WO2014044756A1 - Strontium as anti microbial compound - Google Patents
Strontium as anti microbial compound Download PDFInfo
- Publication number
- WO2014044756A1 WO2014044756A1 PCT/EP2013/069478 EP2013069478W WO2014044756A1 WO 2014044756 A1 WO2014044756 A1 WO 2014044756A1 EP 2013069478 W EP2013069478 W EP 2013069478W WO 2014044756 A1 WO2014044756 A1 WO 2014044756A1
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- WO
- WIPO (PCT)
- Prior art keywords
- strontium
- pharmaceutical composition
- acid
- composition according
- group
- Prior art date
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- 229910052712 strontium Inorganic materials 0.000 title claims description 65
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 title claims description 60
- 239000004599 antimicrobial Substances 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 131
- 159000000008 strontium salts Chemical class 0.000 claims abstract description 93
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 43
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 41
- 238000011282 treatment Methods 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 55
- 238000009472 formulation Methods 0.000 claims description 31
- 239000003826 tablet Substances 0.000 claims description 27
- 239000000499 gel Substances 0.000 claims description 25
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 claims description 25
- 239000000843 powder Substances 0.000 claims description 23
- 239000002775 capsule Substances 0.000 claims description 22
- BDAGIHXWWSANSR-NJFSPNSNSA-N hydroxyformaldehyde Chemical compound O[14CH]=O BDAGIHXWWSANSR-NJFSPNSNSA-N 0.000 claims description 22
- 229910000018 strontium carbonate Inorganic materials 0.000 claims description 22
- 229910001631 strontium chloride Inorganic materials 0.000 claims description 22
- 241000894006 Bacteria Species 0.000 claims description 20
- 239000006071 cream Substances 0.000 claims description 16
- 239000006210 lotion Substances 0.000 claims description 15
- 239000002674 ointment Substances 0.000 claims description 15
- 239000000839 emulsion Substances 0.000 claims description 14
- 239000006260 foam Substances 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 12
- 239000007937 lozenge Substances 0.000 claims description 12
- 239000006187 pill Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- -1 strontium silicates Chemical class 0.000 claims description 11
- 239000000829 suppository Substances 0.000 claims description 11
- 239000003889 eye drop Substances 0.000 claims description 10
- 229940012356 eye drops Drugs 0.000 claims description 10
- 210000000214 mouth Anatomy 0.000 claims description 9
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- 206010040872 skin infection Diseases 0.000 claims description 8
- DHEQXMRUPNDRPG-UHFFFAOYSA-N strontium nitrate Chemical compound [Sr+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O DHEQXMRUPNDRPG-UHFFFAOYSA-N 0.000 claims description 8
- 241000590002 Helicobacter pylori Species 0.000 claims description 7
- 229940037467 helicobacter pylori Drugs 0.000 claims description 7
- 238000007910 systemic administration Methods 0.000 claims description 7
- 241000192125 Firmicutes Species 0.000 claims description 6
- 206010035664 Pneumonia Diseases 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 6
- UBXAKNTVXQMEAG-UHFFFAOYSA-L strontium sulfate Chemical compound [Sr+2].[O-]S([O-])(=O)=O UBXAKNTVXQMEAG-UHFFFAOYSA-L 0.000 claims description 6
- 208000019206 urinary tract infection Diseases 0.000 claims description 6
- 241000191967 Staphylococcus aureus Species 0.000 claims description 5
- 201000008225 Klebsiella pneumonia Diseases 0.000 claims description 4
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 4
- 206010035717 Pneumonia klebsiella Diseases 0.000 claims description 4
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 4
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 4
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 230000000688 enterotoxigenic effect Effects 0.000 claims description 3
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 3
- 229910052917 strontium silicate Inorganic materials 0.000 claims description 3
