CA2334711C - Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies - Google Patents
Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies Download PDFInfo
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- CA2334711C CA2334711C CA002334711A CA2334711A CA2334711C CA 2334711 C CA2334711 C CA 2334711C CA 002334711 A CA002334711 A CA 002334711A CA 2334711 A CA2334711 A CA 2334711A CA 2334711 C CA2334711 C CA 2334711C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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Abstract
The invention relates to the use of bisphosphonic acids and the derivatives thereof for producing medicaments for preventing and treating autoimmune diseases or allergies combined with the autoantigens specifically used for treating the respective autoimmune disease or combined with the allergens specifically used for treating the respective allergy.
Some examples of the bisphosphonic acids or derivatives thereof which are used according to the invention include amino-hydroxy-methylidene-bisphosphonic acid (AMP), 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid (AEP), pamidronic acid, alendronic acid, 2-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (AEP), amidinomethylene-bisphosphonic acid (AEP), ibandronic acid. risedronic acid, zoledronic acid, cimadronic acid, and tiludronic acid. Some examples of autoimmune diseases in which bisphosphonic acids or the derivatives thereof can be used include rheumatoid arthritis, severe myasthenia, diabetes mellitus, uveitis, and scleroderma. The bisphosphonic acids or the derivatives thereof and the autoantigens or allergens can be applied simultaneously or in succession. The preparations of the combinations can be used in solid form, as ointments, as solutions or as sprays.
Some examples of the bisphosphonic acids or derivatives thereof which are used according to the invention include amino-hydroxy-methylidene-bisphosphonic acid (AMP), 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid (AEP), pamidronic acid, alendronic acid, 2-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (AEP), amidinomethylene-bisphosphonic acid (AEP), ibandronic acid. risedronic acid, zoledronic acid, cimadronic acid, and tiludronic acid. Some examples of autoimmune diseases in which bisphosphonic acids or the derivatives thereof can be used include rheumatoid arthritis, severe myasthenia, diabetes mellitus, uveitis, and scleroderma. The bisphosphonic acids or the derivatives thereof and the autoantigens or allergens can be applied simultaneously or in succession. The preparations of the combinations can be used in solid form, as ointments, as solutions or as sprays.
Description
Field of the invention This invention relates to pharmaceutical preparations for the prevention and treatment of autoimmune disorders and of allergies.
It is known that autoimmune disorder:>, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, uveitis etc., and allergies, in particular food allergies, nickel allergy and pollen allergies etc. are attributable to an inappropriate ' reaction by the body's immune system.
It is furthermore known that, due these inappropriate reactions of the immune system, endogenous substances (autoantigens) are perceived as foreign substances and a defence reaction~develops against them which results in damage to the body's own tissue. Depending upon the organ system involved, some 40 autoimmune conditions have been identified. These defence reactions may be directed both against individual cell constituents and against entire cells or organs.
Allergies are known to be the result pf hypersensitivity towards certain substances, the allergens, which gives rise to an over-reaction of the immune system. In other words, affected subjects react to certain substances (the I'i CA 02334711 2000-12-08 2 , allergens) with specific symptoms as a defence against the allergen.
nr, ..r Attempts to treat autoimmune disorders caused by inappropriate reactions of the immune system with non-specifically acting immunosuppressants have proved entirely unsatisfactory as the use of immunosuppressants brings about a general inhibition of inflammatory reactions which may go as far as to shut down large parts of the immune system, so resulting in the occurrence of many side-effects, for example toxic damage, increased susceptibility to infectious diseases and increased risk of the occurrence of malignant diseases.
The alternative approach of avoiding the side-effects associated with the use of non-specifically acting immunosuppressants by using selective suppression (c. f.
Ann. Neurol. 37 Suppl, l, 87-101), with action being purposefully and specifically taken against the allergens or autoantigens at various points in the defence reaction, also met with less than complete success.
One of these methods is based upon the oral or inhalatory administration of autoantigens or allergens specific to the particular disorder. While it is indeed possible in this manner to reinduce the body's resistance to these autoantigens or allergens or to enable the bady to tolerate the autoantigens or allergens which have hitherto been attacked and initiate the enhanced immune response, the overall success rate oftthis patient desensitisation is limited because the desensitisation is inadequate (Ann. N. Y. Acad. Sci. 778, 1-27; Ann. N. Y.
i, 3 , Acad. Sci. 778, 243-250; Science 261, 1727-1730; Annu.
Rev. Med. 48, 341-351).
The mechanism of oral reinduction of tolerance by these substances is not yet completely understood. Tt may, however, be assumed that in the case of oral administration a part is played both by the immune system and by the bacterial flora of the gastrointestinal tract, the T cells (T lymphocytes), in particular the y8-T cells (The Journal of Immunology 158, 3610-~3618~ Res. Immunol.
147, 49-59; Immunology Zetters 48, 97-102).
It was, however, entirely surprising that the reinduction of tolerance achieved with oral or inhalatory administration of autoantigens or allergens specific to the disorder was greatly promoted if the autoantigens or allergens were administered in combination with bisphosphonic acids or the derivatives thereof. These combinations may thus successfully beg used for the prevention and treatment of autoimmun.e disorders or allergies.
The use of bisphosphonic acids and of some of the derivatives thereof in pharmaceutical preparations is already known. The microbiostatic action of bisphosphonic acids (DE 3611522), the action thereof in the treatment of disorders of calcium and phosphate metabolism (DE
2534390, DE 2534391, DE 3334211, DE 3434667, DE 2745083), cytostatic action (DE 3425812), the lipid-reducing action thereof (Arzneimittelforschung 46, 759-762) and the ability thereof to stimulate immune cells (WO 97/38696 A1) are already known. The fact that bisphosphonic acids have an immunomodulatory action (WO 97/38696 A1) is furthermore known and has been used.
i n CA 02334711 2000-12-08 4 . . _ .
However, use of these compounds is associated with many side-effects which are determined by 'the mode of administration. In the case of intravenous infusion, such side-effects are fever, flu-like symptoms with violent shivering, lymphopenia and thrombocytopenia and, in the case of oral administration, they are painful swallowing, oesophagitis, oesophageal erosion, oesophageal ulceration, dyspepsia, diarrhoea etc.. Moreover, oral treatment with bisphosphonates, for e:~ample, requires relatively large quantities of active substance and therapeutic success is still unsatisfactory (Drug-Saf.
14, 158-170) .
It was thus not in the least obvious to use this group of compounds in combination with autoant:igens or allergens in order to reinduce the body's tolerance to autoantigens or allergens.
Description of the invention The invention accordingly relates to <~ novel method of solving the hitherto unsolved problem of the prevention and treatment of autoimmune disorders and of allergies by means of pharmaceutical preparations, namely to use the autoantigens or allergens hitherto used to treat autoimmune disorders and allergies in combination with bisphosphonates or the derivatives the=reof.
