soterenol, Sulfonterol, Terbutaline, Tulobuterol, derived beta agonist, either Supplied in the form of the enan Zinterol, physiologically acceptable derivatives thereof, and tiomerically pure enantiomer or as the enriched enantiomer, pharmaceutically acceptable salts thereof. and which composition further comprises one or more der Where the beta agonist of structural formula II has more matologically acceptable excipients or carriers. 40 than one asymmetric carbon, Such as two symmetric carbon The term “which does not cause sensitization' is meant to atoms, the beta agonist may be provided as the diastereomer define that an enantiomer of a beta agonist does not produce where the asymmetric carbon at C of structural formula II contact sensitization of skin or ear Swelling when applied in a has the R-configuration. Such beta agonists may be selected concentration corresponding to its therapeutically effective from Flerobuterol, Formoterol, Hexoprenaline, Isoetarine, concentration, typically between 0.5% and 5% w/w in the 45 Medroxalol, Procaterol, Protokylol, Rimiterol, Salmefamol, contact sensitization test or ear Swelling challenge test Zilpaterol physiologically acceptable derivatives thereof, and described by Kalish R et al (Kalish R et al. Sensitization of pharmaceutically acceptable salts thereof. mice to topically applied drugs. albuterol, chlorpheniramine, In still other embodiments, the topically administrable clonidine and nadolol. Contact Dermatitis 1996 August; composition comprises as the beta agonist the RR or RS 35(2):76-82). Alternatively, test for skin sensitization may be 50 diastereomeric form of beta agonists selected from Fle carried out according to the Magnusson and Kligman method robuterol, Formoterol, Hexoprenaline, Isoetarine, Medrox (J. Invest. Dermatol. 1969. 52, 268-276) and in accordance alol, Procaterol, Protokylol, Rimiterol, Salmefamol, Zil with O.E.C.D. Guideline N° 406 of Jul. 17th, 1992, and the paterol, a physiologically acceptable derivative thereof, and a test method B.6 of the 96/54 E.E.C Directive. pharmaceutically acceptable salt thereof. The phrase “topical administrable pharmaceutical compo- 55 As mentioned, the present inventor has shown that the sition' encompasses compositions formulated for application R-enantiomer of Salbutamol does not confer skin sensitiza to skin and which are either ready to be applied directly to tion to skin following topical application. Therefore, in a skin without further dilution or are the result of diluting a currently interesting embodiment of the invention, the topical concentrate of the beta agonist in a physiological acceptable composition comprises R-salbutamol or another closely carrier before being applied to skin. 60 related beta agonist, which also has the R configuration at Therefore, the invention provides a topically administrable carbon atom C of structural formula I. pharmaceutical composition comprising as the therapeuti In a currently interesting embodiment, the topically admin cally active ingredient an enantiomerically pure or an enan istrable composition comprises: tiomerically enriched R-enantiomer of a beta agonist or a i) R-salbutamol, a physiologically acceptable derivative physiologically acceptable derivative thereof or a pharma- 65 thereof or a pharmaceutically acceptable salt thereof; and ceutically acceptable salt thereof, wherein the beta agonist is ii) one or more dermatologically acceptable excipients or defined according to structural formula II; carriers. US 8,426,475 B2 19 20 The salt is preferably in the form of the sulphate or hydro In one embodiment, the topical administrable composition chloride salt of R-salbutamol or an amino acid salt of salb is a cream. Creams are typically oil-in-water emulsions that utamol. Such as a salt of Salbutamol with an essential amino contain more than 30% of hydrophilic phase, such as water or acid. aqueous buffers. The skilled person will appreciate that topically adminis A typical dermatological formulation for use in the present trable compositions of the invention may be in any form invention may be provided in the form of an emulsion, such as suitable for being topically applied to skin and with the inten oil-in-water emulsion consisting of an R-enantiomer of a tion to avoid or at least minimise systemic absorption of the beta agonist according to this invention in an amount ranging beta agonist. between 0.01% and 20% by weight and the following derma 10 tologically acceptable ingredients: a fatty component in an Accordingly, the composition may be in the form of an amount ranging between 2 and 30% by weight of the com emulsion Such as a cream or a lotion, a gel, a solution, a position; an oily component in an amount ranging between 2 liniment, an ointment, pasta, a spray, an aerosol, a foam, a and 30% by weight of the composition; water in an amount liquid or a powder, preferably formulated in a manner that ranging between 30% and 90% by weight of the composition; limits the systemic uptake, e.g. Such that less than 15% by 15 an emulsifier in an amount ranging between 0.2 and 10% by weight, such as less than 10%, 8%, 5% and 3% by weight, of weight of the composition; an emollient in an amount ranging the topically administered agonist of the invention enters the between 1 and 20% by weight of the composition; optionally blood stream following topical administration to the skin or is a lipophilic solvent in an amount ranging between 1 and 20% recovered in urine and faeces. by weight of the composition, optionally a hydrophilic Sol In other embodiments of the invention, a systemic uptake is vent in an amount ranging between 1 and 20% by weight of tolerable. Therefore, transdermal formulations may also refer the composition; optionally a thickener in an amount ranging to a dermatological composition of the invention. between 0.2 and 10% by weight of the composition; option The concentration of the beta agonist may vary signifi ally a co-emulsifier in an amount ranging between 0.2 and cantly depending on its potency. The concentration in the 10% by weight of the composition; optionally a preservative compositions would typically be in the range of 0.0001 25 in an amount ranging between 0.05 and 3% by weight of the 50.0% (w/w) depending on the duration of the treatment, the composition; optionally an antioxidant in an amount ranging type of formulation and the number of times that the topical between 0.05 and 3% by weight of the composition; option composition is to be applied daily. More preferable, the con ally a pH adjuster in an amount ranging between 0.05 and 3% centration is in the range of 0.01 and 10% by weight, such as by weight of the composition, optionally a chelating agent in 30 an amount ranging between 0.05 and 3% by weight of the more typically 0.02% and 5%. Even more preferably the composition, with the proviso that all constituents make up concentration is between 0.05 and 5% by weight, 0.05 and 100% by weight of the composition. 