- QSQXISIULMTHLV-UHFFFAOYSA-N strontium;dioxido(oxo)silane Chemical compound [Sr+2].[O-][Si]([O-])=O QSQXISIULMTHLV-UHFFFAOYSA-N 0.000 claims description 3
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 2
- 241000193163 Clostridioides difficile Species 0.000 claims description 2
- 241000193403 Clostridium Species 0.000 claims description 2
- 241000193155 Clostridium botulinum Species 0.000 claims description 2
- 241000193468 Clostridium perfringens Species 0.000 claims description 2
- 241000193449 Clostridium tetani Species 0.000 claims description 2
- 241000194033 Enterococcus Species 0.000 claims description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 claims description 2
- 241000186781 Listeria Species 0.000 claims description 2
- 241000186779 Listeria monocytogenes Species 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 241000191940 Staphylococcus Species 0.000 claims description 2
- 241000194017 Streptococcus Species 0.000 claims description 2
- KQAGKTURZUKUCH-UHFFFAOYSA-L strontium oxalate Chemical compound [Sr+2].[O-]C(=O)C([O-])=O KQAGKTURZUKUCH-UHFFFAOYSA-L 0.000 claims description 2
- 229940079488 strontium ranelate Drugs 0.000 claims description 2
- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 claims description 2
- QRVYVKGHSWMAJI-IYEMJOQQSA-L strontium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Sr+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O QRVYVKGHSWMAJI-IYEMJOQQSA-L 0.000 claims description 2
- CPKHHOBKIQHTLE-UHFFFAOYSA-L strontium;1,2,2-trimethylcyclopentane-1,3-dicarboxylate Chemical compound [Sr+2].CC1(C)C(C([O-])=O)CCC1(C)C([O-])=O CPKHHOBKIQHTLE-UHFFFAOYSA-L 0.000 claims description 2
- RZDNXOOMMJEAFR-UHFFFAOYSA-L strontium;2-hydroxybutanedioate Chemical compound [Sr+2].[O-]C(=O)C(O)CC([O-])=O RZDNXOOMMJEAFR-UHFFFAOYSA-L 0.000 claims description 2
- CCUZKVDGQHXAFK-UHFFFAOYSA-L strontium;2-hydroxypropanoate Chemical compound [Sr+2].CC(O)C([O-])=O.CC(O)C([O-])=O CCUZKVDGQHXAFK-UHFFFAOYSA-L 0.000 claims description 2
- USBIHMTWQAZQAG-UHFFFAOYSA-L strontium;ethanesulfonate Chemical compound [Sr+2].CCS([O-])(=O)=O.CCS([O-])(=O)=O USBIHMTWQAZQAG-UHFFFAOYSA-L 0.000 claims description 2
- QGAPCDHPGCYAKM-UHFFFAOYSA-H tristrontium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Sr+2].[Sr+2].[Sr+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QGAPCDHPGCYAKM-UHFFFAOYSA-H 0.000 claims description 2
- JOPDZQBPOWAEHC-UHFFFAOYSA-H tristrontium;diphosphate Chemical compound [Sr+2].[Sr+2].[Sr+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O JOPDZQBPOWAEHC-UHFFFAOYSA-H 0.000 claims description 2
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- 241000588769 Proteus <enterobacteria> Species 0.000 claims 1
- 241000589516 Pseudomonas Species 0.000 claims 1
- 241000607720 Serratia Species 0.000 claims 1
- 241000607768 Shigella Species 0.000 claims 1
- 241000122971 Stenotrophomonas Species 0.000 claims 1
- 230000000813 microbial effect Effects 0.000 claims 1
- 230000008506 pathogenesis Effects 0.000 abstract description 11
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- 239000005720 sucrose Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- ZTUXEFFFLOVXQE-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCC(O)=O ZTUXEFFFLOVXQE-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- DPUOLQHDNGRHBS-MDZDMXLPSA-N trans-Brassidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-MDZDMXLPSA-N 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 230000007279 water homeostasis Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to pharmaceutical compositions comprising at least one strontium salt and the uses thereof in the treatment of clinical conditions, wherein bacterial infection is a primary factor of the pathogenesis.
- Bacterial infections are an increasing problem in the health care system. Several bacterial species have developed resistance towards traditional antibiotics and patients worldwide are now dying of infections that previously could have been cured by traditional antibiotics like penicillin.
- beta- lactam antibacterials which include the penicillins (produced by fungi in the genus Penicillium), the cephalosporins, and the carbapenems.