The invention relates to the use of b:LSphosphonic acids and the derivatives thereof for the production of pharmaceutical preparations for the prevention and treatment of autoimmune diseases or a:Llergies, wherein the bisphosphonic acids and the derivatives thereof which are used are those of the general formula:
A30-P-C-P-OA1 ( I ) , Rz in which w Al, A2, A3, A4, which may be identical or different and mean hydrogen, substii_uted or unsubstituted alkyl, :>ubstituted or unsubstituted aryl, substituted or unsubstituted aralkyl,, substituted or unsubstituted cycloallcyl or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, A1, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, X, which may also be absent or may be alkylene, alkenylene or hydroxyalkylene, R1, R2, which may be identical or different and mean H, OH, -NH2, a substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloal~;yl, substituted or unsubstituted aralkyl or a substituted or i unsubstituted heteroc5~clic residue or -SR3, C1 and -NR3R4, in which ,.
R3, R4, which may be identical. or different and mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubst:ituted aryl, substituted or unsubst:ituted aralkyl, substituted or unsubst:ituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and the pharmaceutically compatible exalts, esters thereof as well as salts of esters or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues or fragments thereof of they autoantigens or allergens, providing that these each exhibit the same immunological characteristics as the corresponding whole molecules, and wherein the bisphosphonic acids or the derivatives thereof and the autoantigens or allergens or fragments, derivatives or analogues thereof may be administered simultaneously or in succession.
The substances may here be administered both synchronously and with a delay by simultaneous or separate administration of the active: substances.
a t From the group of bisphosphonic acid; and the derivatives thereof of the general formula I, the>se bisphosphonic acids and the derivatives thereof which are preferred for 7 , use for the prevention and treatment of autoimmune disorders or allergies are of the general formula:
A30-P-C-P-OA1 ( I I ) , Rz in which A1, A2, A3, A4, which may be identical or different and mean hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, an aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, R1, means H, OH, NH2, X, which may also be absent or may be alkylene, alkenylene or hydroxyalkylene, in each case having 1 to l2 carbon atoms, R2, means H, OH, -NH2, an <alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted ,i ~' CA 02334711 2000-12-08 by functional groups, or -SR3, Cl and -NR3R4, in which R3, R4, which may be identical. or different and mean H, OH, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups.
Bisphosphonic acids and the derivatives thereof which have proved particularly effective are those of the general formula:
A30-P-C-P-OAl ( I I I ) , RZ
in which A1, A2, A3, A4, which may be identical or different and mean hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, a metal of main group 1, 2 or 3 of the'periodic system, such as Na, K, Ca, Mg, A1, as well as substituted or unsubstituted ammonium or I
ammonium compounds derived from ethylenediamine or amino acids, R1, means H, OH, X, which may also be absent or may mean (CHZ) 1_5, amidino, R2, may mean _NH2 -.N~
(CH2)4-CH3 -N
-N~ NH -S ~ ~ C 1 ~!i N
Some examples of these are:
aminohydroxymethylidenebisphosphonic acid (AMP), 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid (AEP), 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronic acid), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronic acid), 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (AHP), amidinomethylenebisphosphonic acid (AIMP), 3-methylpentylamino-1-hydroxypropylidene-l,l-bisphosphonic acid (ibandronic acid), 2-(3-pyridinyl)-1-hydroxyethylidenebisphosphonic acid (risedronic acid), 1-hydroxy-2-(imidazol-1-yl)-ethylidene-1,1-bisphosphonic acid (zoledronic acid), cycloheptylaminomethylenediphosphonic: acid (cimadronic acid) , 4-chlorophenylthiomethylene-1,1-bisphosphonic acid (tiludronic acid) and the derivatives thereof.
Autoimmune disorders and allergies axe prevented and treated by combined use a bisphosphonic acid or the of derivatives thereof and autoantige:n which initiates an the particular autoimmune disorder, .>uch as for example in multiple sclerosis with myelin basic protein (MBP), further extracts from nervous system tissue, rheumatoid arthritis with type I, II or III
collagen, Hashimoto thyroiditis with thyroglobulin, myasthenia gravis with acetylcholine receptor protein, lupus erythematosus with DNA, diabetes mellitus with islet: cell extracts, human insulin, primary biliary cirrhosis with lives: extracts, active chronic hepatitis with liver. cell extracts, adrenalitis/Addison's with adrenal cortex extracts, disease polymyositis with skin extracts, muscle extracts, dermatomyositis with muscle and/or skin extracts, autoimmune haemolytic with haemopoetic cell line ex-tracts, anaemia a myocarditis with heart:'extracts, myopericarditis scleroderma with skin extracts, skin cell ex-tracts, uveitis (phacouveitis, with eye lens proteins, sympathetic ophthalmia) S-antigens, S-antigen mixtures, pemphigus vulgaris with skin extracts, pemphigoid with skin extracts, pernicious anaemia with gastric cell extracts, parietal cell extracts, intrinsic factor, autoimmune atrophic with gastric cell extracts, gastritis Crohn's disease with inte~~tinal extracts, colitis ulcerosa with inte~~tinal extracts or in allergies with the allergy-specific allergens.
Combined use is also taken to include cases in which autoantigens or allergens are already present. Such cases include, for example, Crohn's disease, in which the autoantigen is already present in the intestine as a result of the disease. In this case, in the event of oral or rectal administration, only the bisphosphonic acids or the derivatives thereof need be administered. It is also unnecessary to administer the allergen if,' during treatment, the affected subject is in an environment in which the allergy-specific allergen is already present (for example pollen during the pollen release season).
Combined use may proceed not only by oral administration, for example by means of tablets etc., but also, for example, by rectal, inhalatory administration, by application onto the skin or mucous membranes. Preferred administration forms are oral and inhalatory administration and application onto the skin or mucous membranes.
Of these administration forms, inhalation has proved to be particularly gentle because elevatE=d activity is achieved with only very small quantities of autoantigen or allergen and bisphosphonic acid or the derivatives thereof and any possible side-effects of the active substances may accordingly be minimised.
The bisphosphonic acids and the derivatives thereof which are preferably used are those which a:re poorly resorbed, which include, for example, aminobisphosphonic acids and the derivatives thereof.
Preferred pharmaceutical compositions are tablets, sugar-coated pills, capsules, pills, granules, suppositories, solutions, suspensions and emwlsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, sugar-coated pills, capsules, pills and granules may contain, apart from the active substances, conventional excipients, such as (a) fillers and e:;tenders, for example starch, lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxymethyl-cellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) suspending agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retardants,, for example paraffin and (f) resorption accelerators, for example quaternary ammonium compounds, (g) wei_ting agents, for example cetyl alcohol, glycerol monost~earate, (h) adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in (a) to (i).
