(12) Patent Application Publication (10) Pub. No.: US 2005/0130935 A1 Weidner (43) Pub

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US 2005O130935A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0130935 A1 Weidner (43) Pub. Date: Jun. 16, 2005

(54) COMBINATION OFA Related U.S. Application Data BETA-2-ADRENOCEPTORAGONSTS AND ANAMINOSUGARS AND THEIR USE FOR (60) Provisional application No. 60/373,615, filed on Apr. THE TREATMENT IMMUNOMODULATORY 19, 2002. DSORDERS (30) Foreign Application Priority Data Apr. 19, 2002 (PA)...... 2002-00586 (76) Inventor: Morten Sloth Weidner, Virum (DK) Publication Classification Correspondence Address: (51) Int. Cl." ...... A61K 31/7008; CO8B 37/00; MERCHANT & GOULD PC CO7H 5/06 P.O. BOX 2903 (52) U.S. Cl...... 514/62; 536/55.2; 536/53 MINNEAPOLIS, MN 55402-0903 (US) (57) ABSTRACT (21) Appl. No.: 10/512,029 The invention relates to combinations of an aminoSugar and a beta-2-adrenoceptor agonist, Such as Salbutamol, for the (22) PCT Fed: Apr. 22, 2003 treatment of diseaseS associated with hyperSensivity and inflamation, in particular hyperSensivity skin diseases. The (86) PCT No.: PCT/DK03/00263 aminoSugar is preferably a monosaccharide derivative. US 2005/O130935 A1 Jun. 16, 2005

COMBINATION OF A BETA-2-ADRENOCEPTOR form a malignant tumour that enlarges and may spread to AGONSTS AND ANAMINOSUGARS AND THEIR adjacent tissueS or through blood and lymph Systems to USE FOR THE TREATMENT other parts of the body. There are numerous forms of cancer IMMUNOMODULATORY DSORDERS of varying Severity. For most types of cancer there is no effective treatment today. FIELD OF THE INVENTION 0008 Generally, the treatment of hypersensitivity and 0001. The present invention relates to the combination of inflammatory diseases, including cancer, requires long-term a beta-2 adrenoceptor agonist and an aminoSugar Suitably administration. Thus, there is a need for therapeutic agents formulated in the form of a chemical complex and/or a for the treatment of hyperSensitivity and inflammatory reac pharmaceutical composition for the Suppression and treat tions, including cancer, in particular agents that have a better ment of hyperSensitivity and inflammatory reactions in Safety profile than presently available drugs. mammals. 0009 Aminosugars are generally recognised as having beneficial effect on inflammatory reactions. AminoSugars BACKGROUND OF THE INVENTION are the building blocks for the in Vivo generation of gly 0002. A number of drug classes are available for the cosaminoglycans, formerly known as mucopolysaccharides. treatment of hyperSensitivity and inflammatory reactions. Glycosaminoglycans are constituents in various tissues in Among these, the corticosteroids are Some of the most numerous mammals, both vertebrates and invertebrates and widely and effective drugs used. Corticosteroids primarily as Such not likely to be associated with adverse reactions exert their pharmacological action by non-Selectively inhib upon administration to mammals. Important examples of iting the function and proliferation of different classes of glycosaminoglycans are chondroitin Sulfates, keratan Sul immune cells resulting in Suppression of hyperSensitivity fates in connective tissue, dermatan Sulfates in Skin tissue and inflammatory reactions. Unfortunately, the corticoster and hyaluronic acid in skin tissue and Synovial joint fluid. oids are associated with a number of Serious Side effects, e.g. 0010 Administration of aminosugars or glycosaminogly immuno-Suppression, osteoporosis and Skin atrophy. cans in high (pharmacological) doses to Individuals Suffer 0003) Non-steroidal anti-inflammatory drugs are another ing from Osteoarthritis has resulted in Some relief of Symp class of drugs extensively used in the treatment of hyper toms and nowadays the use of aminoSugars as Sensitivity and inflammatory reactions. Also this class of chondroprotective agents is widely recognised (Gaby A R, drugs is associated with serious side effects, in particular Natural treatments for Osteoarthritis, Alternative medicine upon long-term use. review, volume 4, No 5, 1999, pages 330-334). For example, the use of aminoSugars and glycosaminoglycans for reduc 0004) Hypersensitivity is defined as a state of altered ing inflammation is mentioned in WO 98/48816. U.S. Pat. reactivity in which the body reacts with an exaggerated No. 6,046,179 relates to the treatment of inflammatory immune response to a Substance (antigen). bowel diseases by colonic administration of N-acetylglu 0005 Hypersensitivity reactions underlie a large number cosamine. of diseases. Among these, allergic and autoimmune condi tions are of great importance. A classification of hypersen 0011 Sympathomimetics are drugs that partially or com sitivity diseases is given in the textbook Clinical Medicine pletely mimic the actions of noradrenaline or adrenaline. (Kumar, P. and Clark, M.: “Clinical Medicine”, 3rd edition, They act either directly on alpha- and/or beta-adrenoceptors p. 147-150, 1994, Baliliere Tindall, London). Hypersensi or indirectly on the presynaptic terminals usually by causing tivity may be classified as type I hyperSensitivity reactions the release of noradrenaline. (IgE mediated allergic reactions) which is known to play a 0012. The effects of adrenoceptor stimulation are various. Significant role include asthma, eczema (atopic dermatitis), Beta-2 adrenoceptor agonists are a class of drugs known to urticaria, allergic rhinitis and anaphylaxis. Type II hyper provide bronchodilation and are widely used in the treatment Sensitivity reactions are caused by cell Surface or tissue of asthma. WO95/19336 relates to phenyl ethanol amine bound antibodies (IgG and IgM) and play a significant role ethers for use as a beta-2 adrenoceptor agonists in bronchitis, in the pathogenesis of myasthenia gravis, Good-pasture's allergic bronchitis and astma bronchiale. Syndrome and Addisonian pernicious anaemia. Type III hyperSensitivity reactions (immune complex) are caused by 0013 EP 069042 relates to drug compositions compris autoantigens or exogenous antigens, Such as certain bacteria, ing a mucopolysaccharide and a drug which is Scarcely fungi and parasites. Soluble in water but Soluble in a water-miscible organic Solvent, Such as Salbutamol. The drug is present as fine 0006 Diseases in which type III hypersensitivity reac crystals or fine particles attached on or between the particles tions play a significant role include lupus erythematosus, of a mucopolysaccharide. rheumatoid arthritis and glomerulonephritis. Type IV hyper Sensitivity reactions (delayed) are caused by cell or tissue SUMMARY OF THE INVENTION bound antigens. This type of hyperSensitivity plays a Sig nificant role in a number of conditions, e.g. graft-verSus-host 0014. It has been found by the present investigator that a disease, leprosy, contact dermatitis and reactions due to combination of a beta-2 adrenoceptor agonist and an ami insect bites. noSugar Significantly Suppresses hyperSensitivity and 0007. In addition cancer may be regarded as a condition inflammatory reactions. asSociated with hyperSensitivity reactions. Cancer is caused 0015 Contrarily to existing therapeutic agents, such as by an uncontrolled proliferation of cells that express varying corticosteroids or non-Steroidal anti-inflammatory drugs, the degrees of fidelity to their precursors. These cancer cells chemical complexes and compositions according to the US 2005/O130935 A1 Jun. 16, 2005 present invention have the advantage of not being likely to prising 1) a beta-2 adrenoceptor agonist; and ii) an amino be associated with any Serious Side effects, as all of their Sugar, comprising the Steps of: components are known to living organisms and are acknowl edged reported as non-toxic and well-tolerated by the organ 0026 i) dissolving said beta-2 adrenoceptor and said ism. The present inventor puts forward the hypothesis that aminoSugar in a volatile Solvent or a mixture of volatile the very beneficial therapeutic index exhibited by the com Solvents, and pleX and compositions comprising Said complex according 0027 ii) removing said suitable solvent so as to obtain to the invention is Superior to the use of the individual a moisture content of at the most 5% w/w. constituents of the complex, and this is due to Synergistic effects and a lower toxic load on the organism. DETAILED DESCRIPTION OF THE INVENTION 0016 Such a combination is advantageously provided in the form of a chemical complex comprising a beta-2 adreno 0028. The present inventor provides data herein indicat ceptor agonist and an aminoSugar. Obviously, the combina ing that a combination of a beta-2 adrenoceptor agonist and tion may also be provided in the form of a pharmaceutical an aminoSugar Significantly reduces the inflammation in the composition, a dietary Supplement or a cosmetic. AS was arachidonic acid ear inflammation test in mice. This reduc further recognised by the present inventor, the aminoSugar tion of inflammation was better for the combination than for according to the present invention may be an aminoSugar each of the individual compounds and also far better than derivative of monosaccharides, oligosaccarides as well as of that obtained by a commonly used Steroid. polysaccharides. However, the aminoSugar may advanta 0029. It is hypothesised by the present inventor that the geously have a molecular weight of less than 5000. very advantageous therapeutic index of the combination of 0017 Thus, the present inventor has recognised the thera a beta-2 adrenoceptor agonist and an aminoSugar in com peutic activity of a combination of beta-2 adrenoceptor parison to each of the Singular components is due to Syner agonist and an aminoSugar, for which reason the Said com gistic effects between the components of the compositions. bination may be regarded as an active therapeutic agent. Advantageously, this allows for the utility of lower dosages, while yet providing a Surprisingly good therapeutic effect. 0.018. Accordingly, the present invention provides a chemical complex or a pharmaceutical composition com 0030 The invention is based, at least in part, on the prising: combined activity of an aminoSugar and a beta-2 adreno ceptor agonist in comparison to either component. This 0019 i) a beta-2 adrenoceptor agonist; and combined activity allows for the use of beta-2 adrenoceptor agonists that are previously not used as therapeutic agents 0020 ii) an aminosugar; and optionally because they were too toxic in therapeutically relevant doses 0021 iii) a pharmaceutically acceptable carrier or car or because high doses were required in order to achieve Said rier. effect. 0031. According to the invention, the combination of a 0022. The chemical complexes and pharmaceutical com beta-2 adrenoceptor agonist and an aminoSugar may be positions according to the invention may in general be provided in the form of a chemical complex; in the form of utilised in the treatment of diseases associated with hyper a composition comprising Said complex and optionally Sensitivity and inflammatory reactions. In general the com pharmaceutically acceptable excipient(s); or in the form of bination may be utilised in i) immuno-modulation, and in a pharmaceutical composition comprising the combination more specific terms they may be utilised in ii) the treatment of beta-2 adrenoceptor agonist and an aminoSugar. or prevention of hyperSensitivity diseaseS Such as atopic eczema, contact dermatitis, Seborrhoeic eczema and/or pSo 0032. Without being limited to a particular theory, advan riasis; ii) the treatment or prevention of IgE mediated tageously, Said combination is provided in the form of a allergic reactions and conditions Such as of asthma, allergic chemical complex for purposes of achieving a homogeneous rhinitis, and/or anaphylaxis; iv) the treatment or prevention mixture of the two agents, which may positively affect the of autoimmune disorderS Such as of diabetes, Crohn's dis resulting therapeutic effect. ease, ulcerative colitis, rheumatoid arthritis, gout or Osteoar 0033 Such chemical complexes are novel and provide a thritis; v) the alleviation of pain; vi) the treatment or Surprisingly effective anti-hyperSensitivity and anti-inflam prevention of cancer. matory effect with a Surprisingly good Safety profile. Thus the chemical complexes or compositions of the invention are 0023. An important aspect of the invention relates to the Virtually non-toxic at active doses and yet very therapeuti use of a combination of a beta-2 adrenoceptor agonist and an cally effective. aminoSugar for the preparation of a product for the treatment 0034. The chemical complexes or compositions of the of diseases i) to vi) as mentioned above. invention provide pharmacological effects upon administra 0024. Still further aspects relate independently to a tion to the living organism Such as immunomodulation, method for treating diseases i) to Vi) as mentioned above in Suppression of hyperSensitivity reactions, Suppression of IgE a mammal, Such as a human, comprising the administration mediated allergic reactions, Suppression of autoimmune of a combination of a beta-2 adrenoceptor agonist and an reactions, reduction of pain, and Suppression of cancer. aminoSugar, pharmaceutically acceptable Salts thereof, or a complex comprising Said combination or Said Salts to Said 0035. Accordingly, the present invention relates to a mammal. chemical complex comprising: 0.025 Moreover, a still further aspect of the invention 0036) i) a beta-2 adrenoceptor agonist; and relates to a process for the preparation of a complex com 0037) ii) an aminoSugar. US 2005/O130935 A1 Jun. 16, 2005