4.5% by weight, 0.05 and 4% by weight, 0.05 and 3.5% by According to another embodiment, the composition is for weight, such as 0.05 and 3% by weight. In still more prefer mulated as an ointment. Ointments are typically water-in-oil ably embodiments of the invention, the dermatological for 35 emulsions that contain up to 70%, but preferably from mulation should comprise a beta agonist in an amount rang approximately 20% to approximately 50%, water or aqueous ing between 0.2 and 7% by weight, preferably between 0.2 phases. Hydrocarbons are especially Suitable as fatty phase; and 6.5% by weight, such as between 0.2 and 6% by weight, e.g. Vaseline, paraffin oil and/or hard paraffins, which prefer 0.2 and 5.5% by weight, 0.2 and 5% by weight, 0.2 and 4.5% ably contain Suitable hydroxy compounds, such as fatty alco by weight, 0.2 and 4% by weight, 0.2 and 3.5% by weight, 40 hols or esters thereof, for example cetyl alcohol or wool wax such as 0.2 and 3% by weight. In still more preferable alcohol or wool wax, in order to improve their capacity to embodiments of the invention, the dermatological formula bind water. Emulsifiers are corresponding lipophilic sub tion should comprise a beta agonist in an amount ranging stances, such as Sorbitan fatty acid esters (Spans), for example between 0.2 and 2.5% by weight, such as about 0.5%. 1, 1.5, sorbitan oleate and/or sorbitan isostearate. Additives to the and 2% by weight. 45 aqueous phase are, interalia, moisture-retaining agents. Such Where the topically administrable composition comprises as polyalcohols, for example glycerol, propylene glycol, Sor R-salbutamol or a physiologically acceptable derivative bitol and/or polyethylene glycol, and preservatives, per thereof or a pharmaceutically acceptable salt thereof, the fumes, etc. preferred concentration with respect to R-salbutamol is According to another embodiment, the composition is for between 0.01 and 5.0% (w/w), preferably between 0.05 and 50 mulated as an fatty ointment which are anhydrous and contain 2.0% (w/w). In view of the good tolerability of R-salbutamol, as base material especially hydrocarbons, for example paraf the composition to be administered may contain even higher fin, Vaseline and/or liquid paraffins, and natural or partially amounts, such as up to 10 and 20% by weight, e.g. between synthetic fats, for example coconut fatty acid triglyceride, or 0.01% and 10% by weight of the composition. preferably hardened oils, for example hydrogenated ground The pharmaceutical compositions of the invention may be 55 nut or castor oil, and fatty acid partial esters of glycerol, for formulated in any solid, semi-solid or fluid form suitable for example glycerol mono- or di-stearate, and also, for example, being administered topically according to conventional phar the fatty alcohols that increase the water absorption capacity maceutical practice, see, e.g., “Remington: The Science and and the emulsifiers and/or additives mentioned in connection practice of pharmacy’ 20th ed. Mack Publishing, Easton Pa., with the ointments. 2000 ISBN 0-912734-04-3 and “Encyclopaedia of Pharma 60 According to another embodiment, the composition is for ceutical Technology', edited by Swarbrick, J. & J. C. Boylan, mulated as paste, which is a cream and ointment with secre Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9. tion-absorbing powder constituents, such as metal oxides, for Generally speaking, dermatological compositions may be example titanium oxide or Zinc oxide, also talc and/or alu provided in several designs such as in the form of an emulsion minium silicates, the function of which is to bind any mois (including a microemulsion and a liposome formulation), gel. 65 ture or secretions present. Solution, liniment, ointment, foam, spray, aerosol, micro According to another embodiment, the composition is for sponge, patch or powder. mulated as a gel. In the case of gels, a distinction is made US 8,426,475 B2 21 22 between aqueous and anhydrous or low-water-content gels esters offatty acids and ethylene oxide, e.g. polyoxyeth which consist of Swellable, gel-forming materials. Especially ylene Sorbitan monooleate (Tween). Typical fatty com transparent hydrogels based on inorganic or organic macro ponents may be selected from the group comprising molecules are used. High molecular weight inorganic com petrolatum, paraffins, vegetable oils, animal fats, syn ponents having gel-forming properties are predominantly thetic glycerides, waxes, lanolin, and liquid polyalkyl water-containing silicates, such as aluminium silicates, for siloxanes. Typical fatty components are but not limited example betonite, magnesium aluminium silicate, for to solid macrogols (polyethylene glycols). example Veegum, or colloidal silica, for example aerosil. As Aaueous phase, which constitutes the hydrophilic phase high molecular weight organic Substances, e.g. natural, semi and which mainly comprise water, hydrophilic solvents, synthetic or synthetic macromolecules are used. Natural and 10 Surfactants, emulsifier, preservatives, pH adjusters, fla semi-synthetic polymers are derived from, e.g. polysaccha Vours, colours and other hydrophilic ingredients. rides having very varied carbohydrate building blocks, such Hydrophilic solvents which may be added to the aqueous as celluloses, starches, tragacanth, gum arabic, agar-agar, phase, such as polar solvents in the form of water, pro