13 , .
The tablets, sugar-coated pills, capsules, pills and granules may be provided with conventional coatings and shells, which optionally contain opac;ifying agents, and may be of a composition such that they release the active substance, optionally with a delay, ~;olely or preferentially in a specific part of the intestinal tract, wherein polymeric substances a.nd waxes may, for example, be used as matrix materials.
The active substance or substances, optionally together with one or more of the above-stated excipients, may also assume microencapsulated form.
Apart from the active substance or substances, _ suppositories may contain conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters ( for example C14 alcohol with C16 fatty acid) or mixtures of these substances.
Apart from the active substance or substances, ointments, pastes, creams and gels may contain conventional excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum and zinc oxide or mixtures of these substances.
Apart from the active substance or substances, powders and sprays may contain conventional e:xcipients, for example lactose, talcum, silica, aluminium hydroxide, calcium silicate and polyamide powder:or mixtures of these substances. Sprays may additionally contain conventional propellants, for example chlorofluoro-carbons.
Apart from the active substance or substances, solutions and emulsions may contain conventional excipients, such as solvents, solubilising agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl_ene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, maize oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances.
Apart from the active substance or substances, suspensions may contain conventional excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline; cellulose, aluminium metahydroxide, bentonite, cigar-agar and tragacanth gum or mixtures of these ~>ubstances.
The stated formulation forms may also contain colorants, preservatives as well as with odour- and flavour-enhancing additives, for example peppermint oil and eucalyptus oil and sweeteners, for e~:ample saccharin.
Bisphosphonic acids or the derivatives thereof of the formula (I) are suitable far simultaneous, separate or temporally staged use with the autoantigens or allergens, and these compounds should accordingl..y be present in the pharmaceutical preparations listed above, preferably in a concentration of approx. 0.1 to 99.5 wt.%, relative to the complete mixture. The concentration of the i, 15 , .
autoantigens or allergens should be ().1 to 99.5 wt.o in this case too.
Apart from the compounds of the formula (I) and the autoantigen or allergen, the pharmaceutical preparations listed above may also contain further pharmaceutical active substances.
The pharmaceutical preparations listed above are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
The stated preparations may be administered to humans or animals orally, rectally, intravaginally, topically (powders, ointments, drops) and in cavities and body cavities. Suitable preparations for oral treatment which may be considered are solutions and :suspensions, gels, infusion formulations, emulsions, ointments or drops.
Topical treatment may be performed upping ophthalmological and dermatological formulations, silver and other salts, ear drops, eye ointments, powders or solutions. For animals, administration may be made ~>y~suitable formulation with feed or drinking wager. Gels, pulverulent formulations, powders, tablets, delayed-release tablets, premixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays, inhalatory preparations may also be used in humans and animals. The compounds according to the invention may furthermore be incorporated into other support materials, such as for example plastics (plastic chains for topical treatment), collagen or bone cement.
The quantities of the individual der:uvatives required to achieve the desired effect vary very widely. In general, it has proved advantageous in both human and veterinary medicine to administer the active substance or substances of the formula (I) in total quantities of approx. 0.5 to approx. 2000 mg per 24 hours, optionally in the form of two or more individual doses, in order to achieve the desired results. An individual dose ~>referably contains the active substance or substances in quantities of approx. 0.5 to approx. 2000 mg. It may, however, be necessary to deviate from the stated dosages, specifically as a function of the species and body weight of the subject to be treated, the nature and severity of the condition, the nature of the preparation and administration of the pharmaceutical preparation and the period of time or interval within which the preparation is administered.
It may accordingly be sufficient in :>ome cases to use less than the above-stated quantity of active substance, while in other cases the active substance must be used in a quantity greater than that stated above. The person skilled in the art will establish the: optimum dosage and mode of administration of the active substances in each case on the basis of his/her experti:>e.
When treating animals, the compounds to be used according to the invention may be given in the conventional concentrations and preparations together with feed or with feed preparations or with drinking water.
Examples Tablets are produced in a manner kno~,rn per se using a mixture of 1. 3-Amino-1-hydroxypropylidene-l,l-- 600 mg bisphosphonate, disodium salt Bovine collagen, type II 10 mg Mannitol _ 400 mg Starch 50 mg Magnesium stearate 10 mg 2. 4-Amino-1-hydroxybutylidene-1,1- 26 mg bisphosphonate (monosodium salt), 3H20 Bovine collagen, type II 10 mg Mannitol 400 _ mg Starch 50 mg Magnesium stearate 10 mg 3. 3-Methylpentylamino-1-hydroxypro~>yl- 1.125 mg idene-1,1-bisphosphonate, monosodium salt, 1H20 Bovine collagen, type II 10 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 mg 4. 3-Amino-1-hydroxypropylidene-l,l- 600 mg bisphosphonate, disodium salt Myelin basic protein (MBP) 8 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 mg i'~ CA 02334711 2000-12-08 18 , .
5. 4-Amino-1-hydroxybutylidene-1,1- 26 mg bisphosphonate (monosodium salt),, 3H20 Myelin basic protein (MBP) 8 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 mg 6. 3-Methylpentylamino-1-hydroxypropyl- 1.125 mg idene-1,1-bisphosphonate, monosodium salt, 1H20 Myelin basic protein (MBP) 8 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 - mg Capsules are produced in a manner known per se using 7. 3-Amino-1-hydroxypropylidene-l,l-- 600 mg bisphosphonate, disodium salt Myelin basic protein (MBP) 8 mg Proteolipid protein 15 mg Magnesium stearate 15 mg 8. 4-Amino-1-hydroxybutylidene-l,l- 26 mg bisphosphonate (monosodium salt),, 3H20 Myelin basic protein (MBP) 8 mg Proteolipid protein 15 mg Magnesium stearate 15 mg a L:
It is known that autoimmune disorder:>, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, uveitis etc., and allergies, in particular food allergies, nickel allergy and pollen allergies etc. are attributable to an inappropriate ' reaction by the body's immune system.
It is furthermore known that, due these inappropriate reactions of the immune system, endogenous substances (autoantigens) are perceived as foreign substances and a defence reaction~develops against them which results in damage to the body's own tissue. Depending upon the organ system involved, some 40 autoimmune conditions have been identified. These defence reactions may be directed both against individual cell constituents and against entire cells or organs.