0038. The term “chemical complex” is intended to Suitably, in di-, oligo- and poly-Saccharides, the amino include the definition defined by IUPAC that read as follows: group may not be the position of glycosidation. “A molecular entity formed by loose association involving 0045 An amino group of an aminosugar may be alky two or more component molecular entities (ionic or lated, arylated or acylated or, alternatively, present as its free uncharged), or the corresponding chemical species. The amine form (NH). Similarly, the hydroxyl groups may be bonding between the components is normally weaker than in optionally protected or derivatised Such as alkylated, ary a covalent bond.” (IUPAC Compendium of Chemical Ter lated or acylated or, alternatively, present in its free hydroxyl minology 2nd Edition (1997)). form. 0.039 Thus, the term “chemical complex” is intended to 0046) The amine of the amino Sugar may exist as its mean any combination of the components provided that the quaternary ammonium Salt using organic or mineral acids, as molecules of each of the components are mixed and loosely is known to the person skilled in the art. Furthermore, other associated with each other. The term “chemical complex' is functional groups on the aminoSugar may be in the form of not intended necessarily to Implie an ionic or otherwise a Salt. Similarly, prodrug derivatives of the aminoSugar are asSociation between the components. It does not either anticipated by the present inventor. The prodrug form may include covalent bonding between the components of the be the result of the derivatisation of the amino group or complex. Moreover, the term “chemical complex” does not another functional group present on the aminoSugar, as is encompass combinations wherein one or both of the com ponents are in the form of particles. However, a chemical known to the perSon Skilled in the art. complex of the invention may not be 100% pure in that some 0047. Furthermore, an aminosugar may have one or more of the components may be present in the form of particles. hydroxy groups replaced by any amino group at any position That is to say that preferably less than 10% of each of the and a further one or more hydroxy groups replaced by a components are in the form of particles in a chemical hydrogen (a deoxy Sugar), a thiol (a thiosugar), a halogen (a complex. More preferably less than 5%, less than 2.5% or deoxyhalo Sugar), an anhydroSugar (a Sugar preparable via less than 1% is in particulate matter. Thus, a composition or an intramolecular displacement with a hydroxyl to form an a chemical complex according to the invention may com oxirane or oxetane), a carbonyl group. prise less than 10% of one of the components in the form of 0048. Furthermore, the term aminosugar is denoted to particulate matter. mean aminoSugars as described Supra but optionally Substi 0040. The complexes of the invention may be prepared tuted. according to a number of different methods, which are 0049. The term “optionally substituted” is intended to obvious to a perSon Skilled in the art. The following proce mean the Substitution of one or more hydrogen atoms, which dures are non-limiting examples of Such methods: is Substituted with another atom, chemical group or entity, 0041. The components of the complex, dosed in appro termed Substituents. Illustrative examples of Substituents priate amounts to give the correct molar ratio between the include carboxyl, formyl, amino, hydroxyl, halogen, nitro, components, are dissolved, dispersed, or Suspended in an Sulphono, Sulphanyl, C-alkyl, aryl, aryloxy, aryloxycar appropriate Solvent, for example water, an organic Solvent or bonyl, arylcarbonyl, heteroaryl, amino, mono- and di(C- mixtures thereof. Non-limiting examples of Suitable organic alkyl)amino; carbamoyl, mono- and di(C6-alkyl)aminocar Solvents are ethanol, methanol, iso-propyl alcohol, acetone, bonyl, amino-C6-alkyl-aminocarbonyl, mono- and di(C- hexane, ethylacetate or mixtures thereof. 6-alkyl)amino-C-alkyl-aminocarbonyl, C1-6- alkylcarbonylamino, cyano, guanidino, carbamido, C.- 0042. The solvent is then removed by a technique Suit alkanoyloxy, C-alkylsulphonyloxy, dihalogen-C-alkyl, able for the complex, for example but not limited to evapo trihalogen-C6-alkyl, C6-alkoxyl, OXO, C6-carboxyl, ration, in Vacou evaporation, Spray drying, freeze-drying, Co-alkoxycarbonyl, C-alkylcarbonyl, where aryl and fluid bed drying or Spin flash drying. Alternatively, the heteroaryl representing Substituents may be Substituted 1-5 complex may be obtained by precipitation and Subsequent times with C-alkyl, C-alkoxy, nitro, cyano, hydroxy, centrifugation or filtering. amino or halogen. In general, the above Substituents may be 0043. In the present context, the term “aminosugar is Susceptible to further optional Substitution. intended to mean one or more amino derivatives of a 0050. The term “halogen' includes fluorine, chlorine, monosaccharide (aldoses and ketoses) and its corresponding bromine and iodine. Sugar alcohols (alditols) Such as trioses, tetroses, pentoses, 0051. In a particularly suitable embodiment of the inven hexoses, heptoses and octoses. The aldose, ketose, or alditol tion, the aminoSugar is Sulphated or phosphorylated at the has one or more hydroxy groups replaced by any amino anomeric, 2-, 3-, 4-, or 6-position, typically at the 2-, 3-, or group at any position, including the anomeric position. An 4-position. In another suitable embodiment of the invention aminoSugar is thus a deoxyamino derivative of an aldose, the aminoSugar is N-acetylated. ketose, or alditol. The term is also intended to mean polyamino Sugars, wherein more than one hydroxy group 0052 Furthermore, a combination of suitable embodi has been replaced by an amino group (e.g. dideoxydiamino-, ments include the aminoSugar Sulphated or phosphorylated trideoxytriamino-derivatives). as well as in its salt form having Na"; K: Mg"; Ca"; or 0044) Moreover, the term “aminosugar is also intended NH as counter ions. to mean amino derivatives of di-, oligo- and poly-Saccha 0053 Particularly suitable aminosugars according to the rides comprising at least one of Said monosaccharides. invention are amino derivates of monosaccharides Selected Consequently, in the case of di-, oligo- and poly-Saccharides, from the group consisting of glucosamine, galactosamine the amino group may be the position of glycosidation. and mannosamine, derivatives and Salts thereof. Typically, US 2005/O130935 A1 Jun. 16, 2005