- penicillins produced by fungi in the genus Penicillium
- cephalosporins produced by fungi in the genus Penicillium
- carbapenems Compounds that are still isolated from living organisms are the aminoglycosides, whereas other antibacterials— for example, the sulfonamides, the quinolones, and the oxazolidinones— are produced solely by chemical synthesis
- Antibacterial antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most target bacterial functions or growth processes. Those that target the bacterial cell wall (penicillins and cephalosporins) or the cell membrane (polymixins), or interfere with essential bacterial enzymes
- “Narrow-spectrum” antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria.
- Strontium is an alkaline earth metal and as other alkaline earth elements strontium has an oxidation number of +2 making it very reactive. Strontium is present in a small amount in normal diet and in most products comprising calcium due to the similarities of the two elements.
- the present invention surprisingly demonstrates that strontium salts function as antibacterial compounds against both gram-positive and gram-negative bacteria.
- a pharmaceutical composition comprising at least one strontium salt for use in treatment of a bacterial infection
- the pharmaceutical composition is for systemic administration and wherein the pharmaceutical composition is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
- a method of treatment and/or prevention of a bacterial infection comprising administration to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising at least one strontium salt and is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
- the present invention also relates to the treatment of clinical conditions, wherein bacterial infection is the primary factor of pathogenesis. It is a further object of the present invention to provide uses of a pharmaceutical composition comprising at least one strontium salt in the manufacture of a medicament for the treatment of bacterial infection.
- Figure 1 Helicobacter pylori zone inhibition test performed as described in example 1.
- treatment refers to the treatment
- the patient to be treated is preferably a mammal, in particular a human being.
- the patients to be treated according to the present invention can be of various ages.
- Pathogenesis refers to the mechanism that causes the disease. The term can also describe the origin and development of the disease, and whether it is acute, chronic, or recurrent. Most diseases are caused by multiple factors, however one factor will be the primary factor of pathogenesis.
- the pharmaceutical composition of the invention is for use in treatment of clinical conditions wherein bacterial infection is the primary factor of pathogenesis.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one strontium salt for use in treatment of a bacterial infection
- the pharmaceutical composition is for systemic administration and wherein the pharmaceutical composition is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
- a method of treatment and/or prevention of a bacterial infection comprising administration to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising at least one strontium salt and is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
- Strontium is an alkaline earth metal and as other alkaline earth elements strontium has an oxidation number of +2 making it very reactive.
- strontium has an oxidation number of +2 making it very reactive.
- the radioactive isotopes 89 and 90 are less preferable to use with the present invention due to their toxicity.
- At least one strontium salt is selected from the group of: strontium ascorbate, strontium aspartate in either L- and/or D-form, strontium benzenesulfonate, strontium camphorate, strontium carbonate, strontium chloride, strontium citrate, strontium ethanesulfonate, strontium fumarate, strontium gluconate, strontium glutamate in either L- and/or D-form, strontium glutarate, strontium lactate, strontium malate, strontium maleate, strontium malonate, strontium methanesulfonate, strontium nitrate, strontium oxalate, strontium phosphate, strontium pyruvate, strontium ranelate, strontium silicate, strontium succinate, strontium sulphate and strontium tartrate.
- at least one strontium salt is selected from the group of: strontium ascorbat
- a strontium silicates according to this invention may be SrSi0 2 and SrSi0 4 .
- a strontium chloride according to this invention may be selected from the group consisting of SrCI 2 , SrCl 2 -2-H 2 0, SrCl 2 -6-H 2 0 differing in the extent of hydration.
- the strontium chloride is Strontium chloride anhydrous.
- Strontium is present in a small amount in normal diet and in most products comprising calcium due to the similarities of the two elements.
- strontium salts such as the carbonate and sulphate salts
- other strontium salts such as strontium chloride, strontium hydroxide, strontium nitrate, strontium oxide and strontium acetate have very high solubilities in the range from 225-800 g/l in water.
- the pharmaceutical composition comprises at least one water-insoluble strontium salt.
- the water soluble strontium salt according to the invention has a solubility in the range from 1 g/100 ml water to 250 g/100 ml water, such as from 5 g/100 ml water to 250 g/100 ml water, for example from 10 g/100 ml water to 250 g/100 ml water, such as from 20 g/100 ml water to 250 g/100 ml water, such as from 40 g/100 ml water to 225 g/100 ml water, for example from 50 g/100 ml water to 200 g/100 ml water.