Allergies are known to be the result pf hypersensitivity towards certain substances, the allergens, which gives rise to an over-reaction of the immune system. In other words, affected subjects react to certain substances (the I'i CA 02334711 2000-12-08 2 , allergens) with specific symptoms as a defence against the allergen.
nr, ..r Attempts to treat autoimmune disorders caused by inappropriate reactions of the immune system with non-specifically acting immunosuppressants have proved entirely unsatisfactory as the use of immunosuppressants brings about a general inhibition of inflammatory reactions which may go as far as to shut down large parts of the immune system, so resulting in the occurrence of many side-effects, for example toxic damage, increased susceptibility to infectious diseases and increased risk of the occurrence of malignant diseases.
The alternative approach of avoiding the side-effects associated with the use of non-specifically acting immunosuppressants by using selective suppression (c. f.
Ann. Neurol. 37 Suppl, l, 87-101), with action being purposefully and specifically taken against the allergens or autoantigens at various points in the defence reaction, also met with less than complete success.
One of these methods is based upon the oral or inhalatory administration of autoantigens or allergens specific to the particular disorder. While it is indeed possible in this manner to reinduce the body's resistance to these autoantigens or allergens or to enable the bady to tolerate the autoantigens or allergens which have hitherto been attacked and initiate the enhanced immune response, the overall success rate oftthis patient desensitisation is limited because the desensitisation is inadequate (Ann. N. Y. Acad. Sci. 778, 1-27; Ann. N. Y.
i, 3 , Acad. Sci. 778, 243-250; Science 261, 1727-1730; Annu.
Rev. Med. 48, 341-351).
The mechanism of oral reinduction of tolerance by these substances is not yet completely understood. Tt may, however, be assumed that in the case of oral administration a part is played both by the immune system and by the bacterial flora of the gastrointestinal tract, the T cells (T lymphocytes), in particular the y8-T cells (The Journal of Immunology 158, 3610-~3618~ Res. Immunol.
147, 49-59; Immunology Zetters 48, 97-102).
It was, however, entirely surprising that the reinduction of tolerance achieved with oral or inhalatory administration of autoantigens or allergens specific to the disorder was greatly promoted if the autoantigens or allergens were administered in combination with bisphosphonic acids or the derivatives thereof. These combinations may thus successfully beg used for the prevention and treatment of autoimmun.e disorders or allergies.
The use of bisphosphonic acids and of some of the derivatives thereof in pharmaceutical preparations is already known. The microbiostatic action of bisphosphonic acids (DE 3611522), the action thereof in the treatment of disorders of calcium and phosphate metabolism (DE
2534390, DE 2534391, DE 3334211, DE 3434667, DE 2745083), cytostatic action (DE 3425812), the lipid-reducing action thereof (Arzneimittelforschung 46, 759-762) and the ability thereof to stimulate immune cells (WO 97/38696 A1) are already known. The fact that bisphosphonic acids have an immunomodulatory action (WO 97/38696 A1) is furthermore known and has been used.
i n CA 02334711 2000-12-08 4 . . _ .
However, use of these compounds is associated with many side-effects which are determined by 'the mode of administration. In the case of intravenous infusion, such side-effects are fever, flu-like symptoms with violent shivering, lymphopenia and thrombocytopenia and, in the case of oral administration, they are painful swallowing, oesophagitis, oesophageal erosion, oesophageal ulceration, dyspepsia, diarrhoea etc.. Moreover, oral treatment with bisphosphonates, for e:~ample, requires relatively large quantities of active substance and therapeutic success is still unsatisfactory (Drug-Saf.
14, 158-170) .
It was thus not in the least obvious to use this group of compounds in combination with autoant:igens or allergens in order to reinduce the body's tolerance to autoantigens or allergens.
Description of the invention The invention accordingly relates to <~ novel method of solving the hitherto unsolved problem of the prevention and treatment of autoimmune disorders and of allergies by means of pharmaceutical preparations, namely to use the autoantigens or allergens hitherto used to treat autoimmune disorders and allergies in combination with bisphosphonates or the derivatives the=reof.
The invention relates to the use of b:LSphosphonic acids and the derivatives thereof for the production of pharmaceutical preparations for the prevention and treatment of autoimmune diseases or a:Llergies, wherein the bisphosphonic acids and the derivatives thereof which are used are those of the general formula:
A30-P-C-P-OA1 ( I ) , Rz in which w Al, A2, A3, A4, which may be identical or different and mean hydrogen, substii_uted or unsubstituted alkyl, :>ubstituted or unsubstituted aryl, substituted or unsubstituted aralkyl,, substituted or unsubstituted cycloallcyl or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, A1, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, X, which may also be absent or may be alkylene, alkenylene or hydroxyalkylene, R1, R2, which may be identical or different and mean H, OH, -NH2, a substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloal~;yl, substituted or unsubstituted aralkyl or a substituted or i unsubstituted heteroc5~clic residue or -SR3, C1 and -NR3R4, in which ,.
R3, R4, which may be identical. or different and mean H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubst:ituted aryl, substituted or unsubst:ituted aralkyl, substituted or unsubst:ituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, and the pharmaceutically compatible exalts, esters thereof as well as salts of esters or compounds which, on administration, form the compounds to be administered as metabolites or catabolites, in combination with the specific autoantigens for the prevention and treatment of the particular autoimmune disorder, or in combination with the specific allergens for the prevention and treatment of the particular allergy, wherein, instead of the particular autoantigens or allergens, it is also possible to use fragments or derivatives thereof and the analogues or fragments thereof of they autoantigens or allergens, providing that these each exhibit the same immunological characteristics as the corresponding whole molecules, and wherein the bisphosphonic acids or the derivatives thereof and the autoantigens or allergens or fragments, derivatives or analogues thereof may be administered simultaneously or in succession.
The substances may here be administered both synchronously and with a delay by simultaneous or separate administration of the active: substances.
a t From the group of bisphosphonic acid; and the derivatives thereof of the general formula I, the>se bisphosphonic acids and the derivatives thereof which are preferred for 7 , use for the prevention and treatment of autoimmune disorders or allergies are of the general formula:
A30-P-C-P-OA1 ( I I ) , Rz in which A1, A2, A3, A4, which may be identical or different and mean hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, an aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, such as Na, K, Ca, Mg, Al, as well as substituted or unsubstituted ammonium or ammonium compounds derived from ethylenediamine or amino acids, R1, means H, OH, NH2, X, which may also be absent or may be alkylene, alkenylene or hydroxyalkylene, in each case having 1 to l2 carbon atoms, R2, means H, OH, -NH2, an <alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted ,i ~' CA 02334711 2000-12-08 by functional groups, or -SR3, Cl and -NR3R4, in which R3, R4, which may be identical. or different and mean H, OH, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups.