the amino derivates of monosaccharides may be in the form 0062 According to the invention the beta-2 adrenoceptor of Salts, Such as the Sulfate Salt and hydrochloride Salts, or agonist may preferably be in the form of the most effective N-acetylated, e.g. glucosamine Sulfate, glucosamine hydro Single enantiomer or optimal mixtures of enantiomers as chloride, N-acetylglucosamine, galactosamine Sulfate, known to a person skilled in the art. galactosamine hydrochloride, N-acetylgalactosamine, man 0063 AS stated the combination of the two agents pro nosamine Sulfate, mannosamine hydrochloride, N-acetylm vides a Surprisingly effective therapeutic agent for Suppres annosamine, as well as other aminoSugars known to the Sion of hyperSensitivity and inflammatory reactions. The person skilled in the art. proper therapeutic efficacy may, in part, be adjusted by 0054. In suitable embodiments the aminosugar is di-, providing the two agents in Suitable molar ratioS or mass oligo-, and poly-Saccharides comprising at least one or more ratioS. of the mentioned amino derivates of monosaccharides. In the embodiment wherein the aminoSugar is an oligo- or 0064. The molar ratio between the beta-2 adrenoceptor polysaccharide, Said oligo- or polysaccharide preferably agonist and the aminosugar may be about 1:10000 to contain monomeric Sugars including D-glucuronic acid, 10000:1, preferably about 1:1000 to 1000:1, such as about L-iduronic acid, D-galacturonic acid, D-galactose, and 1:500 to 500:1, such as 1:100 to 100:1, about 1:50 to 50:1, fucose, each of which may be optionally Sulfonated or or about 1:40 to 40:1, also about 1:30 to 30:1, Such as about O-Substituted with a protective group known to the perSon 1:25 to 25:1, about 1:20 to 20:1, about 1:18 to 18:1, about skilled in the art. 1:16 to 16:1, about 1:14 to 14:1, or about 1:12 to 1:12, also about 1:10 to 10:1, Such as about 1:9 to 9:1, about 1:8 to 8:1, 0055. In a suitable embodiment of the invention, the about 1:7 to 7:1, about 1:6 to 6:1, also from 1:5 to 5:1, Such chemical complex and the composition comprises more than as from 1:4 to 4:1, e.g. from 1:3 to 3:1, such as from 1:2 to one aminoSugar. 2:1. 0056 Preferably, the aminosugar is an amino derivate of 0065. Alternatively defined, the ratio between the beta-2 a monosaccharide as mentioned Supra. In the embodiment adrenoceptor agonist and the aminoSugar may be expressed wherein the aminoSugar is oligo- and poly-Saccharides the as a mass ratio. The mass ratio between the beta-2 adreno molecular weight is preferably less than 5000 Daltons, ceptor agonist and the aminoSugar may be about 1:10000 to preferably less than 4000 Daltons, more preferably less than 10000:1, preferably about 1:1000 to 1000:1, such as about 3000 Daltons. 1:500 to 500:1, such as 1:100 to 100:1, about 1:50 to 50:1, 0057 The aminosugar component of the invention may or about 1:40 to 40:1, also about 1:30 to 30:1, such as about comprise natural, Synthetic or Semisynthetic aminoSugars 1:25 to 25:1, about 1:20 to 20:1, about 1:18 to 18:1, about and may have been chemically modified, while Still retain 1:16 to 16:1, about 1:14 to 14:1, or about 1:12 to 1:12, also ing their function. Such chemical modifications include but about 1:10 to 10:1, Such as about 1:9 to 9:1, about 1:8 to 8:1, are not limited to esterification, Sulfation, polysulfation, about 1:7 to 7:1, about 1:6 to 6:1, also from 1:5 to 5:1, Such acetylation and methylation. as from 1:4 to 4:1, e.g. from 1:3 to 3:1, such as from 1:2 to 2:1. 0.058 As stated, the invention relates to the combination of an aminoSugar with a beta-2 adrenoceptor agonist. The 0066 For the administration to a mammal, such as a term "beta-2 adrenoceptor agonist' is intended to mean any human, the chemical complex may be administered directly, component with the ability to Stimulate a beta-2 adrenocep eventually provided in a capsule or the like. More conve tor or parts thereof. The agonistic activity of a compound nient, the complex may be formulated into a composition towards beta-2 adrenoceptor may be investigated by meth comprising the chemical complex and optionally, one or ods known to the perSon Skilled in the art; eventually using more acceptable excipients. Alternatively, the combination Salmeterol as reference. of the two agents may also be formulated into a composition 0059 Preferably, the beta-2 adrenoceptor agonist may be without being provided as a chemical complex. any that possess at least 10% of the activity of salmeterol in 0067 Thus, an important aspect of the present invention a Suitable test for beta-2 adrenoceptor agonism. Preferably, relates to a composition comprising: the beta-2 adrenoceptor agonist has at least 20%, more preferably at least 40% such as at least 50%, 60%, 75%, 0068) i) a beta-2 adrenoceptor agonist; 80%, 85%, 90% of the activity of salmeterol in a suitable test for beta-2 adrenoceptor agonism. 0069 ii) an aminoSugar; and optionally 0060. The beta-2 adrenoceptor agonist, for illustrative 0070) iii) one or more acceptable excipients or carriers. purposes, may be selected from the group consisting of 0071. It is to be understood that the “beta-2 adrenoceptor bambuterol, bitolterol, carbuterol, clenbuterol, clorprena agonist' and the "aminoSugar of the composition are as line, dioxethedrine, dopexamine, ephedrine, epinephrine, defined Supra. In one embodiment, the composition com etafedrine, ethylnorepinephrine, fenoterol, formoterol, prises the combination of beta-2 adrenoceptor agonist and heXoprenaline, isoetarine, isoproterenol, mabuterol, metap the aminoSugar in the form of a chemical complex as defined roterenol, methoxyphenamine, pirbuterol, procaterol, pro herein. Thus, the aminoSugar may be selected from the tokylol, reproterol, rimiterol, ritodrine, Salbutamol group consisting of glucosamine, galactosamine, man (albuterol), Salmeterol, Soterenol, terbutaline, tretoquinol, nosamine, derivatives and Salts thereof, e.g. wherein the tulobuterol, derivatives, Salts and enantiomeres thereof. aminoSugar is N-acetylglucosamine, N-acetylgalactosamine 0061. In interesting embodiments the beta-2 adrenocep or N-acetylmannosamine. A preferred composition com tor agonist is terbutaline Sulfate, Salbutamol Sulfate or for prises glucosamine Sulfate, glucosamine hydrochloride and/ moterol fumarate dihydrate. or N-acetylglucosamine. Moreover, the molar ratio or mass US 2005/O130935 A1 Jun. 16, 2005 ratio between the beta-2 adrenoceptor agonist and the ami in the art of pharmaceutical formulation may find guidance noSugar in the composition may be as defined for the in e.g., “Remington: The Science and practice of pharmacy” complex, as discussed Supra. 20" ed. Mack Publishing, Easton Pa., 2000 ISBN 0-912734 04-3. A pharmaceutically acceptable excipient is a Sub 0.072 The term “composition” is intended to mean cos stance, which is Substantially harmless to the individual to metic compositions, pharmaceutical compositions, nutri which the composition will be administered. Such an excipi tional compositions Such as food Supplements as well as ent Suitably fulfils the requirements given by the national compositions in the field of cosmeceuticals and neutraceu drug agencies. Official pharmacopeias-Such as the British ticals. Pharmacopeia, the United States of America Pharmacopeia 0073. According to the invention, the above-mentioned and the European Pharmacopeia Set Standards for well chemical complexes or compositions may be combined with known pharmaceutically acceptable excipients. any other therapeutically active agents in order to Strengthen, improve, potentiate, or prolong the therapeutic 0080 For topical, trans-mucosal and trans-dermal com actions of Said complexes and Said compositions. Thus positions, Such as administration to the mucosa or the skin, according to the invention, the composition or complexes the compositions for use according to the invention may may further comprise one or more therapeutically active contain conventional non-toxic pharmaceutically acceptable agents. carriers and excipients including microSpheres and lipo SOCS. 0.074 The compositions according to the present inven 0081. The topical, trans-mucosal and trans-dermal com tion may be formulated for oral, topical, transdermal, or positions for use according to the invention include an array parenteral administration, preferably oral or topical admin of Solid, Semi-Solid and fluid compositions. Compositions of istration. In a Suitable embodiment of the invention, the particular relevance are e.g. pastes, ointments, hydrophilic compositions are used for oral administration. In another ointments, creams, gels, hydrogels, Solutions, emulsions, Suitable embodiment of the invention the compositions are Suspensions, lotions, liniments, resoriblets, Suppositories, used for topical administration. enema, pessaries, moulded pessaries, Vaginal capsules, Vagi 0075. The beta-2 adrenoceptor agonist and the amino nal tablets, Shampoos, jellies, Soaps, Sticks, sprays, powders, Sugar may together be comprised in a single formulation or films, foams, pads, Sponges (e.g. collagen Sponges), pads, may each individually be comprised in Separate formula dressings (such as, e.g., absorbent wound dressings), tions. The separate formulations may be administered in a drenches, bandages, plasters and transdermal delivery Sys Simultaneous or non-Simultaneous manner. AS Stated, the temS. beta-2 adrenoceptor agonist and the aminoSugar are together 0082 The pharmaceutically acceptable excipients for comprised in a single formulation. topical, trans-mucosal and trans-dermal compositions may 0.076 The active ingredients of the chemical complex or include Solvents, buffering agents, preservatives, humec pharmaceutical composition of the present invention need tants, chelating agents, antioxidants, Stabilizers, emulsifying not be administered as one pharmaceutical entity, but may of agents, Suspending agents, gel-forming agents, ointment course be administered as individual compounds or phar bases, Suppository bases, penetration enhancers, perfumes, maceutical compositions. skin protective agents, diluents, disintegrating agents, bind ing agents, lubricants and Wetting agents. 0077. In addition to the formulations described previ ously, the compositions of the invention may also be for 0083. The oral compositions for use according to the mulated as a depot preparation. Such long acting formula invention include an array of Solid, Semi-Solid and fluid tions may be administered by implantation (for example compositions. Compositions of particular relevance are e.g. Subcutaneously or intramuscularly) or by Intramuscular Solutions, Suspensions, emulsions, uncoated tablets, imme injection. Thus, for example, the compositions may be diate-release tablets, modified-release tablets, gastro-resis formulated with suitable polymeric or hydrophobic materi tant tablets, orodispersible tablets, efferverscent tablets, als (for example as an emulsion in an acceptable oil) or ion chewable tablets, Soft capsules, hard capsules, modified eXchange resins, or as sparingly Soluble derivatives, for release capsules, gastro-resistant capsules, uncoated gran example, as a sparingly Soluble Salt. ules, effervescent granules, granules for the preparation of liquids for oral use, coated granules, gastro-resistant gran 0078. The pharmaceutical compositions for oral, topical, ules, modified-release granules, powders for oral adminstra transdermal, or parenteral administration may be in form of, tion and powders for the preparation of liquids for oral use. e.g., Solid, Semisolid or fluid compositions and formulated according to conventional pharmaceutical practice, See, e.g., 0084. The pharmaceutically acceptable excipients may “Remington: The science and practice of pharmacy” 20" ed. include Solvents, buffering agents, preservatives, humec Mack Publishing, Easton Pa., 2000 ISBN 0-912734-04-3 tants, chelating agents, antioxidants, Stabilizers, emulsifying and “Encyclopedia of Pharmaceutical Technology', edited agents, Suspending agents, gel-forming agents, diluents, by Swarbrick, J. & J. C. Boylan, Marcel Dekker, inc., New disintegratig agents, binding agents, lubricants, coating York, 1988 ISBN 0-8247-2800-9. agents and Wetting agents. 0079 The choice of pharmaceutically acceptable excipi 0085 Typical solvents may be selected from the group ents in a composition for use according to the invention and comprising water, alcohols, vegetable or marine oils (e.g. the optimum concentration thereof is determined on the edible oils like almond oil, castor oil, cacao butter, coconut basis of the Selection of the beta-2 adrenoceptor agonist, oil, corn oil, cottonseed oil, linseed oil, olive oil, palm oil, Selection of the aminoSugar, the kind of dosage form chosen peanut oil, poppySeed oil, rapeseed oil, Sesame oil, Soybean and the mode of administration. However, a person skilled oil, Sunflower oil, and teaseed oil), mineral oils, fatty oils, US 2005/O130935 A1 Jun. 16, 2005 liquid paraffin, polyethylene glycols, propylene glycols, 0094 Suitable diluents and disintegrating agents may be glycerol, liquid polyalkylsiloxanes, and mixtures thereof. Selected from the group comprising lactose, Saccharose, emdex, calcium phosphates, calcium carbonate, calcium 0.086 Typical buffering agents may be selected from the Sulphate, mannitol, Starches and microcrystaline cellulose. group comprising of citric acid, acetic acid, tartaric acid, lactic acid, hydrogenphosphoric acid, diethylamine etc. 0095 Suitable binding agents may be selected from the group comprising Saccharose, Sorbitol, gum acacia, Sodium 0.087 Typical preservatives may be selected from the alginate, gelatine, Starches, cellulose, Sodium carboxymeth group comprising parabens, Such as methyl, ethyl, propyl ylcellulose, methylcellulose, hydroxypropylcellulose, poly p-hydroxybenzoate, butylparaben, isobutylparaben, isopro Vinylpyrrolidone and polyetyleneglycol. pylparaben, potassium Sorbate, Sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, 0096 Typical wetting agents may be selected from the MDM hydantoin, iodopropynyl butylcarbamate, EDTA, group comprising Sodium laurylsulphate and polySorbate 80. benzalconium chloride, and benzylalcohol, or mixtures of 0097 Suitable lubricants may be selected from the group preservatives. comprising talcum, magnesium Stearate, calcium Stearate, Silicium oxide, precirol and polyethylenglycol. 0088 Typical humectants may be selected from the group 0098 Suitable coating agents may be selected from the comprising glycerin, propylene glycol, Sorbitol, lactic acid, group comprising hydroxypropylcellulose, hydroxypropyl urea, and mixtures thereof. Typical chelating agents are but methylcellulose, polyvinylpropylidone, ethylcellulose and not limited to Sodium EDTA and citric acid. Typical anti oxidants may be Selected from the group comprising buty polymethylacrylates. lated hydroxy anisole (BHA), ascorbic acid and derivatives 0099 Typical suppository bases may be selected from the thereof, tocopherol and derivatives thereof, cysteine, and group comprising oleum cacao, adepS Solidus and polyeth mixtures thereof. Suitable emulsifying agents may be ylenglycols. Selected from the group comprising naturally occurring 0100. The present inventor has recognised the therapeutic gums, e.g. gum acacia or gum tragacanth; naturally occur effect of the complexes and compositions of this invention, ring phosphatides, e.g. Soybean lecithin; Sorbitan partly by observing the reduced inflammation of the arachi monooleate derivatives, wool fats, wool alcohols, Sorbitan donic acid induced inflamed mouse ear upon administering esters; monoglycerides; fatty alcohols, fatty add esters (e.g. the complexes and compositions. This test model is a triglycerides of fatty acids); and mixtures thereof. commonly employed method for Screening and evaluation 0089 Suitable suspending agents may be selected from of anti-inflammatory drugs. the group comprising celluloses and cellulose derivatives 0101 Thus, in a broadly sense the chemical complexes or Such as, e.g., carboxymethyl cellulose, hydroxyethylcellu compositions provides an immunomodulating effect. More lose, hydroxypropylcellulose, hydroxypropylmethylcellu over, the inventor has recognised that a number of diseases lose, carrageenan, acacia gum, arabic gum, tragacanth, and or conditions with Similarities in the etiology of the inflam mixtures thereof. matory reactions that are provoked in the arachidonic acid induced inflamed mouse ear may be effectively treated by 0090 Suitable gel bases and viscosity-increasing com the present complexes and compositions of the invention. ponents may be Selected from the group comprising liquid Such diseases and conditions relate in general to those paraffin, polyethylene, fatty oils, colloidal Silica or alu asSociated with hyperSensitivity reactions and inflammatory minium, Zinc Soaps, glycerol, propylene glycol, tragacanth, reactions. In a more specific Sense, the chemical complexes carboxyvinyl polymers, magnesium-aluminium Silicates, or compositions of the invention provides Suppression of Carbopolf), hydrophilic polymerS Such as, e.g. Starch or hyperSensitivity reactions, Suppression of inflammatory cellulose derivatives Such as, e.g., carboxymethylcellulose, reactions, Suppression of IgE mediated allergic reactions, hydroxyethylcellulose and other cellulose derivatives, Suppression of autoimmune reactions, reduction of pain, and water-SWellable hydrocolloids, carragenans, hyaluronates Suppression of cancer. (e.g. hyaluronate gel optionally containing Sodium chloride), and alginates including propylene glycol alginate. 0102 Correspondingly, a further aspect of the invention relates to a method for immunomodulation in a mammal, 0.091 Typical ointment bases may be selected from the Such as a human, comprising the administration to Said group comprising beeSWax, paraffin, cetanol, cetyl palmi mammal an effective amount of a combination of a beta-2 tate, vegetable oils, Sorbitan esters of fatty acids (Span), adrenoceptor agonist and an aminoSugar, or pharmaceuti polyethylene glycols, and condensation products between cally acceptable Salts thereof, or a chemical complex com Sorbitan esters of fatty acids and ethylene oxide, e.g. poly prising a beta-2 adrenoceptor agonist and an aminoSugar, or oxyethylene Sorbitan monooleate (Tween). pharmaceutically acceptable Salts thereof. 0092 Typical hydrophobic ointment bases may be 0103) As used herein, the term “effective amount” relates Selected from the group comprising paraffins, vegetable oils, to the effective dose to be determined by a qualified prac animal fats, Synthetic glycerides, waxes, lanolin, and liquid titioner, who may titrate dosages to achieve the desired polyalkylsiloxanes. Typical hydrophilic ointment bases are response. Factors for consideration of dose will include but not limited to Solid macrogols (polyethylene glycols). potency, bioavailability, desired pharmacokinetic/pharma codynamic profiles, condition of treatment, patient-related 0.093 Suitable powder components may be selected from factors (e.g. Weight, health, age, etc.), presence of co the group comprising alginate, collagen, lactose, powder, administered medications (e.g., anticoagulants), time of which is able to form a gel when applied to a wound (absorbs administration, or other factors known to a medical practi liquid/wound exudate). tioner. US 2005/O130935 A1 Jun. 16, 2005