gelatine, alginic acid and salts thereof, for example sodium pylene glycol, glycerol, Sorbitol, ethanol, industrial alginate, and derivatives thereof. Such as lower alkylcellulo 15 methylated spirit, polyethylene glycols, propylene gly ses, for example methyl- or ethyl-celluloses, and carboxy- or cols, propylene carbonate, and triacetin. hydroxy lower alkylcelluloses, for example carboxymethyl Lipophilic solvents, such as nonpolar solvents in the form or hydroxyethyl-celluloses. The building blocks of synthetic, of isopropyl alcohol and medium chain triglycerides gel-forming macromolecules are, e.g. corresponding Substi (MCT) which may be added to the lipophilic phase. tuted unsaturated aliphatic compounds. Such as vinyl alcohol, Emollients, such as fatty acid mono, di or triglycerides, vinylpyrrolidine, acrylic acid or methacrylic acid. Examples and fatty acid esters, dodecane, squalane, cholesterol, of Such polymers are polyvinyl alcohol derivatives, such as isohexadecane, isononylisononanoate, PPG Ethers, pet polyviol, polyvinylpyrrolidines, such as collidine, polyacry rolatum, lanolin, safflower oil, castor oil, coconut oil, lates and polymethacrylates, such as Rohagit S or Eudispert. cottonseed oil, palm kernel oil, palm oil, peanut oil, Customary additives, such as preservatives or perfumes, may 25 Soybean oil, polyol carboxylic acid esters, derivatives be added to the gels. thereof and mixtures thereof. According to another embodiment, the composition is for Emulsifiers (emulsifying agents), which may be added mulated as a foam. Foams are administered, e.g. from pres either to the aqueous phase or to the oil phase: Compo Surised containers and are oil-in-water emulsions in aerosol sitions of the present invention can include one or more form, there being used as propellants halogenated hydrocar 30 emulsifiers to emulsify the composition. As used herein, bons, such as chlorofluoro-lower alkanes, e.g. dichlorodifluo the term "emulsifier” means an amphiphilic molecule romethane or dichlorotetrafluoroethane. As oily phase e.g. possessing both polar and non-polar regions which are hydrocarbons, such as paraffin oil, fatty alcohols, for example covalently bound and capable of reducing the Surface cetyl alcohol, fatty acid esters, such as isopropylmyristate, tension of water and for the interfacial tension between and/or other waxes are used. AS emulsifiers, the following 35 water and an immiscible liquid. The term is meant to mixtures are used: e.g. mixtures of those having predomi include Soaps, detergents, emulsifiers, Surface active nantly hydrophilic properties, such as polyoxyethylene Sor agents, and the like. The emulsifier can be cationic, bitan fatty acid esters (Tweens), and those having predomi anionic, non-ionic, or amphoteric. This includes a wide nantly lipophilic properties, such as Sorbitan fatty acid esters variety of conventional emulsifiers; (Spans). The customary additives, such as preservatives, etc. 40 Non-ionic Emulsifiers. Examples of non-ionic emulsifiers are added thereto. include, but are not limited to, Polyol esters including Typically, a dermatologically acceptable ingredient to be glycols (e.g. ethylene glycol, diethylene glycol, glycol used in the various formulations can be selected from the Stearate and propylene glycol monoesters of fatty acids following ingredients: (propylene glycol Stearate, propylene glycol oleate or Oily components, which are constituents of the hydropho 45 propylene glycol palmitostearate)) and glycerol esters bic phase of the various dermatological compositions (e.g. glyceryl Stearate, glyceryl monooleate, glyceryl forms and which may be made of one of the following monolaurate, glyceryl ricinolate, glyceryl monocapry dermatologically acceptable ingredients or a mixture of late); two or more thereof: almond oil, castor oil, cacao butter, Sorbitan derivatives, that consists of esters of cyclic anhy coconut oil, corn oil, cottonseed oil, linseed oil, olive oil, 50 drides of sorbitol with a fatty acid (C12-C18). Sorbitan palm oil, peanut oil, poppy seed oil, rapeseed oil, sesame derivatives are divided into two groups i) sorbitan esters oil, soybean oil, Sunflower oil, and teaseed oil), mineral of fatty acids (e.g. Sorbitan monolaurate, Sorbitan oils, fatty oils, liquid paraffin, mineral oil, isopropyl monooleate, sorbitan monostearate (SPAN 60TM), sor myristate, beewax, cottonseed oil, cetosteraryl alcohol bitan monopalmitate, Sorbitan sesquioleate, Sorbitan tri (including mixtures of cetosteraryl alcohol and sodium 55 oleate or Sorbitan tristearate) and ii) polyoxyethylene laurilsulfate), lanolin, white soft paraffin, yellow soft Sorbitan esters (e.g. polyoxyethylene Sorbitan paraffin, canola oil, cetyl alcohol (cetanol), peanut oil, monostearate (TWEEN 60 TM), polyoxyethylene sorbi oleic acid, isopropyl palmitate, castor oil, Stearyl alco tantristearate (TWEEN 65TM), polyoxyethlene sorbitan hol, jojoba oil, Stearic acid and silicone oils. monooleate (TWEEN 80TM); Fatty components which are constituents of the hydropho 60 Polyoxyethylene esters (also called macrogol esters) are bic phase of the various dermatological compositions mixtures of mono- or di-fatty acids esters (from C12 to forms and may be used in combination with or instead of C18) of polyoxyethylene glycol (PEG), e.g. stearate the oil phase and typically includes one or more ingre esters of PEG (PEG-40, PEG-50 and PEG-55), laurate, dients selected from beeswax, paraffin, petrolatum, trig oleate, and myristate esters of PEG, lycerides, cetyl palmitate, vegetable oils, Sorbitan esters 65 Polyoxyethylene ethers are ethers of macrogol and fatty offatty acids (Span), Solid macrogols (polyethylene gly alcohols, such as ethers of the alcohols: stearyl (steareth cols), and condensation products between Sorbitan emulsifiers), cetosteraryl (including mixtures of ceto US 8,426,475 B2 23 24 steraryl alcohol and sodium laurilsulfate, ceteareth 8 and 20, such as in the range between 10 and 20. Most emulsifiers) and oleyl (oleth emulsifiers); preferred emulsifiers have an HLB of at least 12, such as at Poloxamers that are polyoxyethylene-polyoxypropylene least 15. One or more emulsifiers may be used in the compo derivatives