- the water insoluble strontium salt according to the invention has a solubility in the range from 0.0001 g/100 ml water to 0.900 g/100 ml water, such as from 0.0001 g/100 ml water to 0.500 g/100 ml water, for example from 0.0001 g/100 ml water to 0.100 g/100 ml water, such as from 0.001 g/100 ml water to 0.05 g/100 ml water, for example from 0.001 g/100 ml water to 0.06 g/100 ml water.
- the pharmaceutical composition comprises at least one water soluble strontium salt with a solubility above 20 g/100 ml water combined with at least one water insoluble strontium salt with a solubility below 0.0001 g/100 ml water.
- the pharmaceutical composition comprises at least on strontium salt with a solubility above 20g/100 ml water.
- the pharmaceutical composition comprises at least one strontium salt with a solubility below 0.0001 g/100 ml water.
- Suitable strontium salts for use according to the invention may be prepared from an organic or inorganic acid.
- the inorganic acid for preparing strontium salts may be selected from the group consisting of boric acid, bromous acid, chloric acid, diphosphoric acid, disulfuric acid, dithionic acid, dithionous acid, fulminic acid, hydrazoic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, hydrogen sulphide, hypophosphoric acid, hypophosphorous acid, iodic acid, iodous acid, metaboric acid, metaphosphoric acid, metaphosphorous acid, metasilicic acid, nitrous acid, orthophosphoric acid, orthophosphorous acid, orthosilicic acid, phosphoric acid, phosphinic acid, phosphonic acid, pyrophosphorous acid, selenic acid, sulfonic acid, thiocyanic acid and thiosulfuric acid.
- the organic acid for making strontium salts may be selected from the group consisting of C 2 H 5 COOH, C 3 H 7 COOH, C 4 H 9 COOH, (COOH) 2 , CH 2 (COOH) 2 , C 2 H 4 (COOH) 2 , C 3 H 6 (COOH) 2 , C 4 H 8 (COOH) 2 , C 5 H 10 (COOH) 2 , fumaric acid, maleic acid, malonic acid, lactic acid, citric acid, tartaric acid, oxalic acid, ascorbic acid, benzoic acid, salicylic acid, pyruvic acid, L- and D-aspartic acid, phthalic acid, carbonic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, camphoric acid, gluconic acid, L- and D- glutamic acid, trifluoroacetic acid, ranelic acid, 2,3,5,6-tetrabromobenzoic acid, 2,3,5,6- t
- the at least one water insoluble strontium salt is combined with at least one water soluble strontium salt.
- the water soluble strontium salt may be selected from the group consisting of: strontium chloride, strontium bromide, strontium nitrate, strontium hydroxide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium pyruvate, strontium alpha-ketoglutarate, strontium maleate, strontium succinate, strontium fumarate, strontium ascorbate, strontium tartate, strontium glutarate, strontium methanesulfonate, strontium benzenesulfonate and strontium sulphide.
- the water insoluble strontium salt may be selected from the group consisting of: strontium carbonate and strontium sulphate.
- the pharmaceutical composition comprise 55-99.95 % of strontium in the form of a water soluble strontium salt and 0.05 to 45 % strontium in the form of a water insoluble strontium salt, or such as 60-95 % strontium in the form of a water soluble strontium salt and 5-40 % strontium in the form of a water insoluble strontium salt, or such as 70-90 % strontium in the form of a water soluble strontium salt and 10-30 % strontium in the form of a water insoluble strontium salt, or such as 75 % strontium in the form of a water soluble strontium salt and 25 % strontium in the form of a water insoluble strontium salt.
- the pharmaceutical composition comprise 55-99.95 % of strontium in the form of a water insoluble strontium salt and 0.05 to 45 % strontium in the form of a water soluble strontium salt, or such as 60-95 % strontium in the form of a water insoluble strontium salt and 5-40 % strontium in the form of a water soluble strontium salt, or such as 70-90 % strontium in the form of a water insoluble strontium salt and 10-30 % strontium in the form of a water soluble strontium salt, or such as 75 % strontium in the form of a water insoluble strontium salt and 25 % strontium in the form of a water soluble strontium salt.
- strontium salts for use according to the present invention may be found herein below in the section "Pharmaceutical composition - strontium”.