0104 Moreover, further aspects of the invention relates Immunomodulation of a mammal, Such as a human. The to a method for the treatment of hyperSensitivity disease or immunomodulation typically results in the Suppression of inflammation comprising the administration of the above hyperSensitivity and Suppression of inflammatory reactions. mentioned chemical complexes or compositions of the The immodulation may be associated with diseases and invention to a mammal, preferentially a human. disorderS Selected from the group consisting of hyperSensi tivity Skin disease Such as atopic eczema, contact dermatitis, 0105. As used herein, the “term treatment” relates to Seborrhoeic eczema and/or psoriasis, IgE mediated allergic treatment of Symptoms or prevention the relapse of Symp reactions Such as asthma, allergic rhinitis or anaphylaxis, toms in a perSon diagnosed with a disease related to inflam autoimmune disease Such as chronic inflammatory disease, mation, hyperSensitivity, cancer or pain. Crohn's disease, ulcerative colitis, rheumatoid arthritis, gout 0106 According to the invention, the therapeutic action or Osteoarthritis, pain and cancer. of the complexes or compositions of the invention may be relevant to diseases involving hyperSensitivity reactions or 0112 Accordingly, the chemical complexes or composi inflammatory reactions. Hence, the therapeutic action of the tions of the invention are Suitable for the treatment or complexes or compositions of the invention may be relevant prevention of diseases caused by inflammation of various to the treatment of conditions and diseases associated with tissues, Such as the Inflammation of the prostate, in particu hyperSensitivity reactions, Such as infections (viral, bacte lar prostatitis. rial, fungal, parasitic), cold and flu, contact dermatitis, insect 0113. A still further aspect of the invention relates to a bites, allergic vasculitis, post-operative reactions, transplan process for the preparation of a complex comprising i) a tation rejection (graft-Versus-host disease), and So forth. beta-2 adrenoceptor agonist; and ii) an aminoSugar, com 0107 A further aspect of the invention relates to the use prising the Steps of of a complex of the invention for the treatment of autoim 0114 i) dissolving said beta-2 adrenoceptor and said mune disorders. Correspondingly, the invention further aminoSugar in a volatile Solvent or a mixture of volatile relates to a method for the treatment or prevention of Solvents, and autoimmune disorders comprising the administration of the chemical complexes or compositions of the invention to a 0115 ii) removing said suitable solvent so as to obtain mammal, preferentially a human. Typically, the autoimmune a moisture content of at the most 5% w/w. disorders may be autoimmune hepatitis, Primary biliary 0116. In principle, a plethora of solvents and mixture of cirrhosis, Primary Sclerosing cholangitis, Autoimmune solvents can be used in the preparation of complexes accord hemolytic anemias, Grave's disease, Myasthenia gravis, ing to the invention. Suitable solvents or mixture of solvents Type 1 Diabetes Mellitus, inflammatory myopathies, Mul are those being Substantially removed upon evaporation at tiple Sclerosis, Hashimoto's thyreoiditis, Autoimmune room temperature, at elevated temperature, under atmo adrenalitis, Crohn's Disease, Ulcerative Colitis, Glomeru Spheric or reduced preSSure, or upon Spray drying or freeze lonephritis, Progressive Systemic Sclerosis (Scleroderma), drying. Furthermore, Solvents and mixture of Solvents Sjögren's Disease, Lupus Erythematosus, Primary vasculi should be Suitable for dissolving or at least partially dis tis, Rheumatoid Arthritis, Juvenile Arthritis, Mixed Connec Solving Said beta-2 adrenoceptor and Said aminoSugar at tive Tissue Disease, Psoriasis, Pemfigus, Pemfigoid, and room temperature or optionally upon heating. In a preferred Dermatitis Herpetiformis. embodiment of the invention, the beta-2 adrenoceptor and 0108) A still further aspect of the invention relates to a Said aminoSugar are fully dissolved in the Suitable Solvent or method for the treatment or prevention of an IgE mediated mixture of suitable solvents. Preferably, no traces of undis allergic reaction or condition comprising administration of Solved beta-2 adrenoceptor and Said aminoSugar is present in the chemical complexes or compositions of the invention to the Solution. a mammal, preferably to a human. The therapeutic action 0117 Thus, according to the invention the volatile sol may be relevant to IgE mediated allergic reactions and vent is Selected from the group consisting of water, water conditions in general Such as asthma, eczema (e.g. atopic miscible, Volatile organic Solvents and mixtures thereof. dermatitis), urticaria, allergic rhinitis, anaphylaxis. Suitable water-miscible organic Solvents is Selected from the 0109 Moreover, the chemical complex or composition of group consisting of methanol, ethanol, propanol, iso-pro the present invention may be used in a method for the panol, butanol, iso-butanol, tert-butanol, acetone, acetic acid, acetonitrile, ethers, chloroform and dichlormethane. treatment or prevention of any condition associated with Further Suitable Solvents relates to organic Solvents capable pain. The applicant proposes the hypothesis that the thera of both dissolving hydrophobic and hydrophilic Substances, peutic action is related to immunomodulation, possibly to a Such as those organic Solvents Selected from the group Suppressing effect on hyperSensitivity reactions. consisting of dimethethylsulfoxide and dimethylformamids. 0110 Still further, the chemical complexes or composi Moreover, any other azeotrope Solvents is preferred. tions of the invention may be employed for the treatment or 0118 AS stated, the process for preparation of a complex prevention of cancer of any type and at any Stage. The comprises removing of Solvent So as to obtain a complex that present inventor puts forward the hypothesis that the anti is essentially dry, in Solid form and in accordance with the cancer effect is due to a combination of immunomodulating IUPAC definition of a chemical complex. That is to say so and tumour-Suppressing effects of the complexes and com as to form a complex with low moisture content and/or positions of the invention. wherein the components are loosely associated at the 0111. A still further aspect of the invention relates to the molecular level and mixed with each other. The moisture use of a combination of a beta-2 adrenoceptor agonist and an being residues of water and/or residues of the water miscible aminoSugar for the preparation of a medicament for the organic Solvents. Thus, in a interesting embodiment of the US 2005/O130935 A1 Jun. 16, 2005