with polyoxyethylene groups (e.g. poloxam sitions of the present invention at a suitable level to produce ers-188); the desired result. In a preferred embodiment, the one or more Nonylphenyl ethers (nonoxinols) that are ethoxylated non emulsifier are present in a total amount of at least 0.1 wt %, ylphenols; more preferably at least 0.5 wt %, and even more preferably Propylene glycol Diacetate; at least 1.0 wt %, based on the total weight of the ready to use Polyvinyl alcohol: composition. In order to avoid irritation caused by an emul Alkanolamides prepared from reaction of fatty acids with 10 sifier, in a preferred embodiment the emulsifier is present in a mono or diethanolamine; total amount of no greater than 10 wt %, more preferably no Fatty alcohols (e.g. cetyl alcohol and Stearate alcohol); greater than 5 wt %, even more preferably no greater than 3 wt alkyl glucosides; %, and even more preferably no greater than 2 wt %, based on alkyl polyglucosides; polyhydroxy fatty acid amides; the total weight of the ready to use composition. Sucrose esters; 15 Polymeric thickeners which may be added to the hydro fatty acid alkanolamides; philic phase; e.g. gums such as acacia, alginates, carag ethoxylated fatty acids: eenan, chitosan, collagen, tragacanth and Xantham; cel ethoxylated aliphatic acids; luloses, such as Sodium carboxymethyl-, ethoxylated fatty alcohols (e.g., octyl phenoxy poly hydroxymethyl-, hydroxypropyl- and hydroxypropylm ethoxyethanoal available under the trade name TRITON ethyl celluloses; acrylic acids, Such as carbomers and X-100 and nonyl phenoxy poly(ethyleneoxy) ethanol polycarbophil; colloidal solids such as silica, clays and available under the trade name NONIDET P-40, both microcrystalline cellulose; hydrogels such as polyvinyl from Sigma, St. Louis, Mo.); alcohol and polyvinylpyrrolidone; thermoreversible ethoxylated and/or propoxylated aliphatic alcohols; polymers such as poloxamers. ethoxylated glycerides; 25 pH adjuster (buffering agents) which may be added to the ethoxylated propoxylated block copolymers such as PLU hydrophilic phase, such as diethanolamine, lactic acid, RONIC and TETRONIC Surfactants available from monoethanolamine, triethanolamine, Sodium hydrox BASF. ide, Sodium phosphate, citric acid, acetic acid, tartaric Cationic Emulsifiers. Examples of cationic emulsifiers acid, hydrogen phosphoric acid, phosphate salts and include, but are not limited to: Salts of primary, secondary, or 30 diethylamine. tertiary fatty amines that optionally may be polyoxyalkylena Permeation enhancers which may be added either to the ted; quaternary ammonium salts, such as tetraalkylammo hydrophilic or lipophilic phase in order to increase the nium, alkylamidoalkyltrialkylammonium, trialkylbenzylam penetration of Oxaprozin within stratum corneum. monium, trialkylhydroxyalkylammonium, O Preservatives, such as antimicrobial agents like benzalko alkylpyridinium halides (preferably chlorides or bromides) as 35 niumchloride, benzyl alcohol, chlorhexidine, imidazo well as other anionic counter-ions. Such as but not limited to, lidinyl urea, phenol, potassium Sorbate, benzoic acid, alkyl sulfates, such as but not limited to, methosulfate and bronopol, chlorocresol, parabens esters, phenoxyetha ethosulfate; imidazoline derivatives; amine oxides of a cat nol and sorbic acid and mixtures thereof. ionic nature (e.g., at an acidic pH). Examples of amineoxide Humectants may be selected from glycerin, propylene gly emulsifiers include those which are lauryidimethylamine 40 col, Sorbitol, lactic acid, urea, and mixtures thereof. oxide, laurylamidopropyldimethylamine oxide, and cetyl Chelating agents, such as citric acid and edetic acid. amine oxide. Antioxidants, such as alfa-tocopherol, ascorbic acid, ascor Anionic Emulsifiers. Examples of anionic emulsifiers byl palmitate, butylated hydroxyanisole, butylated include, but are not limited to, sarcosinates, glutamates, alkyl hydroxytoluene, cysteinesodium ascorbate, Sodium Sulfates, Sodium or potassium alkyleth Sulfates, ammonium 45 metabisulphite alkyleth Sulfates, ammonium laureth-n-sulfates, laweth-n- Suspending agents that may be selected from the group Sulfates, isethionates, glycerylether Sulfonates, Sulfo Succi comprising celluloses and cellulose derivatives Such as, nates, alkylglyceryl ether Sulfonates, alkyl phosphates, e.g., carboxymethyl cellulose, hydroxyethylcellulose, aralkyl phosphates, alkylphosphonates, and aralkylphospho hydroxypropylcellulose, hydroxypropylmethylcellu nates. These anionic emulsifiers may have a metal or organic 50 lose, carrageenan, acacia gum, arabic gum, tragacanth, ammonium counterion. and mixtures thereof. Amphoteric Emulsifiers. Emulsifiers of the amphoteric Gel-forming agents (Thickener). Suitable gel bases and type include emulsifiers having tertiary amine groups, which viscosity-increasing components (thickeners) may be may be protonated, as well as quaternary amine containing Selected from the group comprising liquid paraffin, Zwitterionic emulsifiers. Examples of Such amphoteric emul 55 polyethylene, fatty oils, colloidal silica or aluminium, sifiers include, but are not limited to: certain betaines Such as Zinc Soaps, glycerol, propylene glycol, tragacanth, car cocobetaine and cocamidopropyl betaine; monoacetates Such boxyvinyl polymers, magnesium-aluminium silicates, as sodium lauroamphoacetate; diacetates Such as disodium Carbopol R, hydrophilic polymers such as, e.g. starch, or lauroamphoacetate; amino- and alkylamino-propionates cellulose derivatives Such as, e.g., carboxymethylcellu Such as lauraminopropionic acid. Ammoniurn Sulfonate 60 lose, hydroxyethylcellulose and other cellulose deriva Amphoterics. This class of amphoteric emulsifiers refers to tives, water-Swellable hydrocolloids, carrageenans, “sultaines’ or “sulfobetaines, such as cocamidopropyl-hy hyaluronates (e.g. hyaluronate gel optionally containing droxysultaine. Sodium chloride), and alginates including propylene Preferred emulsifiers are those that have an HLB (i.e., glycol alginate. Further examples are high molecular hydrophilic to lipophilic balance) of at least 4 and more 65 weight polysaccharide gum, Such as Xanthan gum. preferably at