Bisphosphonic acids and the derivatives thereof which have proved particularly effective are those of the general formula:
A30-P-C-P-OAl ( I I I ) , RZ
in which A1, A2, A3, A4, which may be identical or different and mean hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues may additionally be substituted by functional groups, a metal of main group 1, 2 or 3 of the'periodic system, such as Na, K, Ca, Mg, A1, as well as substituted or unsubstituted ammonium or I
ammonium compounds derived from ethylenediamine or amino acids, R1, means H, OH, X, which may also be absent or may mean (CHZ) 1_5, amidino, R2, may mean _NH2 -.N~
(CH2)4-CH3 -N
-N~ NH -S ~ ~ C 1 ~!i N
Some examples of these are:
aminohydroxymethylidenebisphosphonic acid (AMP), 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid (AEP), 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronic acid), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronic acid), 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (AHP), amidinomethylenebisphosphonic acid (AIMP), 3-methylpentylamino-1-hydroxypropylidene-l,l-bisphosphonic acid (ibandronic acid), 2-(3-pyridinyl)-1-hydroxyethylidenebisphosphonic acid (risedronic acid), 1-hydroxy-2-(imidazol-1-yl)-ethylidene-1,1-bisphosphonic acid (zoledronic acid), cycloheptylaminomethylenediphosphonic: acid (cimadronic acid) , 4-chlorophenylthiomethylene-1,1-bisphosphonic acid (tiludronic acid) and the derivatives thereof.
Autoimmune disorders and allergies axe prevented and treated by combined use a bisphosphonic acid or the of derivatives thereof and autoantige:n which initiates an the particular autoimmune disorder, .>uch as for example in multiple sclerosis with myelin basic protein (MBP), further extracts from nervous system tissue, rheumatoid arthritis with type I, II or III
collagen, Hashimoto thyroiditis with thyroglobulin, myasthenia gravis with acetylcholine receptor protein, lupus erythematosus with DNA, diabetes mellitus with islet: cell extracts, human insulin, primary biliary cirrhosis with lives: extracts, active chronic hepatitis with liver. cell extracts, adrenalitis/Addison's with adrenal cortex extracts, disease polymyositis with skin extracts, muscle extracts, dermatomyositis with muscle and/or skin extracts, autoimmune haemolytic with haemopoetic cell line ex-tracts, anaemia a myocarditis with heart:'extracts, myopericarditis scleroderma with skin extracts, skin cell ex-tracts, uveitis (phacouveitis, with eye lens proteins, sympathetic ophthalmia) S-antigens, S-antigen mixtures, pemphigus vulgaris with skin extracts, pemphigoid with skin extracts, pernicious anaemia with gastric cell extracts, parietal cell extracts, intrinsic factor, autoimmune atrophic with gastric cell extracts, gastritis Crohn's disease with inte~~tinal extracts, colitis ulcerosa with inte~~tinal extracts or in allergies with the allergy-specific allergens.
Combined use is also taken to include cases in which autoantigens or allergens are already present. Such cases include, for example, Crohn's disease, in which the autoantigen is already present in the intestine as a result of the disease. In this case, in the event of oral or rectal administration, only the bisphosphonic acids or the derivatives thereof need be administered. It is also unnecessary to administer the allergen if,' during treatment, the affected subject is in an environment in which the allergy-specific allergen is already present (for example pollen during the pollen release season).
Combined use may proceed not only by oral administration, for example by means of tablets etc., but also, for example, by rectal, inhalatory administration, by application onto the skin or mucous membranes. Preferred administration forms are oral and inhalatory administration and application onto the skin or mucous membranes.
Of these administration forms, inhalation has proved to be particularly gentle because elevatE=d activity is achieved with only very small quantities of autoantigen or allergen and bisphosphonic acid or the derivatives thereof and any possible side-effects of the active substances may accordingly be minimised.
The bisphosphonic acids and the derivatives thereof which are preferably used are those which a:re poorly resorbed, which include, for example, aminobisphosphonic acids and the derivatives thereof.
Preferred pharmaceutical compositions are tablets, sugar-coated pills, capsules, pills, granules, suppositories, solutions, suspensions and emwlsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, sugar-coated pills, capsules, pills and granules may contain, apart from the active substances, conventional excipients, such as (a) fillers and e:;tenders, for example starch, lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxymethyl-cellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) suspending agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retardants,, for example paraffin and (f) resorption accelerators, for example quaternary ammonium compounds, (g) wei_ting agents, for example cetyl alcohol, glycerol monost~earate, (h) adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances stated in (a) to (i).
13 , .
The tablets, sugar-coated pills, capsules, pills and granules may be provided with conventional coatings and shells, which optionally contain opac;ifying agents, and may be of a composition such that they release the active substance, optionally with a delay, ~;olely or preferentially in a specific part of the intestinal tract, wherein polymeric substances a.nd waxes may, for example, be used as matrix materials.
The active substance or substances, optionally together with one or more of the above-stated excipients, may also assume microencapsulated form.
Apart from the active substance or substances, _ suppositories may contain conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters ( for example C14 alcohol with C16 fatty acid) or mixtures of these substances.
Apart from the active substance or substances, ointments, pastes, creams and gels may contain conventional excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum and zinc oxide or mixtures of these substances.
Apart from the active substance or substances, powders and sprays may contain conventional e:xcipients, for example lactose, talcum, silica, aluminium hydroxide, calcium silicate and polyamide powder:or mixtures of these substances. Sprays may additionally contain conventional propellants, for example chlorofluoro-carbons.
Apart from the active substance or substances, solutions and emulsions may contain conventional excipients, such as solvents, solubilising agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl_ene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, maize oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances.
Apart from the active substance or substances, suspensions may contain conventional excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline; cellulose, aluminium metahydroxide, bentonite, cigar-agar and tragacanth gum or mixtures of these ~>ubstances.
The stated formulation forms may also contain colorants, preservatives as well as with odour- and flavour-enhancing additives, for example peppermint oil and eucalyptus oil and sweeteners, for e~:ample saccharin.
Bisphosphonic acids or the derivatives thereof of the formula (I) are suitable far simultaneous, separate or temporally staged use with the autoantigens or allergens, and these compounds should accordingl..y be present in the pharmaceutical preparations listed above, preferably in a concentration of approx. 0.1 to 99.5 wt.%, relative to the complete mixture. The concentration of the i, 15 , .
autoantigens or allergens should be ().1 to 99.5 wt.o in this case too.
Apart from the compounds of the formula (I) and the autoantigen or allergen, the pharmaceutical preparations listed above may also contain further pharmaceutical active substances.
The pharmaceutical preparations listed above are produced in the conventional manner using known methods, for example by mixing the active substance or substances with the excipient or excipients.
The stated preparations may be administered to humans or animals orally, rectally, intravaginally, topically (powders, ointments, drops) and in cavities and body cavities. Suitable preparations for oral treatment which may be considered are solutions and :suspensions, gels, infusion formulations, emulsions, ointments or drops.