invention, the moisture content is at the most 3% w/w, Example 33 to 51 preferably at the most about 2% w/w, more preferably at the most about 10% w/w, even more preferably at the most Molar Ratio Beta-2 Adrenoceptor about 0.5% w/w, most preferably at the most about 0.2% Agonist/Aminosugar Derivative 1:6496 (mol/mol) w/w. 0124 EXAMPLES 0119) The following examples describe the preparation of chemical complexes of the present invention. Beta-2 adrenoceptor agonist 1 mol Aminosugar 6332 mol General Method Example 1-164 Example 33. formoterol fumerate Glucosamine HCI dihydrate 0120) The beta-2 adrenoceptor agonist and the amino Example 34. bambuterol HCl Glucosamine 3 sulfate, Nasalt Sugar derivative are dissolved in as little Solvent as possible. Example 35. Bitoltrol mesylate Galactosamine 3,6 sulfate, The Solvent is removed by Spray drying or freeze-drying. K salt Example 36. Clenbuterol HC N-acetylgalactosamine After the solvent is removed the complex is a white to Example 37. Chlorprenaline HCl, HO N-acetylglucosamine yellowish powder. Example 38. Dopexamine 2HCl Glucosamine sulfate Example 39. Isoetarine Glucosamine HCI 0121 The solvent is water:ethanol in any V/v % combi Example 40. Isoproterenol Mannosamine HCI nation. Example 41. Mabuterol HCI N-acetylmannosamine Example 42. Metaproterenol Glucosamine sulfate 0122) The complex is suitable for any type of product e.g. Example 43. Methoxyphenamine HCl N-acetylglucosamin pharmaceutical products, dietary Supplements and cosmetic Example 44. Pirbuterol monoacetate N-acetylgalactosamine formulations. Non-limiting examples of Such products are Example 45. Procaterol N-acetylgalactosamine sulfate tablets, capsules, ointments and lotions as described above. Example 46. Protokylol N-acetylglucosamine Example 47. Reproterol HCI Glucosamine 6 sulfate, Nasalt Example 1 to 32 Example 48. Rimiterol HBr Glucosamine 3 sulfate, Nasalt Example 49. Ritodrine HCI Galactosamine 3,6 sulfate, K salt Molar Ratio Beta-2 Adrenoceptor Example 50. Salbutamol sulfate N-acetylgalactosamine Agonist/Aminosugar Derivative 1:10000 (mol/mol) Example 51. Salimetrol Glucosamine HCl 0123) Example 52 to 73 beta-2 adrenoceptor agonist 1 mol Aminosugar 10000 mol Molar Ratio Beta-2 Adrenoceptor Example 1. Salbutamol Glucosamine Agonist/Aminosugar Derivative 1:832 (mol/mol) Example 2. Bambuterol Glucosamine HCI Example 3. bitolterol Glucosamine sulfate 0125) Example 4. Carbuterol Glucosamine 2 sulfate, free acid Example 5. Clenbuterol Glucosamine 2 sulfate, Nasalt Example 6. Clorprenaline Glucosamine 2 sulfate, K salt Example 7. Dioxethedrine N-acetylglucosamine 3,4,6 sulfate, tri Beta-2 adrenoceptor Na+ salt agonist 1 mol Aminosugar 1500 mol Example 8. Dopexamine Galactosamine 3,6 sulfate, K salt Example 9. Ephedrine N-acetylgalactosamine Example 52. Soterenol N-acetylgalactosamine Example 10. Epinephrine N-acetylgalactosamine sulfate Example 53. Terbutaline Glucosamine HCI Example 11. Etafedrine N-acetylglucosamine Example 54. Tretoquinol HCl Glucosamine 6 sulfate, free acid Example 12. Ethylnorepinephrine Glucosamine 6 sulfate, Na' salt Example 55. Tulobuterol Glucosamine sulfate Example 13. Fenoterol Glucosamine 3 sulfate, Nasalt Example 56. Salbutamol sulfate Glucosamine HCI Example 14. Formoterol Galactosamine 3,6 sulfate, K salt Example 57. Formoterol Glucosamin 3 sulfate, K salt Example 15. Hexoprenaline N-acetylgalactosamine fumerate dihydrate Example 16. Isoetarine Glucosamine HCI Example 58. Dopexamine Galactosamine 3,6 sulfate, K salt Example 17. Isoproterenol Mannosamine HCI Example 59. Ephedrine N-acetylgalactosamine Example 18. Mabuterol N-acetylmannosamine Example 60. Epinephrine N-acetylgalactosamine sulfate Example 19. Metaproterenol Glucosamine sulfate Example 61. Etafedrine N-acetylglucosamine Example 20. Methoxyphenamine N-acetylglucosamin Example 62. Ethylnorepinephrine Glucosamine 6 sulfate, Na' salt Example 21. Pirbuterol N-acetylgalactosamine Example 63. Fenoterol HBr Glucosamine 3 sulfate, Nasalt Example 22. Procaterol N-acetylgalactosamine sulfate Example 64. Formoterol Galactosamine 3,6 sulfate, K salt Example 23. Protokylol N-acetylglucosamine Example 65. Isoproterenol Mannosamine HCI Example 24. Reproterol Glucosamine 6 sulfate, Nasalt sulfate dihydrate Example 25. Rimiterol Glucosamine 3 sulfate, Nasalt Example 66. Mabuterol N-acetylmannosamine Example 26. Ritodrine Galactosamine 3,6 sulfate, K salt Example 67. Metaproterenol HCl Glucosamine sulfate Example 27. Salbutamol N-acetylgalactosamine Example 68. Methoxyphenamine N-acetylglucosamin Example 28. Salimetrol Glucosamine HCI Example 69. Salbutamol N-acetylgalactosamine Example 29. Soterenol Mannosamine HCI Example 70. Salmeterol Glucosamine HCI Example 30. Terbutaline N-acetylmannosamine Example 71. Soterenol Mannosamine HCI Example 31. Tretoquinol Glucosamine sulfate Example 72. Terbutaline sulfate N-acetylmannosamine Example 32. tulobuterol N-acetylglucosamin Example 73. Tretoquinol Glucosamine sulfate US 2005/O130935 A1 Jun. 16, 2005