least 6. Even more preferred emulsifiers are Thus, in topically administrable compositions of the inven hydrophilic emulsifiers having an HLB in the range between tion, the beta agonist will usually be distributed in a liquid US 8,426,475 B2 25 26 carrier system Such as water or any aqueous solution contain However, in preferred embodiments of the invention, the ing organic or inorganic materials. Additionally, the compo beta agonist may be the sole therapeutically active ingredient sitions may contain one or more ingredients to modify or or the primary/first therapeutically active ingredient admin enhance their texture, appearance, scent performance or sta istered or present in a medicament because of safety con bility. Illustrative additives to the compositions include: oily cerns. Likewise, dermatological compositions of the inven components, fatty components, ointment bases, hydrophilic tion preferably comprise as the sole therapeutically active Solvents, lipophilic solvents, emollients, water, buffering ingredient, or as the primary therapeutically active ingredient, agents, pH-adjusting agents, preservatives, humectants, a beta agonist as defined herein. chelating agents, antioxidants, stabilizers, emulsifying Where it is desirable to add additional therapeutically agents, Suspending agents, gel-forming agents, perfumes, 10 active ingredients, one or more of the following agents may skin protective agents, fragrances, antiseptics and preserva be excluded from or not applied in Substantial amounts in tives. uses, methods, medicaments and dermatological composi Topical administrable compositions of the invention are tions of the invention, because of safety concerns: physically and chemically stable. Where phase-separation of An antihistamine oran analogue thereof, for example those the lipophilic and hydrophilic phase of an emulsion is a prob 15 disclosed in the patent application US2005192261. lem, it has been found important to select an emulsifier that is A corticosteroid, e.g. as disclosed in the patent application less sensitive to electrolytes. Therefore, in certain preferred US20051922.61. embodiments of the invention, non-ionic emulsifiers shall be Ibudilast and related compounds as defined by structural selected as the emulsifier. Exemplary non-ionic emulsifiers formula I in the patent application WO05051293. (Co include, but are not limited to polyol esters including glycols administration with a corticosteroid or a glucocorticoid and glycerol esters; Sorbitan derivatives including Sorbitan receptor modulator) esters of fatty acids and polyoxyethylene Sorbitan esters; Selective serotonin reuptake inhibitors (SSRI), e.g. as polyoxyethylene esters; polyoxyethylene ethers; poloxam those disclosed in the patent application ers; nonylphenyl ethers. The preferred ones are sorbitan esters US2OO422O153. of fatty acids and polyoxyethylene Sorbitan esters. 25 Non-steroidal immunophilin-dependent immunosuppres The physical stability can be recognised by observing the sant (NSIDI) or an NSIDI enhancer (NSIDIE), e.g. as tendency of phase separation of the emulsion after challeng disclosed in the patent application US2004224876. ing the emulsion to physical stress. For example, the emulsion A steroid, e.g. a steroid as disclosed in the patent applica can be exposed to repeating cycles of “freeze and thaw', for tion WO2OO3O92617. example 6 times, followed by centrifugation. Alternatively, 30 Thus, in one embodiment of the invention, a medicament the phase separation can be observed after prolonged storage oratopically administrable composition of the invention does of the emulsion at either 25°C., 40°C., or 60° C. for 1 month, not contain substantial amounts of a steroid, such as a corti 3 months, 6 months, 12 months, optionally after centrifuga costeroid. In still further embodiments, the composition does tion of the dermatological composition. In a certain embodi not comprise Ibudilast or a related compound; a selective ment of the invention, the dermatological composition is 35 serotonin reuptake inhibitor (SSRI); a non-steroidal immu an-oil-in-water emulsion, e.g. provided as a cream or lini nophilin-dependent immunosuppressant (NSIDI) and/or an ment. The ratio between the hydrophilic and lipophilic phase aminosugar. may be adapted in a manner so as to modify the diffusion/ In another embodiment of the invention, a medicament or solubility of the beta agonist within stratum corneum. a topically administrable composition of the invention does The dermatologically administrable pharmaceutical 40 not contain Substantial amounts of an anti-histamine; Ibudi preparations are prepared in a manner known perse by mix last or a related compound; a selective serotonin reuptake ing with pharmaceutical adjuncts that are customary for that inhibitor (SSRI); a non-steroidal immunophilin-dependent purpose, for example by dissolving or Suspending the active immunosuppressant (NSIDI) and/or an aminosugar. ingredient in the base material or in a portion thereof, if Likewise, these methods of treating exclude co-adminis necessary. In order to prepare emulsions in which the active 45 tration of substantial amounts of one or more or all of the ingredient is dissolved in one of the liquid phases, the active following drug agents; a steroid; Ibudilast or a related com ingredient is, as a rule, dissolved therein before the emulsifi pound; a selective serotonin reuptake inhibitor (SSRI); a non cation; in order to prepare Suspensions in which the active steroidal immunophilin-dependent immunosuppressant ingredient is Suspended in the emulsion, the active ingredient (NSIDI) and an aminosugar, or exclude the co-administration is mixed with a portion of the base material after the emulsi 50 ofan anti-histamine; Ibudilast or a related compound; a selec fication and then added to the remainder of the formulation. tive serotonin reuptake inhibitor (SSRI); a non-steroidal Further Ingredients immunophilin-dependent immunosuppressant (NSIDI) or an Further ingredients, either therapeutically active ingredi aminosugar. ents or dermatologically acceptable ingredients can be co The term “does not contain a Substantial amount' is meant administered together with the beta agonist or added to a 55 to define that the amount does not add any contribution to the medicament or dermatological composition of the invention treatment of a connective skin disease according to this inven in order to strengthen, improve, potentiate, or prolong the tion. Typically, Such amounts are less than 5%. Such as less therapeutic action demonstrated herein or to provide a less than 1% or even more preferable less than 0.1% by weight. In toxic, safer, more convenient, better tolerated, or less expen even more preferable embodiments, the amount is nil mean sive treatment approach. 