Topical treatment may be performed upping ophthalmological and dermatological formulations, silver and other salts, ear drops, eye ointments, powders or solutions. For animals, administration may be made ~>y~suitable formulation with feed or drinking wager. Gels, pulverulent formulations, powders, tablets, delayed-release tablets, premixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays, inhalatory preparations may also be used in humans and animals. The compounds according to the invention may furthermore be incorporated into other support materials, such as for example plastics (plastic chains for topical treatment), collagen or bone cement.
The quantities of the individual der:uvatives required to achieve the desired effect vary very widely. In general, it has proved advantageous in both human and veterinary medicine to administer the active substance or substances of the formula (I) in total quantities of approx. 0.5 to approx. 2000 mg per 24 hours, optionally in the form of two or more individual doses, in order to achieve the desired results. An individual dose ~>referably contains the active substance or substances in quantities of approx. 0.5 to approx. 2000 mg. It may, however, be necessary to deviate from the stated dosages, specifically as a function of the species and body weight of the subject to be treated, the nature and severity of the condition, the nature of the preparation and administration of the pharmaceutical preparation and the period of time or interval within which the preparation is administered.
It may accordingly be sufficient in :>ome cases to use less than the above-stated quantity of active substance, while in other cases the active substance must be used in a quantity greater than that stated above. The person skilled in the art will establish the: optimum dosage and mode of administration of the active substances in each case on the basis of his/her experti:>e.
When treating animals, the compounds to be used according to the invention may be given in the conventional concentrations and preparations together with feed or with feed preparations or with drinking water.
Examples Tablets are produced in a manner kno~,rn per se using a mixture of 1. 3-Amino-1-hydroxypropylidene-l,l-- 600 mg bisphosphonate, disodium salt Bovine collagen, type II 10 mg Mannitol _ 400 mg Starch 50 mg Magnesium stearate 10 mg 2. 4-Amino-1-hydroxybutylidene-1,1- 26 mg bisphosphonate (monosodium salt), 3H20 Bovine collagen, type II 10 mg Mannitol 400 _ mg Starch 50 mg Magnesium stearate 10 mg 3. 3-Methylpentylamino-1-hydroxypro~>yl- 1.125 mg idene-1,1-bisphosphonate, monosodium salt, 1H20 Bovine collagen, type II 10 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 mg 4. 3-Amino-1-hydroxypropylidene-l,l- 600 mg bisphosphonate, disodium salt Myelin basic protein (MBP) 8 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 mg i'~ CA 02334711 2000-12-08 18 , .
5. 4-Amino-1-hydroxybutylidene-1,1- 26 mg bisphosphonate (monosodium salt),, 3H20 Myelin basic protein (MBP) 8 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 mg 6. 3-Methylpentylamino-1-hydroxypropyl- 1.125 mg idene-1,1-bisphosphonate, monosodium salt, 1H20 Myelin basic protein (MBP) 8 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 - mg Capsules are produced in a manner known per se using 7. 3-Amino-1-hydroxypropylidene-l,l-- 600 mg bisphosphonate, disodium salt Myelin basic protein (MBP) 8 mg Proteolipid protein 15 mg Magnesium stearate 15 mg 8. 4-Amino-1-hydroxybutylidene-l,l- 26 mg bisphosphonate (monosodium salt),, 3H20 Myelin basic protein (MBP) 8 mg Proteolipid protein 15 mg Magnesium stearate 15 mg a L:
9. 3-Methylpentylamino-1-hydroxypropyl- 1.125 mg idene-l,l-bisphosphonate, monosodium salt, 1H20 Myelin basic protein (MBP) g mg Proteolipid protein 15 mg Magnesium stearate 15 mg 10. 3-Amino-1-hydroxypropylidene-1,1-- 600 mg bisphosphonate, disodium salt Bovine collagen, type II 10 mg Magnesium stearate 15 mg 11. 4-Amino-1-hydroxypropylidene-1,1-~ 26 mg bisphosphonate (monosodium salt), 3H20 Bovine collagen, type II 10 mg Magnesium stearate 15 mg 12. 3-Methylpentylamino-1-hydroxypropyl- 1.125 mg idene-1,1-bisphosphonate, monosodium salt, 1H20 Bovine collagen, type II 10 mg Magnesium stearate 15 mg wherein the above~constituents are mixed together and then introduced in conventional manner into a hard gelatine capsule.
a t A preparation for inhalation for a 2 :ml dose is produced using:
a t A preparation for inhalation for a 2 :ml dose is produced using:
13. 4-Amino-1-hydroxybutylidene-l,l- 1.3 mg bisphosphonate (monosodium salt), 3H20 Myelin basic protein 15 mg ~i-Cyclodextrin hydrate ~ mg pH 7.2 phosphate buffer 0.2 ml water for injection;
14. 3-Amino-1-hydroxypropylidene-l,l- 30 mg bisphosphonate, disodium salt Myelin basic protein 15 mg (3-Cyclodextrin hydrate ~ mg pH 7.2 phosphate buffer 0.2 - ml water for injection;
15. 3-Methylpentylamino-1-hydroxypropyl- 0.25 mg idene-1,1-bisphosphonate, monosodium salt, 1 H20 -myelin basic protein 15 mg ~i-Cyclodextrin hydrate ~ mg cH 7.2 phosphate buffer 0.2 ml water for injection;
16. 4-Amino-1-hydroxybutylidene-1,1- 1.3 mg bisphosphonate (monosodium salt), 3H20 Bovine collagen, type II 10 mg (3-Cyclodextrin hydrate ~ mg pH 7.2 phosphate buffer 0.2 ml water for injection;
r 17. 3-Amino-1-hydroxypropylidene-l,l- 30 mg bisphosphonate, disodium salt Bovine collagen, type II 10 mg (3-Cyclodextrin hydrate 7 mg pH 7.2 phosphate buffer 0.2 ml water for injection;
r 17. 3-Amino-1-hydroxypropylidene-l,l- 30 mg bisphosphonate, disodium salt Bovine collagen, type II 10 mg (3-Cyclodextrin hydrate 7 mg pH 7.2 phosphate buffer 0.2 ml water for injection;
18. 3-Methylpentylamino-1-hydroxypropyl- 0.25 mg idene-1,1-bisphosphonate, monosodium salt, 1H20 Bovine collagen, type II 10 mg ~3-Cyclodextrin hydrate 7 mg pH 7.2 phosphate buffer 0.2 ml water fer injection. -r~:e bisphosphonate (for example alendronate) and the ~utcantigen (for example MBP) are dissolved in a phosphate buffer solution and the ~3-cyclodextrin hydrate .s dissolved therein. The solution is made up to the ~.esi=ed volume with water for injection, sterilised by =_ltration and aseptically packaged in containers suitable for inhalation by atomisation.