- the present invention relates to a pharmaceutical composition comprising at least one strontium salt for use in treatment of a bacterial infection, wherein the pharmaceutical composition is for systemic administration.
- the pharmaceutical composition of the present invention may preferably be in the form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
- the pharmaceutical composition is in the form selected from the group consisting of: cream, ointment, gel, lotion, foam and emulsified gel.
- the pharmaceutical composition is in the form selected from the group consisting of: stick, patch, membrane, tampon, suppositories, sponges and strip.
- the pharmaceutical composition is in the form selected from the group consisting of: capsule, tablet, powder, pill, cachet, dispersible granule and lozenge.
- the pharmaceutical composition is in the form of eye drops.
- the pharmaceutical composition is in the form of an inhalator.
- the amount of strontium obtained in 1 gram of strontium salt depends on the molecular weight of the compound, relative to the number of strontium molecules therein, thus a salt with low molecular weight per strontium molecule maybe preferred.
- the Re of the strontium salt comprised by the strontium comprising pharmaceutical composition is more than 0.20, or more than 0.25 or 0.30, such as more than 0.31 such as more than 0.32, such as more than 0.33, such as more than 0.34, such as more than 0.36, such as more than 0.38 more preferably more than 0.40, or such as more than 0.42, such as more than 0.44 such as more than 0.46, such as more than 0.50, such as more than 0.52, such as more than 0.54, such as more than 0.56, such as more than 0.58 or such as more than 0.60.
- the Re of the strontium salt comprised by the strontium comprising pharmaceutical composition is more than 0.35 preferably more than 0.40 and most preferably at least 0.45 or 0.5.
- the high Re of strontium carbonate makes it a preferred salt as low amounts of the salt provide high amounts of the active ingredient.
- the at least one strontium salt is strontium carbonate.
- the solubility or availability of strontium in the stomach may be improved by combining two or more strontium salts.
- the pharmaceutical composition comprises at least two strontium salts or such three strontium salts, or more than three strontium salts.
- the pharmaceutical composition comprises two strontium salts.
- the pharmaceutical composition comprises at least two strontium salts.
- the strontium salts for use in said pharmaceutical composition may be any strontium salt which may be prepared from an organic or inorganic acid. Examples of organic and inorganic acids from which strontium salts may be prepared can be found herein above in the section "Strontium”.
- the effective ratio (Re) described above may also be considered in relation to compositions comprising at least two strontium salts. Then the ratio is calculated as the total weight of strontium divided by the total weight of the at least two strontium salts (' and ").
- the Re of the at least two strontium salts is more than 0.30, such as more than 0.31 such as more than 0.32, such as more than 0.33, such as more than 0.34, such as more than 0.36, such as more than 0.38, such as more than 0.40, or such as more than 0.42, such as more than 0.44 such as more than 0.46, such as more than 0.50, such as more than 0.52, such as more than 0.54, such as more than 0.56, such as more than 0.58.
- the Re of the at least two strontium salts is 0.30-1 .00, such as 0.35- 0.80, such as 0.40-0.59, preferably 0.46-0.58 or more preferably 0.50-0.57.
- the Re of the strontium salt comprised by the strontium composition is more than 0.35 preferably more than 0.40 and most preferably at least 0.45 or 0.5.
- the pharmaceutical composition comprises at least two strontium salts.
- Such a combination may further serve to optimize the effect of the composition and/or minimize undesirable effect of the compounds used.
- high intake of certain compounds, such as carbonates may alter the pH in the stomach and intestine and thereby affect the uptake and secretion of other compounds in an unfavorable way.
- this may be an advantage as carbonate may neutralize the gastric juice, this may be particular favorable in situation of acidity of the stomach or acid indigestion.
- the pharmaceutical composition comprises strontium carbonate and at least one other strontium salt as described herein above in the section "Strontium”.
- the pharmaceutical composition comprises strontium chloride and at least one other strontium salt as described herein above in the section "Strontium”.
- the first strontium salt is strontium carbonate and the second strontium salt is selected from the group consisting of: strontium chloride and strontium silicate.
- the pharmaceutical composition comprises two strontium salts it is preferred that the first strontium salt is strontium carbonate and the second strontium salt is strontium chloride.
- strontium comprising pharmaceutical composition according to the invention may comprise the two strontium salts in different percentage.