60 ing that the above-mentioned compounds are excluded from Therefore, in some embodiments of the invention, the compositions, methods and uses described herein. medicament, methods, uses and dermatological composi The term “steroid' or “corticosteroid' is meant to define tions further comprise one or more additional therapeutically any naturally occurring or synthetic compound characterized active ingredient(s). For example therapeutically active by a hydrogenated cyclopentanoperhydrophenanthrene ring ingredients generally applied in the treatment of connective 65 system. Naturally occurring corticosteroids are generally tissue diseases of the skin, such as NSAID's, and immuno produced by the adrenal cortex. Synthetic corticosteroids Suppressive agents. may be halogenated. Examples of corticosteroids are pred US 8,426,475 B2 27 28 nisolone, cortisone, dexamethasone, hydrocortisone, methyl tetroses, pentoses, hexoses, heptoses and octoses. The aldose, prednisolone, fluticaSone, prednisone, triamcinolone, and ketose, oralditol has one or more hydroxy groups replaced by Diflorasone. any amino group at any position, including the anomeric The term "Ibudilast or a related compound is meant to position. An aminosugar is thus a deoxyamino derivative of define Ibudilast or a derivative of a pyrazolopyridine as analdose, ketose, oralditol. The term is also intended to mean defined in the patent application WO 2005/051293: polyamino Sugars, wherein more than one hydroxy group has The term “selective serotonin reuptake inhibitor (SSRI) is been replaced by an amino group (e.g. dideoxydiamino, meant to define any member of the class of compounds that (i) trideoxytriamino-derivatives). Moreover, the term "amino inhibit the uptake of serotonin by neurons of the central Sugar is also intended to mean amino derivatives of di-, nervous system, (ii) have an inhibition constant (Ki) of 10 nM 10 or less, and (iii) a selectivity for serotonin over norepineph oligo- and poly-saccharides comprising at least one of said rine (i.e., the ratio of Ki(norepinephrine) over Ki(serotonin)) monosaccharides. Consequently, in the case of di-, oligo- and of greater than 100. Typically, SSRIs are administered in poly-saccharides, the amino group may be the position of dosages of greater than 10 mg per day when used as antide glycosidation. pressants. Examples of SSRIs for use in the invention are 15 The term "pyridazine derivative' is meant to include those fluoxetine, fluvoxamine, paroxetine, Sertraline, citalopram, compounds described by the formula (1) in US20050176714 and Venlafaxine. or WO2003104204. Such pyridazine derivatives are phos The term “non-steroidal immunophilin-dependent immu phodiesterase IV inhibitors. nosuppressant or (NSIDI)” includes any non-steroidal agent Furthermore, one or more of the following agents are unde that decreases proinflammatory cytokine production or secre sirable in dermatological compositions: a skin irritant, a can tion, binds an immunophilin, or causes a down regulation of nabinoid or cannabinoid receptor agonist (as disclosed and the proinflammatory reaction. Ns|DIs include calcineurin defined in the patent application WO05102296), an antigen inhibitors, such as cyclosporine, tacrolimus, ascomycin, (as disclosed and defined in WO03088997), a scrubbing pimecrolimus, as well as other agents (peptides, peptide frag agent (such as those defined in the patent application ments, chemically modified peptides, or peptide mimetics) 25 JP7304647), a compound of the plant of pepper family (e.g. that inhibit the phosphatase activity of calcineurin. Ns|DIs Piper nigrum L. Piper longum L. Piper angustifolium), (Such also include rapamycin (sirolimus) and everolimus, which as compounds defined and disclosed in the patent application binds to an FK506-binding protein, FKBP-12, and block JP9110674), a dissolution assistant agent (such as those antigen-induced proliferation of white blood cells and cytok defined and disclosed in JP 61-1542.01), an inorganic salt or ine secretion. 30 an organic acid (such as those disclosed and defined in the The term “anti-histamine' defines a compound that blocks patent application JP 06-048497), a hypoglycemic agent the action of histamine. Classes of antihistamines include, but (such as those disclosed and defined in the U.S. Pat. No. are not limited to, ethanolamines, ethylenediamine, phenothi 4,088,756. azine, alkylamines, piperazines, and piperidines. Examples EXAMPLES of Anti-histamines are bromodiphenhydramine, clemizole, 35 cyproheptadine, desloratadine, loratadine, thiethylperazine maleate, and promethazine. Example 1 Furthermore, one or more of the following agents may be Topically administrable composition of a beta-adreno excluded from co-administration with the beta agonist or to ceptor agonist. be included in a medicament or a dermatological composition 40 of the invention: A pharmaceutical composition according to the invention 1,3-bis-(substituted-phenyl)-2-propen-1-ones as disclosed was prepared by dissolving R-salbutamol Sulphate in the in the patent application US2003236298, e.g. 1,3-bis watery phase prior to mixing the oily phase and watery phase (Substituted-phenyl)-2-propen-1-ones that has at least of the following composition (w/w): one phenyl Substituent that is an aryl, heteroaryl or het 45 erocyclic moiety. An aminosugar as disclosed in the patent applications Hydrophobic phase: US2005.130935 or WO 2003097073, such as an amino Sugar selected from the group consisting of glu Petrolatum S.0% Paraffin oil 10.0% cosamine, galactosamine, mannosamine, derivatives 50 Cetylan (mixture of 9 parts of cetosteraryl alcohol S.0% and salts thereof, e.g. wherein the aminosugar is and 1 part of sodium laurilsulfate) N-acetylglucosamine, N-acetylgalactosamine or Glyceryl monosterate 6.0% N-acetylmannosamine is excluded from uses, methods Polyoxyethylene sorbitan monooleate (Tween 80) O.S9/o and compositions of the invention. Hydrophilic phase: pyridazine derivatives as described in US20050176714 or 55 R-Salbutamol Sulphate O.S9/o WO2OO3104204 Propylene glycol S.0% The term “1,3-bis-(substituted-phenyl)-2-propen-1-ones' Benzylalcohol O.S9/o refers to those compounds defined by the general formula (1) Water: Ad 100% in the patent application US2003236298, e.g. 1,3-bis-(substi tuted-phenyl)-2-propen-1-ones that has at least one phenyl 60 The emulsion was prepared by first dissolving R-salbuta Substituent that is an aryl, a heteroaryl or Sheterocyclic moi mol Sulphate in the watery phase, heating the two phases to ety. 70° C. and then mixing the two phases and finally cooling the The term an "aminosugar is meant to include those mixture under agitation. defined in the patent applications, US2005130935 and Examples 2 to 5 concern the treatment of cutaneous mani WO2003097073, such as to encompass one or more amino 65 festation in patients Suffering from discoid Lupus Erythema derivatives of a monosaccharide (aldoses and ketoses) and its tosus or Subacute Lupus Erythematosus with the topical com corresponding Sugar alcohols (alditols) such as trioses, position of Example 1 under the control of a medical doctor of US 8,426,475 B2 29 30 Bispebjerg Hospital, Denmark. The composition was applied 268-276) and in accordance with O.E.C.D. Guideline N° 406 to affected areas once or twice per day. of Jul.17th, 1992, and the test method B.6 of the 96/54 E.E.C Directive. Example 2 Procedure: The test item (R-salbutamol as the sulphate salt) was A 50 year old woman had been suffering from discoid diluted with distilled water to prepare a concentration of 0.5% Lupus Erythematosus for 18 years. Her arms were somewhat (w/v). affected and the fingers were severely affected with acrocy Albino guinea pigs of Dunkin-Hartley Strain were exposed anosis. During the years, the woman had regularly been to the test item after an acclimatisation period of at least five treated with strong topical steroids, but with limited effect. 10 days. During an aggravation of the disease, which especially The Maximum Non Necrotizing Concentration affected the fingers, the woman initiated a treatment with the (M.N.N.C.) was determined by injecting by intradermal route emulsion according to example 1 on the fingers. After 6 the following concentrations of the test item 0.25%, 0.125%, weeks of treatment the Subject experienced an almost com 15 0.0625%, 0.0312% and 0.0156% diluted in physiological plete recovery and the symptoms of discoid Lupus Erythe saline Solution. matosus had virtually gone. The treatment was continued for Pre-Maximum Non Irritant Concentration (pre-M.N.I.C.) another 3 months maintaining the fingers free of symptoms. was determined by application of the test item under an occlu Example 3 sive dressing during 24 hours, at the following concentra tions: 0.5%, 0.25%, 0.125% and 0.0625% diluted in physi A 59 year old woman had been suffering from discoid ological Saline Solution. Lupus Erythematosus for 6 years. The symptoms started on Maximum Non Irritant Concentration (M.N.I.C.) was the chin, but had spread to most of the face. The woman had determined by initially establishing an induction phase by periodically been treated with strong topical corticosteroids, intradermal injection with a physiological saline Solution and topical tacrolimus and systemic methotrexate, but without 25 by topical application of distilled water followed by a 18-day significant improvement of the disease. During an aggrava rest phase. In the challenge phase where the test item is under tion of the symptoms, the Subject initiated a twice daily treat occlusive dressing for 24 hours, the test item was applied to ment with the emulsion according to example 1. After 4 the skin of the Albino guinea pigs at the following concentra weeks of treatment, there was a significant reduction in facial tions: 0.5%, 0.25%, 0.125% and 0.0625% diluted in physi erythema. Newer, Smaller patches of erythema disappeared 30 ological saline Solution. The induction phase was performed completely after 1 to 2 weeks of treatment. by intradermal injection at day 0 the test item at a concentra tion of 0.5% and by topical application at day 7 of the test item Example 4 at 0.5% after brushing with a solution of sodium lauryl sul fate. A 66 year old woman had been suffering from discoid 35 Results: Lupus Erythematosus for 32 years. The disease was very No macroscopic cutaneous reactions attributable to allergy severe with a strong affection of the arms and the back and was recorded during the examination following the removal with elements spread to other parts of the body. The woman of the occlusive dressing (challenge phase) from the treated had been treated with ercoquin and strong topical corticos test animals. No cutaneous intolerance reaction was recorded teroids, but with limited effect. 40 in animals from the negative control group. During an aggravation of the symptoms, the woman initi ated a twice daily treatment with the emulsion of example 1. Example 7 During the first 6 weeks of treatment the subject experienced a significant improvement of larger elements, while Small, The efficacy and safety of a beta agonist in the treatment of new elements disappeared completely within days of treat 45 patients with cutaneous LE can be determined according to a ment. placebo controlled and double blind proof of concept study. Patients (at least 30 divided in two groups) with clinical Example 5 diagnosis of either SLE or DLE presenting with a newly developed discoid lesion in the skin are to be enrolled in the An 81 year old woman had been suffering from subacute 50 study. Lupus Erythematosus for 16 years. The subject was affected Only fresh inflammatory lesions will be examined in the on large areas of the body with elements on the back, the study. Investigators will select one lesion (target lesion) on breast and the face. each patient and examine this particular lesion at each visit. The woman has previously been treated with oral predniso The treated area must not exceed 100 cm. lone, chlorochin, thalidomide and strong topical steroids, but 55 There will be two treatment groups: Half of the patients all with limited or no effect. enrolled in the study will treat the selected lesional area with During an aggravation of the symptoms, the woman initi the cream 0.5% of example 1 and half of the patients will treat ated a twice daily treatment with the emulsion according to the selected lesional area with placebo cream. Treatments will example 1. After 3 weeks of treatment, a significant reduction be performed twice daily for 8 weeks. Investigator will assess of all elements was observed. After 7 weeks of treatment, the 60 signs and symptoms (Erythema, Scale/Hypertrophy, Dyspig back was completely free of elements. mentation, Scarring/Atrophy/Panniculitis and Induration), measure lesion area and the patient will asses itching and pain Example 6 (confined to the target lesion) on a visual analogue scale at baseline and after 2, 4, 6 and 8 weeks of treatment. Assessment of sensitising properties of R-salbutamol. Test 65 General improvement (scored by investigator) and for skin sensitization is carried out according to the Magnus patient's assessment of global improvement of the treated son and Kligman method (J. Invest. Dermatol. 1969. 52, lesion will be assessed after 2, 4, 6 and 8 weeks of treatment. US 8,426,475 B2 31 32 The investigator's assessment of erythema will be per The invention claimed is: formed according to the following score: 0-absent, 1 pink; 1. A method of treating cutaneous lupus erythematosus, faint erythema, 2-red, 3-dark red; purple/violaceous/ comprising topically administering to the skin of an indi crusted/hemorrhagic. vidual with cutaneous lupus erythematosus a composition The investigator's assessment of scale/hypertrophy will be 5 comprising R-salbutamol, a physiologically acceptable performed according to the following score: 0–absent, derivative thereof, or a pharmaceutically acceptable salt 1-scale, 2-verrucous/hypertrophic, The investigator's thereof and assessment of dyspigmentation will be performed according wherein the cutaneous lupus erythematosus is selected to the following score: 0-absent, 1-dyspigmentation. from the group consisting of Subacute Cutaneous Lupus The investigator's assessment of scarring/atrophy/pan 10 niculitis will be performed according to the following score: Erythematosus, Chronic Cutaneous Lupus Erythemato 0-absent, 1-scarring, 2-severely atrophic scarring or pan Sus, Discoid Lupus Erythematosus, Lupus Panniculitis, niculitis. and Lupus Erythematosus Profundus. The investigator's assessment of induration will be per 2. The method according to claim 1, wherein the R-salb formed according to the following score: 0-absent, 1-indu 15 utamol is the sole therapeutically active agent in the compo ration, 2-severe induration. sition. The investigator's assessment of general improvement of 3. The method according to claim 1, wherein the compo the target lesion will be performed according to the following sition comprises R-salbutamol in an amount ranging between score: -1 -worsened, 0-no change, 1-mild improvement, 0.01 and 10% by weight. 2 moderate improvement, 3-completely healed. 4. The method according to claim 1, wherein the compo The patients will be asked to assess the global improve sition comprises R-salbutamol in an amount ranging between ment of the target lesion according to the following score: 0.2 and 2.5% by weight. -1 worsened, 0-no change, 1-mild improvement, 2-mod 5. The method of claim 1, wherein the individual has cuta erate improvement, 3-completely healed neous lupus erythematosus that was not successfully treated Patients will assess pain and itching in the target lesion by prior therapy. using a visual analog scale from 0 to 10. UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,426,475 B2 Page 1 of 1 APPLICATIONNO. : 11/402255 DATED : April 23, 2013 INVENTOR(S) : Morten Sloth Weidner and Hans Christian Wulf It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

IN THE SPECIFICATION

Column 1, line 4, please insert the following: -- CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Denmark Application PA 2005 00529 filed, April 13, 2005, which is incorporated herein by reference in its entirety. --

Signed and Sealed this Eighth Day of October, 2013 2 2-Y xx 26-e-s? 2.*é-...sé -13 . . Teresa Stanek Rea Deputy Director of the United States Patent and Trademark Office UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,426,475 B2 Page 1 of 1 APPLICATIONNO. : 11/402255 DATED : April 23, 2013 INVENTOR(S) : Morten Sloth Weidner et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

This certificate supersedes the Certificate of Correction issued October 8, 2013. The certificate is vacated since request for the Certificate of Correction treated as a petition under 37 CFR 1.55(c), seeking to incorporate by reference the prior-filed application, was dismissed by the Office of Petitions. The Certificate of Correction was published in error and should not have been issued for this patent.

Signed and Sealed this Third Day of December, 2013

Margaret A. Focarino Commissioner for Patents of the United States Patent and Trademark Office UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,426,475 B2 Page 1 of 1 APPLICATIONNO. : 11/402255 DATED : April 23, 2013 INVENTOR(S) : Morten Sloth Weidner et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

ON THE TITLE PAGE OF THE PATENT

Please insert the following priority claim on the face of the Patent. -- (30) Foreign Application Priority Data

Apr. 13, 2005 (DK)...... PA 2005 00529 --

IN THE SPECIFICATION

Column 1, line 4, please insert the following:

-- CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Denmark Application PA 2005 00529 filed, April 13, 2005, which is incorporated herein by reference in its entirety. --

Signed and Sealed this Fourteenth Day of January, 2014 74-4-04- 2% 4 Michelle K. Lee Deputy Director of the United States Patent and Trademark Office