Claims (5)
1. Use of a bisphosphonic acid or a derivative thereof for the production of a pharmaceutical preparation for prevention or treatment of autoimmune diseases or allergies, wherein the bisphosphonic acid or derivative is of the general formula:
in which A1, A2, A3, A4, which are identical or different, are selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, and substituted or unsubstituted ammonium or ammonium compounds derived from ethylene diamine or an amino acid, X, is alkylene, alkenylene hydroxyalkylene, amino, or is absent, R1, R2, which are identical or different, are selected from H, OH, NH2, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or a substituted or unsubstituted heterocyclic residue, -SR3, C1 and -NR3R4, in which R3, R4, which are identical or different, are selected from H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl and a substituted or unsubstituted heterocyclic residue, and a pharmaceutically compatible salt, ester or salt of an ester thereof, or a compound which, on administration, forms the bisphosphonic acid or derivative to be administered as a metabolite or catabolite thereof, wherein the bisphosphonic acid or derivative or compound which on administration forms the metabolite or catabolite which correspond to the bisphosphonic acid or derivative, is used in combination with a specific autoantigen for the prevention and treatment of the autoimmune disorder, or in combination with a specific allergen for the prevention and treatment of the allergy, or a fragment or derivative of said autoantigen or allergen, or an analogue or fragment thereof, provided the analogues and fragments exhibit the same immunological characteristics as the corresponding autoantigen or allergen.
in which A1, A2, A3, A4, which are identical or different, are selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic residue, a metal of main group 1, 2 or 3 of the periodic system, and substituted or unsubstituted ammonium or ammonium compounds derived from ethylene diamine or an amino acid, X, is alkylene, alkenylene hydroxyalkylene, amino, or is absent, R1, R2, which are identical or different, are selected from H, OH, NH2, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or a substituted or unsubstituted heterocyclic residue, -SR3, C1 and -NR3R4, in which R3, R4, which are identical or different, are selected from H, OH, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl and a substituted or unsubstituted heterocyclic residue, and a pharmaceutically compatible salt, ester or salt of an ester thereof, or a compound which, on administration, forms the bisphosphonic acid or derivative to be administered as a metabolite or catabolite thereof, wherein the bisphosphonic acid or derivative or compound which on administration forms the metabolite or catabolite which correspond to the bisphosphonic acid or derivative, is used in combination with a specific autoantigen for the prevention and treatment of the autoimmune disorder, or in combination with a specific allergen for the prevention and treatment of the allergy, or a fragment or derivative of said autoantigen or allergen, or an analogue or fragment thereof, provided the analogues and fragments exhibit the same immunological characteristics as the corresponding autoantigen or allergen.
2. Use of a bisphosphonic acid or a derivative thereof according to claim 1, wherein in the general formula (I) A1, A2, A3, A4, which are identical or different, are selected from hydrogen, an alkyl residue having 1 to 12 carbon atoms, which may be branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues are unsubstituted or substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, a substituted or unsubstituted ammonium or ammonium compound derived from ethylene diamine or an amino acid, R1, is H, OH or NH2, X, is alkylene, alkenylene or hydroxyalkylene, in each case having 1 to 12 carbon atoms, or is absent, R2, is H, OH, NH2, an alkyl residue having 1 to 12 carbon atoms, which is branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues are unsubstituted or substituted by functional groups, or is -SR3, Cl or -NR3R4, in which R3, R4, which are identical or different, are H, OH, an alkyl residue having 1 to 12 carbon atoms, which is branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues are unsubstituted or substituted by functional groups.
3. Use of a bisphosphonic acid or a derivative according to claim 1, wherein in general formula (I) A1, A2, A3, A4, which are identical or different are selected from hydrogen, an alkyl residue having 1 to 12 carbon atoms, which is branched or unbranched, an aryl residue, aralkyl residue, cycloalkyl residue or a heterocyclic residue, wherein these residues are unsubstituted or substituted by functional groups, a metal of main group 1, 2 or 3 of the periodic system, and a substituted or unsubstituted ammonium or ammonium compound derived from ethylene diamine or an amino acid, R1, is H or OH, X, is absent, or is (CH2) 1-5 or amino, R2 is
4. Use of a bisphosphonic acid or a derivative thereof in combination with an autoantigen or allergen for the production of a pharmaceutical preparation for the prevention or treatment of an autoimmune condition or allergy according to claim 1, 2 or 3, wherein the autoantigen or allergen is as indicated hereinafter for the treatment of the indicated disease:
multiple sclerosis myelin basic protein (MBP), further extracts from nervous system tissue, rheumatoid arthritis type I, II or III collagen, Hashimoto thyroiditis thyroglobulin, myasthenia gravis acetylcholine receptor protein, lupus erythematus DNA, diabetes mellitus ~islet cell extracts, human insulin, primary biliary ~liver extracts, cirrhosis active chronic hepatitis ~liver cell extracts, adrenalitis/Addison's ~adrenal cortex extracts, disease polymyositis ~skin extracts, muscle extracts, dermatomyositis ~at least one of muscle and skin extracts, autoimmune haemolytic ~haemopoetic cell line extracts, anaemia myocarditis ~heart extracts, myopericarditis scleroderma ~skin extracts, skin cell extracts, uveitis ~eye lens proteins, (phacouveitis, S-antigens, ~S-antigen mixtures, sympathetic ophtalmia), pemphigus vulgaris ~~skin extracts, pemphigoid ~~~skin extracts, pernicious anaemia ~~gastric cell extracts, parietal cell extracts, intrinsic factor, autoimmune atrophic ~~gastric cell extracts, gastritis Crohn's disease ~~intestinal extracts, colitis ulcerosa ~~intestinal extracts allergies ~~~allergy-specific allergens.
multiple sclerosis myelin basic protein (MBP), further extracts from nervous system tissue, rheumatoid arthritis type I, II or III collagen, Hashimoto thyroiditis thyroglobulin, myasthenia gravis acetylcholine receptor protein, lupus erythematus DNA, diabetes mellitus ~islet cell extracts, human insulin, primary biliary ~liver extracts, cirrhosis active chronic hepatitis ~liver cell extracts, adrenalitis/Addison's ~adrenal cortex extracts, disease polymyositis ~skin extracts, muscle extracts, dermatomyositis ~at least one of muscle and skin extracts, autoimmune haemolytic ~haemopoetic cell line extracts, anaemia myocarditis ~heart extracts, myopericarditis scleroderma ~skin extracts, skin cell extracts, uveitis ~eye lens proteins, (phacouveitis, S-antigens, ~S-antigen mixtures, sympathetic ophtalmia), pemphigus vulgaris ~~skin extracts, pemphigoid ~~~skin extracts, pernicious anaemia ~~gastric cell extracts, parietal cell extracts, intrinsic factor, autoimmune atrophic ~~gastric cell extracts, gastritis Crohn's disease ~~intestinal extracts, colitis ulcerosa ~~intestinal extracts allergies ~~~allergy-specific allergens.