- strontium chloride may contribute with 1 -99.95 % of the total amount of strontium comprised by the
- the pharmaceutical composition comprises at least 50 % strontium chloride.
- the pharmaceutical composition may preferably comprise more strontium in the form of strontium chloride than in the form of strontium carbonate, with respect to molar percentages.
- the compositions comprise such as 55- 99.95 % of strontium in the form of strontium chloride and 0.05 to 45 % strontium in the form of strontium carbonate, or such as 60-95 % strontium in the form of strontium chloride and 5-40 % strontium in the form of strontium carbonate, or such as 70-90 % strontium in the form of strontium chloride and 10-30 % strontium in the form of strontium carbonate, or such as 75 % strontium in the form of strontium chloride and 25 % strontium in the form of strontium carbonate.
- the pharmaceutical composition comprises 100% strontium chloride.
- the pharmaceutical composition comprises strontium carbonate, wherein the amount of strontium carbonate contribute with such as at least 0.05 % of the strontium of the composition in other embodiments strontium carbonate contribute with at least 0.1 %, such as 1 %, such as at least 5 or 10 %, even such as at least 15 or 20 % of strontium is contributed by strontium carbonate.
- strontium carbonate contribute with at least 25 %, such as 30 % or alternatively such as 40 or 50 % of the strontium of the composition.
- strontium carbonate contribute with at least 60%, such as 70% or alternatively such as 75-95% of the strontium of the composition.
- composition - Secondary active ingredients
- the pharmaceutical composition of the present invention may be combined with a secondary active ingredient.
- the secondary active ingredient may be administered separately, sequentially and/or simultaneously with the pharmaceutical composition of the invention.
- the secondary active ingredient may be administered as a separate medicament or together with the strontium comprising pharmaceutical composition in a combined medicament.
- compositions containing a strontium salt according to the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19 th edition, Easton, Pa, unless otherwise described herein.
- compositions may be formulated in a number of different ways depending on the condition to be treated, the individual to be treated and the location of disease. Accordingly, the pharmaceutical composition is preferably formulated according to the need of the specific embodiment of the present invention.
- the pharmaceutical composition may be in a form selected from the group consisting of cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
- the pharmaceutical composition according to the present invention may in one embodiment be formulated in a wide variety of formulations for local administration, such as a gel, an emulsified gel, an ointment, a cream, a foam, a solution or a lotion.
- the pharmaceutical composition of the present invention is formulated in a wide variety of formulations for oral administration, such as in the form of a powder, tablet, pill, capsule, cachet, dispersible granule or lozenge.
- Other forms suitable for oral administration may include liquid form preparations including emulsions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
- the pharmaceutical composition of the present invention is in the form of a tablet or capsule. This is particularly useful when the bacterial infection to be treated is present in or associated with the gastrointestinal tract. Tablets or capsules may also be used when general systemic administration is needed. Tablets are solid pharmaceutical dosage forms containing the strontium salt with or without suitable diluents and may be prepared by different methods known to the person skilled in the art. Tablets may vary in shape and may accordingly be discoid, round, oval, oblong, cylindrical or triangular. They may vary in size and weight depending on the amount of strontium salt present and the intended method of administration.
- Capsules are solid pharmaceutical dosage forms in which the strontium salt is enclosed in either a hard or soft, soluble container or shell of a suitable material, e.g. gelatine. Capsules are usually oblong in shape and can vary in size depending on the amount of strontium salt present and the intended method of administration.
- Tablets and capsules may contain pharmaceutically acceptable carriers together with the strontium salt.
- the pharmaceutically acceptable carriers can be either solid or liquid.
- a solid carrier can be one or more excipients which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
- compositions may also contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the pharmaceutical composition of the present invention is in the form of a capsule.
- the pharmaceutical composition is in the form of a powder.
- the carrier is a finely divided solid which is a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,
- methylcellulose sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the pharmaceutical composition is in the form of an emulsion.
- Emulsions may be prepared in solutions in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
- Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents.
- Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
- composition of the present invention may in one embodiment be formulated in a wide variety of formulations for parenteral administration, such as in the form suitable for injection, infusion, topical delivery, nasal delivery, pulmonary delivery, bronchial delivery or transdermal delivery.