Example 74 to 91 Example 116 to 124 Molar Ratio Beta-2 Adrenoceptor Molar Ratio Beta-2 Adrenoceptor Agonist/Aminosugar Derivative 1:405 (mol/mol) Agonist/Aminosugar Derivative 1:19 (mol/mol) 0126) 0128

Beta-2 adrenoceptor Beta-2 adrenoceptor agonist 1 mol Aminosugar 405 mol agonist 1 mol Aminosugar 19 mol Example 74. Salbutamol N-acetylglucosamin Example 116. Salbutamol Glucosamine sulfate Example 75. bitolterol Galactosamine Example 117. Salbutamol sulfate Glucosamine 2 sulfate, K' salt Example 76. Carbuterol Glucosamine HCI Example 118. Bitolterol Galactosamine Example 77. Clenbuterol HC Glucosamine sulfate Example 119. Carbuterol Glucosamine Example 78. Clorprenaline Galactosamine 3,6 sulfate, Example 120. Clenbuterol N-acetylgalactosamine 4 sulfate, di Nasalt K salt Example 79. Dioxethedrine N-acetylglucosamin HCl Example 121. Clorprenaline N-acetyl-glucosamine HCl Example 80. Ethylnorepinephrine HCI Glucosamine 6 sulfate, Na' salt Example 122. Tretoquinol Galactosamine 2 sulfate, Nasalt Example 81. Fenoterol Glucosamine 3 sulfate, Nasalt Example 123. Hexoprenaline Mannosamine HCI Example 82. Formoterol Galactosamine 3,6 sulfate, Example 124. Isoetarine N-acetylmannosamine K salt Example 83. Isoproterenol Mannosamine HCI Example 84. Mabuterol HC N-acetylmannosamine Example 85. Metaproterenol HCl Glucosamine sulfate Example 86. Methoxyphenamine N-acetylglucosamin Example 125 to 137 Example 87. Salbutamol sulfate N-acetylgalactosamine Example 88. Salimetrol Glucosamine HCI Molar Ratio Beta-2 Adrenoceptor Example 89. Soterenol HC Mannosamine HCI Example 90. Terbutaline sulfate N-acetylmannosamine Agonist/AminoSugar Derivative 1:1 (mol/mol) Example 91. Tretoquinol Glucosamine sulfate 0129

Example 92 to 115 Beta-2 adrenoceptor Molar Ratio Beta-2 Adrenoceptor agonist 1 mol Aminosugar 1 mol Agonist/Aminosugar Derivative 1: 130 (mol/mol) Example 125. Bambuterol HC Glucosamine HCI Example 126. Bitolterol mesylate N-acetyl-glucosamine O127) Example 127. Salbutamol Galactosamine sulfate Example 128. Formoterol fumerate Glucosamine 3,4,6 sulfate, free dihydrate acid Example 129. Tretoquinol HCl N-acetylgalactosamine HCI Example 130. Hexoprenaline sulfate N-acetylgalactosamine Beta-2 adrenoceptor Example 131. Broxaterol Glucosamine HCI agonist 1 mol Aminosugar 130 mol Example 132. Isoproterenol Mannosamine HCI Example 92. Salbutamol Glucosamine sulfate Example 133. Mabuterol N-acetylmannosamine Example 93. Clenbuterol Galactosamine Example 134. Metaproterenol sulfate Glucosamine sulfate Example 94. Clorprenaline N-acetylgalactosamine 3,6 sulfate, Example 135. Methoxyphenamine N-acetylglucosamin K salt Example 136. Pirbuterol 2HCl N-acetylgalactosamine Example 95. Dioxethedrine Glucosamine sulfate Example 137. Procaterol N-acetylgalactosamine sulfate Example 96. Dopexamine N-acetylglucosamine HCI Example 97. Ephedrine N-acetylglucosamine 3 sulfate, free acid Example 98. Epinephrine Galactosamine 4 sulfate, K salt Example 138 to 143 Example 99. Etafedrine N-acetylgalactosamine 3,6 sulfate, Nasalt Molar Ratio Beta-2 Adrenoceptor Example 100. Ethylnorepinephrine Glucosamine 6 sulfate, K' salt Example 101. Fenoterol Glucosamine 23 sulfate, di Agonist/AminoSugar Derivative 5:1 (mol/mol) Nasalt Example 102. Formoterol fumerate N-acetylglucosamine HCI 0130 dihydrate Example 103. Hexoprenaline Glucosamine sulfate Example 104. Salimetrol Glucosamine HCI Example 105. Soterenol Mannosamine HCI Beta-2 adrenoceptor Example 106. Terbutaline N-acetylmannosamine agonist 5 mol Aminosugar 1 mol Example 107. Tretoquinol Glucosamine sulfate Example 108. Hexoprenaline N-acetylgalactosamine Example 138. Salbutamol Galactosamine 4 sulfate, K salt Example 109. Isoetarine Glucosamine HCI Example 139. Formoterol fumerate N-acetylglucosamin Example 110. Isoproterenol Mannosamine HCI dihydrate Example 111. Mabuterol N-acetylmannosamine Example 140. Fenoterol HBr N-acetylgalactosamine Example 112. Metaproterenol Glucosamine sulfate Example 141. Mabuterol HC Mannosamine Example 113. Methoxyphenamine N-acetylglucosamin Example 142. Methoxyphenamine N-acetylglucosamine HCI Example 114. Pirbuterol N-acetylgalactosamine HCI Example 115. Procaterol N-acetylgalactosamine sulfate Example 143. Reproterol Glucosamine sulfate US 2005/O130935 A1 Jun. 16, 2005

Example 144 to 148 Example 160 to 164 Molar Ratio Beta-2 Adrenoceptor Molar Ratio Beta-2 Adrenoceptor Agonist/Aminosugar Derivative 50:1 (mol/mol) Agonist/Aminosugar Derivative 10000:1 (mol/mol) 0134) 0131)

Beta-2 adrenoceptor agonist 10000 mol Aminosugar 1 mol Beta-2 adrenoceptor agonist Example 160. Pirbuterol 2HCl Glucosamine sulfate 50 mol Aminosugar 1 mol Example 161. Methoxyphenamine N-acetylglucosamine Example 162. salbutamol Galactosamine HCl Example 144. Dioxethedrine Glucosamine sulfate Example 163. Isoetarine N-acetylgalactosamine 3,6 sulfate, dil Na' salt Example 145. Dopexamine 2HCl N-acetylglucosamine Example 164. Fenoterol HCl N-acetylglucosamin HCl Example 146. Ephedrine HCI Galactosamine HCl Example 147. Epinephrine N-acetylmannosamine Example 148. Salbutamol sulfate N-acetylglucosamin HCl General Method Example 165-176 0135) A quantity of the beta-2 adrenoceptor agonist and the aminoSugar derivative are transferred to a hard gelatine capsule. Example 149 to 153 Example 165 to 170 Molar Ratio Beta-2 Adrenoceptor Agonist/AminoSugar Derivative (mol/mol) Capsule 500 mg, Molar Ratio Beta-2 Adrenoceptor Agonist/Aminosugar Derivative 1:1000 (mol/mol) 0132) 0136

Beta-2 adrenoceptor agonist Beta-2 adrenoceptor agonist 1 mol Aminosugar 1000 mol 500 mol Aminosugar 1 mol Example 165. Salbutamol 239.31 g/mol Glucosamin HCI 0.55 mg 215.6 g/mol Example 149. Rimiterol Glucosamine sulfate 499.45 mg Example 150. Bitolterol mesylate N-acetylglucosamine Example 166. Salbutamol sulfate 576.7 g/mol N-acetylglucosamine 1.3 mg 221.2 g/mol. Example 151. Salbutamol Galactosamine HCl 498.7 mg Example 152. Salimetrol xinafoate Mannosamine Example 167. Formoterol fumerate Glucosamine sulfate dihydrate 840.91 g/mol 605.1 g/mol 499.3 mg Example 153. Clenbuterol HC N-acetylglucosamin HCl 0.7 mg Example 168. Formoterol 344.41 g/mol Galactosamine HCl 0.8 mg 215.6 g/mol 499.2 mg Example 169. Fenoterol 303.36 g/mol Mannosamine HCI 0.7 mg 215.6 g/mol 499.3 mg Example 154 to 159 Example 170. Mabuterol 310.75 g/mol N-acetylmannosamine 0.7 mg 221.2 g/mol Molar Ratio Beta-2 Adrenoceptor 499.3 mg Agonist/Aminosugar Derivative 1000:1 (mol/mol) 0133) Example 171 to 176 Capsule 750 mg, Molar Ratio Beta-2 Adrenoceptor Agonist/Aminosugar Derivative 1:53(mol/mol). Beta-2 adrenoceptor agonist 1000 mol Aminosugar 1 mol 0137)

Example 154. Mabuterol HC Glucosamine sulfate Example 155. Clenbuterol N-acetylglucosamine Beta-2 adrenoceptor Example 156. Salbutamol sulfate Galactosamine HCI agonist 1 mol Aminosugar 53 mol Example 157. Tulobuterol HC N-acetylgalactosamine 3,6 sulfate, di Na Salt Example 171. Dopexamine 356.51 g/mol Glucosamin HCI 22.7 mg 215.6 g/mol 727.3 mg Example 158. Ritodrine HCI N-acetylglucosamin HCl Example 172. Salbutamol sulfate 576.7 g/mol N-acetylglucosamine Example 159. Protokylol Mannosamine HCI 35.16 mg 221.2 g/mol 714.84 mg US 2005/O130935 A1 Jun. 16, 2005 11