5. Use of a bisphosphonic acid or derivative thereof for the production of a pharmaceutical preparation for the prevention or treatment of an autoimmune condition or allergy according to claim 1, 2 or 3, wherein the combination preparation is in a form for administration in solid form, as an ointment, as a solution or as a spray.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19828450A DE19828450A1 (en) | 1998-06-26 | 1998-06-26 | Use of bisphosphonic acid compounds and autoantigens or allergens |
| DE19828450.0 | 1998-06-26 | ||
| PCT/DE1999/001844 WO2000000182A2 (en) | 1998-06-26 | 1999-06-24 | Medicaments containing bisphosphonic acids and derivatives thereof which are provided for preventing and treating autoimmune diseases and allergies |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2356262A1 (en) | 1998-12-23 | 2000-07-06 | Jomaa Pharmaka Gmbh | Use of bisphosphonates for the prevention and treatment of infectious processes |
| WO2000038693A1 (en) * | 1998-12-25 | 2000-07-06 | Toray Industries, Inc. | Interleukin-6 production inhibitors |
| EP1392325B1 (en) * | 2001-05-02 | 2006-06-21 | Novartis AG | Method of administration of bisphosphonates by inhalation in the treatment or prevention of bone resorption and osteoporosis |
| PT1408984E (en) | 2001-07-20 | 2008-12-26 | Bioagency Ag | Organo-phosphorous compounds for activating gamma/delta t cells |
| GB0307989D0 (en) * | 2003-04-07 | 2003-05-14 | Mcewen Lab Ltd | Therapeutic composition |
| EP1713489B1 (en) * | 2004-08-23 | 2011-01-19 | Teva Pharmaceutical Industries Ltd | Crystalline form of ibandronate sodium and processes for preparation thereof |
| EP1931326A4 (en) * | 2005-09-12 | 2009-12-16 | Reddys Lab Ltd Dr | Crystalline trihydrate of zoledronic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2114946T3 (en) * | 1991-09-05 | 1998-06-16 | Toray Industries | DERIVATIVE OF METHANODIPHOSPHONIC ACID, ITS PRODUCTION AND MEDICINAL USE. |
| WO1996022790A1 (en) * | 1995-01-23 | 1996-08-01 | Xenotech Incorporated | Composition to ameliorate osteolysis and metastasis |
-
1998
- 1998-06-26 DE DE19828450A patent/DE19828450A1/en not_active Withdrawn
-
1999
- 1999-06-24 AT AT99941383T patent/ATE224734T1/en active
- 1999-06-24 EP EP99941383A patent/EP1089761B1/en not_active Expired - Lifetime
- 1999-06-24 EA EA200100080A patent/EA200100080A1/en unknown
- 1999-06-24 DK DK99941383T patent/DK1089761T3/en active
- 1999-06-24 AU AU55033/99A patent/AU740605B2/en not_active Ceased
- 1999-06-24 JP JP2000556767A patent/JP2002519319A/en active Pending
- 1999-06-24 WO PCT/DE1999/001844 patent/WO2000000182A2/en not_active Application Discontinuation
- 1999-06-24 HU HU0102873A patent/HUP0102873A3/en unknown
- 1999-06-24 DE DE59902856T patent/DE59902856D1/en not_active Expired - Lifetime
- 1999-06-24 TR TR2000/03821T patent/TR200003821T2/en unknown
- 1999-06-24 EE EEP200000756A patent/EE200000756A/en unknown
- 1999-06-24 CA CA002334711A patent/CA2334711C/en not_active Expired - Fee Related
- 1999-06-24 SK SK1960-2000A patent/SK19602000A3/en unknown
- 1999-06-24 NZ NZ509505A patent/NZ509505A/en not_active IP Right Cessation
- 1999-06-24 IL IL13996699A patent/IL139966A0/en unknown
- 1999-06-24 ES ES99941383T patent/ES2184496T3/en not_active Expired - Lifetime
- 1999-06-24 MX MXPA00012338A patent/MXPA00012338A/en unknown
- 1999-06-24 ID IDW20002676A patent/ID27515A/en unknown
- 1999-06-24 PT PT99941383T patent/PT1089761E/en unknown
- 1999-06-24 KR KR1020007014813A patent/KR20010053211A/en not_active Application Discontinuation
- 1999-06-24 PL PL99345287A patent/PL345287A1/en unknown
-
2000
- 2000-11-29 HR HR20000820A patent/HRP20000820A2/en not_active Application Discontinuation
- 2000-12-01 IS IS5748A patent/IS5748A/en unknown
- 2000-12-21 NO NO20006572A patent/NO20006572L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE224734T1 (en) | 2002-10-15 |
| KR20010053211A (en) | 2001-06-25 |
| DE19828450A1 (en) | 1999-12-30 |
| WO2000000182A2 (en) | 2000-01-06 |
| HUP0102873A3 (en) | 2002-04-29 |
| AU740605B2 (en) | 2001-11-08 |
| PL345287A1 (en) | 2001-12-03 |
| TR200003821T2 (en) | 2001-06-21 |
| DK1089761T3 (en) | 2003-02-03 |
| EA200100080A1 (en) | 2001-06-25 |
| NO20006572L (en) | 2001-02-21 |
| HRP20000820A2 (en) | 2001-12-31 |
| HUP0102873A2 (en) | 2001-12-28 |
| NZ509505A (en) | 2002-11-26 |
| CA2334711A1 (en) | 2000-01-06 |
| NO20006572D0 (en) | 2000-12-21 |
| PT1089761E (en) | 2003-02-28 |
| EP1089761B1 (en) | 2002-09-25 |
| MXPA00012338A (en) | 2003-04-25 |
| EP1089761A2 (en) | 2001-04-11 |
| DE59902856D1 (en) | 2002-10-31 |
| IL139966A0 (en) | 2002-02-10 |
| JP2002519319A (en) | 2002-07-02 |
| AU5503399A (en) | 2000-01-17 |
| SK19602000A3 (en) | 2001-07-10 |
| ID27515A (en) | 2001-04-12 |
| IS5748A (en) | 2000-12-01 |
| ES2184496T3 (en) | 2003-04-01 |
| EE200000756A (en) | 2002-04-15 |
| WO2000000182A3 (en) | 2000-03-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20150625 |