- the formulations may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
- the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules, vials, pre-filled syringes, infusion bags, or can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
- sterile liquid excipient for example, water
- Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
- oily or non-aqueous carriers examples include propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters, and may contain formulatory agents such as preserving, wetting, emulsifying or
- the formulations for injection will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution.
- the compounds may also be administered topically.
- Regions for topical administration include the skin surface and also mucous membrane tissues of the vagina, rectum, nose, mouth, and throat.
- the topical composition will typically include a pharmaceutically acceptable carrier adapted for topical administration.
- the composition may take the form of a ointment, lotion, sexual lubricant, cream, foam, aerosol, suppository, implant, inhalant, tablet, capsule, dry powder, balm or lozenge, for example. Methods for preparing such compositions are well known in the pharmaceutical industry.
- the compounds of the present invention may be formulated for topical administration to the epidermis in situations where the bacterial infection is present as a skin infection.
- Topical administration forms may be in the form of an ointment, cream or lotion, or as a transdermal patch. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
- the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin or a fatty acid.
- the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
- Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
- Patches may take many different forms.
- a patch comprises a polymer and an adhesive.
- the strontium salt may be deposited on the patch in the form of a solution, gel, cream and/or ointment.
- the patch may be an occlusive patch.
- the patch may be in the form of a thin membrane. This may in particular be the case for administration of strontium salt to a mucosal membrane, for example for nasal administration, for administration to the mouth or for buccal administration, or for administration to the genital region.
- Lotions according to the present invention also include those suitable for application to the eye in situations where the bacterial infection is present in the eye.
- An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide.
- the pharmaceutical composition is intended for nasal, pulmonary and/or bronchial administration. This is particularly useful when the bacterial infection to be treated is a bacterial infection of the upper or lower pulmonary tract.
- Formulations for use in nasal, pulmonary and/or bronchial are particularly useful when the bacterial infection to be treated is a bacterial infection of the upper or lower pulmonary tract.
- aerosol particles are used herein to describe the liquid or solid particle suitable for nasal, bronchial or pulmonary administration, i.e., that will reach the mucous membranes.
- aerosols are administered by use of a mechanical devices designed for pulmonary and/or bronchial delivery, including but not limited to nebulizers, metered dose inhalers, and powder inhalers.
- any form of aerosolization known in the art including but not limited to spray bottles, nebulization, atomization or pump aerosolization of a liquid formulation, and aerosolization of a dry powder formulation, can be used.
- Liquid Aerosol Formulations in general contain a compound of the present invention in a pharmaceutically acceptable diluent.
- Pharmaceutically acceptable diluents include but are not limited to sterile water, saline, buffered saline, dextrose solution, and the like.
- Formulations for dispensing from a powder inhaler device will normally comprise a finely divided dry powder containing pharmaceutical composition of the present invention and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device.
- Dry powder formulations for inhalation may also be formulated using powder-filled capsules, in particularly capsules the material of which is selected from among the synthetic plastics.
- the formulation is formulated to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy and known to the person skilled in the art.
- the propellant may be any propellant generally used in the art. Specific non-limiting examples of such useful propellants are a chlorofluorocarbon, a hydrofluorocarbon, a
- hydrochlorofluorocarbon or a hydrocarbon
- the formulations for nasal administration may in one embodiment involve solutions or suspensions which are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
- the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray this may be achieved for example by means of a metering atomizing spray pump.
- the formulations of the present embodiment may also include other agents useful for pH maintenance, solution stabilization, or for the regulation of osmotic pressure.
- the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
- composition of the present invention may be administered in many different formulation forms as outlined herein above. Common for all the administration forms of the present invention it is preferred that the subject to which the
- compositions are administered is exposed to the pharmaceutical composition for a prolonged period of time.
- Systemic administration in general e.g. oral and parenteral administration
- the pharmaceutical composition may be in the form intended for local administration, e.g. a patch or membrane containing the pharmaceutical composition.
- a local administration within the scope of the present invention is intended to be left at the site of treatment for more than 5 minutes of time, such as for more than 10 minutes, for example for more than 15 minutes, such as for more than 20 minutes, for example for more than 25 minutes, such as for more than 30 minutes, for example for more than 45 minutes such as for more than 1 hour.