0153. Animal Randomisation and Allocation -continued 0154) On the day of arrival the animals were randomly Beta-2 adrenoceptor allocated to groups of 8 mice. agonist 1 mol Aminosugar 53 mol O155 Body Weight Example 173. Formoterol fumerate dihydrate Glucosamine sulfate 840.91 g/mol 605.1 g/mol 0156 The animals were weighed on the day of dosing. 19.16 mg 730.84 mg Example 174. Salbutamol 239.31 g/mol N-acetylglucosamine O157 Procedure 15.0 mg 221.2 g/mol 735.0 mg 0158. The test Substances and reference compound were Example 175. Ephedrine 165.24 g/mol N-acetylmannosamine administered intraperitoneally in Volumes of 20 ml per kg 10.4 mg 221.2 g/mol body weight 30 minutes before application of arachidonic 739.6 mg acid to the ear. Example 176. Formoterol 344.41 g/mol Glucosamin HCl 21.94 mg 215.6 g/mol 0159 All groups were treated with 20 ul arachidonic 728.06 mg acid, 100 mg/ml in acetone, on the right ear. 0160 The doses were as follows: Example 177 0138) Objective 0.139. The objective of this study is to assess the effect of Drug Dose, mg/kg three doses of two chemical complexes of the invention Vehicle, PBS -, i.p. Compound 92 1000 mg/kg, i.p. Systemically administered in the arachidonic acid induced Compound 92 300 mg/kg, i.p. ear inflammation test in the mouse, a commonly employed Compound 92 100 mg/kg, i.p. method for Screening and evaluation of antiinflammatory Compound 33 1000 mg/kg, i.p. drugs. Dexamethasone was employed as reference com Compound 33 300 mg/kg, i.p. pound. Compound 33 100 mg/kg, i.p. Dexamethasone 6 mg/kg, i.p. 0140 Test Articles and Vehicle Dexamethasone 2 mg/kg, i.p. 0.141. The test articles are the complexes of the invention prepared according to example 33 and example 92 (Com 0.161. One hour after the arachidonic acid application the pound 33 and Compound 92 in the following). Compound mice were Sacrificed, the ears cut from the tip with a punch 33, Compound 92 and dexamethasone are obtained from biopsy knife (8 mm diameter) and weighed. Astion A/S, Denmark. 0162 Mean weights and standard deviations were calcu 0142] Animals lated. Relative ear Oedema was assessed as the weight 0143. The study was performed in female BALB/ca mice difference between right and left ear of each mouse from M & B A/S, DK-8680 Ry. At start of the acclimatisa expressed as percent of the left ear. Percent inhibition of the tion period the mice were in the weight range of 20 g (+/-5 relative ear oedema compared with the vehicle treated g). groups was calculated for the test Substance and reference compound treated groups. 0144 Housing 0145 The study took place in an animal room provided 0163 Clinical Signs with filtered air. The temperature in the room was set at 0.164 All visible signs of ill health and any behavioural 21-23 C. and the relative humidity to 230%. The room was changes were recorded daily during the Study. Any deviation illuminated to give a cycle of 12 hours light and 12 hours from normal was recorded with respect to time of onset, darkness. Light was on from 06.00 till 18.00 h. duration and intensity. 0146 The animals were housed in Macrolon type III 0165 Statistics cages (40x25x14 cm), 10 in each cage. The cages were cleaned and the bedding changed at least once a week. 0166 Differences in relative ear oedema between the vehicle treated groups and the test Substance and reference 0147 Beddinq compound treated groups were tested for Significance employing a non-parametric Statistical method of analysis, 0148. The bedding was sawdust (Tapvel 4HV) from the Mann-Whitney U test. The required level of significance Tapvel Oy, 73620 Kortteinen, Finland. was p-0.05. 0149 Diet 0.167 All statistical analysis was performed employing 0150. A complete pelleted rodent diet “Altromin 1324” the Statistical Software package Analyse-it V. 1.62. from Chr. Petersen, DK-4 100 Ringsted, was available ad libitum. 0168 Results 0151. Drinking Water 0169 Clinical Signs 0152 The animals had free access to bottles with domes 0170 Arachidonic add caused an inflammation in the tic quality drinking water. The drinking water was changed right ears, which was visible after about 30 minutes. It could daily. clearly be observed that the right ears were bright red and the US 2005/O130935 A1 Jun. 16, 2005 left ears pale. The test articles to Some extent prevented the 21-23 C. and the relative humidity to 230%. The room was reaction in the right ear. No test Substance related adverse illuminated to give a cycle of 12 hours light and 12 hours reactions were observed. darkness. Light was on from 06.00 till 18.00 h. 0171 Ear Oedema 0.184 The animals were housed in Macrolon type III 0172 The various concentrations of the test articles cages (40x25x14 cm), 10 in each cage. The cages were inhibited the relative oedema as shown in the table below: cleaned and the bedding changed at least once a week. 0185. Bedding 0186 The bedding was sawdust (Tapvel 4HV) from %. Inhibition Tapvel Oy, 73620 Kortteinen, Finland. Dose, mg per of relative Drug application ear oedema Mann-Whitney U test 0187 Diet Vehicle, PBS -, i.p. 0188 A complete pelleted rodent diet “Altromin 1324” Compound 92 1000 mg/kg, i.p. 65 p < 0.0001 from Chr. Petersen, DK-4 100 Ringsted, was available ad Compound 92 300 mg/kg, i.p. 44 p = 0.0009 libitum. Compound 92 100 mg/kg, i.p. 14 p = 0.0652 Compound 33 1000 mg/kg, i.p. 79 p = 0.0002 0189 Drinking Water Compound 33 300 mg/kg, i.p. 64 p < 0.0001 Compound 33 100 mg/kg, i.p. 47 p = 0.0052 0190. The animals had free access to bottles with domes Dexamethasone 6 mg/kg, i.p. O p = 0.8359 tic quality drinking water. The drinking water was changed Dexamethasone 2 mg/kg, i.p. O p = 0.6008 daily. 0191 Animal Randomisation and Allocation 0173 Compound 92 and Compound 33 yielded a dose 0.192 On the day of arrival the animals were randomly dependent and at all doses Statistically Significant inhibition allocated to groups of 10 mice. of ear Oedema. Dexamethasone, the reference compound, surprisingly did not inhibit ear oedema. This is attributed to 0193 Body Weight a slower onset of action. Thus, the data imply that Com 0194 The animals were weighed on the day of dosing pound 92 and Compound 33 have a faster onset of action and termination of the Study. than dexamethasone. 0195 Procedure 0174 Conclusion 0196. The test Substances and reference compound were 0.175. The data imply that systemically administered administered intraperitoneally in Volumes of 20 ml per kg Compound 92 and Compound 33 are potent Inhibitors of body weight 30 minutes before application of arachidonic arachidonic acid induced ear oedema, with a faster onset of acid to the ear. action than dexamethasone. 0.197 All groups were treated with 20 ul arachidonic Example 178 acid, 100 mg/ml in acetone, on the right ear. 0198 The doses were as follows: 0176) Objective 0177. The objective of this study is to assess the effect of a dose of a complex according to compared to the effect of the corresponding doses of the components of the complex. Drug Dose, mg/kg All compounds were Systemically administered in the Vehicle, PBS -, i.p. Compound 92 1000 mg/kg, i.p. arachidonic acid induced ear inflammation test in the mouse, Glucosamine sulfate 997 mg/kg, i.p. a commonly employed method for Screening and evaluation Salbutamol 3.0 mg/kg, i.p. of antiinflammatory drugs. Methylprednisolone was Methylprednisolone 30 mg/kg, i.p. employed as reference compound. 0178 Test Articles and Vehicle 0199. One hour after the arachidonic acid application the 0179 The test articles are the complex of the invention mice were Sacrificed, the ears cut from the tip with a punch prepared according to example 92 (Compound 92 in the biopsy knife (8 mm diameter) and weighed. following) and its components Salbutamol and glucosamine 0200 Mean weights and standard deviations were calcu Sulfate. The Substances were obtained from Astion A/S, lated. Relative ear Oedema was assessed as the weight Denmark. difference between right and left ear of each mouse 0180 Animals expressed as percent of the left ear. Percent inhibition of the relative ear oedema compared with the vehicle treated 0181. The study was performed in female BALB/ca mice groups was calculated for the test Substance and reference from M & B A/S, DK-8680 Ry. At start of the acclimatisa compound treated groups. tion period the mice were in the weight range of 20 g (+/-5 g). 0201 Clinical Signs 0202 All visible signs of ill health and any behavioural 0182 Housing changes were recorded daily during the Study. Any deviation 0183 The study took place in an animal room provided from normal was recorded with respect to time of onset, with filtered air. The temperature in the room was set at duration and intensity. US 2005/O130935 A1 Jun. 16, 2005

0203 Statistics been under treatment with different analgesics including 0204 Differences in relative ear oedema between the ibuprofen and celecoxib with limited Success. The last year vehicle treated group and the other groups were tested for She had continuously been taking a Supplement of glu Significance employing a non-parametric Statistical method cosamine Sulfate, 1500 mg a day, but only obtained a Small of analysis, the Mann-Whitney U test. The required level of improvement of her symptoms. She was then treated with significance will be p<0.05. Similarly, the difference the complex of the invention disclosed in example 56 (1500 between the compound 92 treated group and the groups mg/day) instead of glucosamine Sulfate. After two days she treated with the corresponding amounts of Salbutamol and could feel a Significant improvement compared to taking the glucosamine Sulfate respectively, were tested for Signifi aminoSugar alone. After two weeks she was Symptom free cance to establish whether Compound 92 displays a signifi for the first time in 6 years, which persisted for another 6 cantly better effect than its components at the dose they weeks of treatment, where after the treatment was termi occur in Compound 92. All Statistical analysis was per nated. No adverse effects were observed. formed employing the Statistical Software package Analyse it v. 1.62. Example 180 0205 Results 0215. A male, 68 years had been suffering from osteoar thritis of the knees for 8 years and had for periods been under 0206 Clinical Signs treatment with different analgesics including diclofenac 0207 Arachidonic acid caused an inflammation in the codeine and rofecoxib with limited Success. He had also right ears, which was visible after about 30 minutes. It could tried the recommended dose of glucosamine in different clearly be observed that the right ears were bright red and the formulations, but with very limited effect. He was then left ears pale. The test articles to Some extent prevented the treated with the complex of the invention disclosed in reaction in the right ear. No test Substance related adverse example 56 (1500 mg/day). After four days he experienced reactions were observed. a significant improvement of his major Symptom pain in the knees in relation to walking. The improvement continued 0208 Ear Oedema and after two weeks he was completely Symptom free. The 0209 The various concentrations of the test articles improvement persisted for the entire treatment period of 10 inhibited the relative oedema as shown in the table below: weeks, where after the treatment was terminated. No adverse effects were observed.

%. Inhibition of 1-53. (canceled) relative ear Mann-Whitney U 54. A chemical complex comprising: Drug Dose, mg/kg oedema test i) a beta-2 adrenoceptor agonist; and Vehicle, PBS Compound 92 1000 mg/kg 73 p < 0.0001 ii) an aminoSugar Selected from the group consisting of Glucosamine sulfate 997 mg/kg 9 p = 0.1399 glucosamine, mannosamine, Salts and derivatives Salbutamol 3.0 mg/kg 55 p < 0.0001 thereof, wherein the derivatives thereof is selected from Methylprednisolone 30 mg/kg 55 p < 0.0001 the group consisting of derivatives wherein the amino group and/or hydroxyl group of the aminoSugar is alkylated, arylated or acylated, and wherein the ano 0210 Compound 92 yielded a statistically significant meric, 2-, 3-, 4-, or 6-position is Sulphated or phospho inhibition of ear oedema. Glucosamine Sulfate inhibited ear rylated. oedema mildly, and not statistically Significantly, while 55. A chemical complex according to claim 54, wherein Salbutamol inhibited ear oedema Significantly. In the group the beta-2 adrenoceptor agonist is Selected from the group receiving Compound 92 the relative ear oedema was 71% consisting of bambuterol, bitolterol, broXaterol, carbuterol, and 40% lower than in the groups receiving the correspond clenbuterol, clorprenaline, dioxethedrine, dopexamine, ing doses of glucosamine Sulfate and Salbutamol, respec ephedrine, epinephrine, etafedrine, ethylnorepinephrine, tively. These differences were Statistically significant, fenoterol, formoterol, hexoprenaline, isoetarine, isoproter p<0.0001 and p=0.0076, respectively, and since Compound enol, mabuterol, metaproterenol, methoxyphenamine orci 92 reached a higher level of inhibition than the sum of prenaline, pirbuterol, procaterol, protokylol, reproterol, rim inhibition of the corresponding doses of glucosamine Sulfate iterol, ritodrine, Salbutamol (albuterol), Salmeterol, and Salbutamol, the data imply a Synergistic effect. Soterenol, terbutaline, tretoquinol, tulobuterol, derivatives 0211 Compound 92 yielded a 41% lower ear oedema and Salts thereof. than methylprednisolone and this difference was significant 56. The chemical complex according to claim 54, wherein (p=0.0021). the aminoSugar is glucosamine hydrochloride or glu 0212 Conclusion cosamine Sulfate. 0213 The data imply that systemically administered 57. The chemical complex according to claim 54, wherein Compound 92 is a potent inhibitor of arachidonic acid the beta-2 adrenoceptor agonist is Salbutamol Sulfate, terb induced ear Oedema and that the Surprisingly strong inhibi utaline Sulfate or formoterol fumarate dihydrate. tion is obtained through a Synergistic effect between the 58. A composition comprising: components of the complex. i) a beta-2 adrenoceptor agonist; Example 179 ii) an aminoSugar Selected from the group consisting of 0214) A woman (70 years old) had been suffering from glucosamine, mannosamine, Salts and derivatives Significant muscular pain for 6 years and had for periods thereof, wherein the derivatives thereof is selected from US 2005/O130935 A1 Jun. 16, 2005 14

the group consisting of wherein the amino group and/or 71. The method according to claim 65 for the treatment or hydroxyl group of the aminoSugar is alkylated, arylated prevention of autoimmune disease and/or chronic inflam or acylated, and wherein the anomeric, 2-, 3-, 4-, or matory. 6-position is Sulphated or phosphorylated; and 72. The method according to claim 71, for the treatment of autoimmune hepatitis, Primary biliary cirrhosis, Primary iii) one or more acceptable excipients or carriers. Sclerosing cholangitis, Autoimmune hemolytic anemias, 59. The composition according to claim 58, wherein the Grave's disease, Myasthenia gravis, Type 1 Diabetes Mel beta-2 adrenoceptor agonist is Selected from the group litus, Inflammatory myopathies, Multiple Sclerosis, Hash consisting of bambuterol, bitolterol, carbuterol, clenbuterol, imoto's thyreoiditis, Autoimmune adrenalitis, Crohn's Dis clorprenaline, dioxethedrine, dopexamine, ephedrine, epi ease, Ulcerative Colitis, Glomerulonephritis, Progressive nephrine, etafedrine, ethylnorepinephrine, fenoterol, for Systemic Sclerosis (Scleroderma), Sjögren's Disease, Lupus moterol, heXoprenaline, isoetarine, isoproterenol, Erythematosus, Primary vasculitis, Rheumatoid Arthritis, mabuterol, metaproterenol, methoxyphenamine, pirbuterol, Juvenile Arthritis, Mixed Connective Tissue Disease, Pso procaterol, protokylol, reproterol, rimiterol, ritodrine, Salb riasis, Pemfigus, Pemfigoid or Dermatitis Herpetiformis. utamol (albuterol), Salmeterol, Soterenol, terbutaline, treto 73. The method according to claim 72, for the treatment quinol, tulobuterol, derivatives and Salts thereof. or prevention of diabetes, Crohn's disease, ulcerative colitis, 60. The composition according to claim 58, wherein the rheumatoid arthritis, multiple Sclerosis, gout or Osteoarthri aminoSugar is glucosamine hydrochloride or glucosamine tis. Sulfate. 74. The method according to claim 65, wherein the 61. The composition according to claim 58, wherein the mammal is a human. beta-2 adrenoceptor agonist is Salbutamol Sulfate, terbuta 75. The method according to claim 65, wherein the line sulfate or formoterol fumarate dihydrate. combination of the beta-2 adrenoceptor agonist and the 62. The composition according to claim 58, wherein the aminoSugar is a chemical complex comprising: beta-2 adrenoceptor agonist and the aminoSugar is in the form of a chemical complex comprising: i) a beta-2 adrenoceptor agonist; and i) a beta-2 adrenoceptor agonist; and ii) an aminoSugar Selected from the group consisting of ii) an aminoSugar Selected from the group consisting of glucosamine, mannosamine, Salts and derivatives glucosamine, mannosamine, Salts and derivatives thereof, wherein the derivatives thereof is selected from thereof, wherein the derivatives thereof is selected from the group consisting of derivatives wherein the amino the group consisting of derivatives wherein the amino group and/or hydroxyl group of the aminoSugar is group and/or hydroxyl group of the aminoSugar is alkylated, arylated or acylated, and wherein the ano alkylated, arylated or acylated, and wherein the ano meric, 2-, 3-, 4-, or 6-position is Sulphated or phospho meric, 2-, 3-, 4-, or 6-position is Sulphated or phospho rylated. rylated. 76. The method according to claim 65, wherein the 63. The composition according to claim 58, further com combination of a beta-2 adrenoceptor agonist and the ami prising one or more therapeutically active agents other than noSugar is a composition comprising: a beta-2 adrenoceptor agonist and the aminoSugar. 64. The composition according to claim 58 in a form i) a beta-2 adrenoceptor agonist; Selected from the group consisting of oral formulation, ii) an aminoSugar Selected from the group consisting of topical formulation, transdermal formulation, and parenteral glucosamine, mannosamine, Salts and derivatives formulation. thereof, wherein the derivatives thereof is selected from 65. A method for the Suppression of hypersensitivity the group consisting of wherein the amino group and/or and/or inflammatory reactions in a mammal, comprising the hydroxyl group of the aminoSugar is alkylated, arylated administration to Said mammal of a combination of a beta-2 or acylated, and wherein the anomeric, 2-, 3-, 4-, or adrenoceptor agonist and an aminoSugar, or pharmaceuti 6-position is Sulphated or phosphorylated; and cally acceptable Salts thereof, the aminoSugar being Selected from the group consisting of glucosamine, mannosamine, iii) one or more acceptable excipients or carriers. salts and derivatives thereof, wherein the derivatives thereof 77. The method according to claim 65, wherein the is Selected from the group consisting of wherein the amino combination of a beta-2 adrenoceptor agonist and an ami group and/or hydroxyl group of the aminoSugar is alkylated, noSugar, or pharmaceutically acceptable Salts thereof, are arylated or acylated, and wherein the anomeric, 2-, 3-, 4-, or together comprised in a single formulation or are each 6-position is Sulphated or phosphorylated. individually comprised in Separate formulations. 66. The method according to claim 65, for the treatment 78. The method according to claim 65, wherein the or prevention of hyperSensitivity skin disease in a mammal. combination of a beta-2 adrenoceptor agonist and an ami 67. The method according to claim 66, for the treatment noSugar is administered by means of oral, topical, transder or prevention of atopic eczema, contact dermatitis, Sebor mal, or parenteral administration, or combinations thereof. rhoeic eczema and/or psoriasis. 79. The method according to claim 77, wherein the 68. The method according to claim 66, for the treatment Separate formulations are administered in a simultaneous or or prevention of contact dermatitis or psoriasis. non-simultaneous manner. 69. The method according to claim 65 for the treatment or 80. The method according to claim 65, further comprising prevention of IgE mediated allergic reaction and/or condi administering one or more therapeutically active Substances tion. other than the Said beta-2 adrenoceptor agonist and Said 70. The method according to claim 69, for the treatment aminoSugar. or prevention of asthma, allergic rhinitis, and/or anaphy laxis.