- the pharmaceutical composition comprising at least strontium salt as described herein above in the section "Pharmaceutical composition” is for treatment and/or prevention of a Gram-positive bacterial infection.
- Gram-positive bacteria are bacteria that are stained dark blue or violet by Gram staining. Most pathogens in humans are Gram-positive organisms.
- Gram-positive bacteria of medical interest are among others: Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium and Listeria.
- the pharmaceutical composition of the invention is used in treatment and/or prevention of a bacterial infection by a bacterium selected from the group consisting of Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes.
- a bacterium selected from the group consisting of Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes.
- the pharmaceutical composition comprising at least strontium salt as described herein above in the section "Pharmaceutical composition” is for treatment and/or prevention of a Gram-positive bacterial infection.
- Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol.
- Gram-negative bacteria of medical interest include a multitude of species. Some of them primarily causes respiratory problems (Hemophilus influenza, Klebsiella pneumonia, Legionella pneumophila, Pseudomonas aeruginosa), some cause primarily urinary problems (Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens), some causing sexsually transmitted diseases
- the pharmaceutical composition of the invention is for treatment and/or prevention of a bacterial infection caused by a bacterium selected from the group consisting of Helicobacter pylori, Eschericha coli, Enterotoxigenic Eschericha coli (ETEC), Pseudomonas aeruginosa, Klebsiella pneumonia, Campylobacter jejuni, Legionella pneumophila and Niesseria gonorrhoeae.
- a bacterium selected from the group consisting of Helicobacter pylori, Eschericha coli, Enterotoxigenic Eschericha coli (ETEC), Pseudomonas aeruginosa, Klebsiella pneumonia, Campylobacter jejuni, Legionella pneumophila and Niesseria gonorrhoeae.
- the pharmaceutical composition of the invention is used in treatment and/or prevention of a bacterial infection caused by a bacterium selected from the group consisting of Helicobacter pylori, Eschericha coli, Enterotoxigenic Eschericha coli (ETEC), Pseudomonas aeruginosa, Klebsiella pneumonia, and Niesseria gonorrhoeae.
- a bacterium selected from the group consisting of Helicobacter pylori, Eschericha coli, Enterotoxigenic Eschericha coli (ETEC), Pseudomonas aeruginosa, Klebsiella pneumonia, and Niesseria gonorrhoeae.
- the present invention relates to a pharmaceutical composition for use in the treatment of clinical conditions, wherein bacterial infection is a primary factor of the pathogenesis
- Clinical conditions to be treated according to the present invention is any clinical condition associated with bacterial infection.
- Clinical conditions wherein bacterial infections are a primary factor of pathogenesis may according to the invention in one embodiment be any of the clinical conditions selected from the group consisting of: botulism, pseudomembranous colitis, tetanus, listoriosis, skin infection, acute infective endocarditis, septicemia, middle ear infection, necrotizing pneumonia, toxic shock syndrome, pneumonia, meningitis, acute enteritis, scarlet fever, urinary tract infections, peptic ulcer, upper respiratory tract infections, bronchitis, Legionnaire's disease, gonorrhea, septic arthritis and rheumatic fever.
- the pharmaceutical composition of the present invention may be used in the treatment of peptic ulcers as described herein below.
- a peptic ulcer also known as PUD or peptic ulcer disease is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm. As many as 70-90% of such ulcers are associated with Helicobacter pylori.
- a major causative factor (60% of gastric and up to 90% of duodenal ulcers) is chronic inflammation due to Helicobacter pylori that colonizes the antral mucosa.
- the pharmaceutical composition of the present invention may be used in the treatment of bacterial infections in the oral cavity as described herein below.
- Bacterial infections in the oral cavity may be the caused by oral bacteria which includes streptococci, lactobacilli, staphylococci, and corynebacteria.
- a major oral bacteria is Streptococcus mutans, which may be the cause of caries.
- the pharmaceutical composition of the present invention may be used in the treatment of pneumonia as described herein below.
- Pneumonia is most commonly caused by an infection with primarily Streptococcus pneumoniae, and sometimes by Haemophilus influenzae, Chlamydophila pneumoniae, Mycoplasma pneumoniae and less often by Staphylococcus aureus, Moraxella catarrhalis, Legionella pneumophila and gram-negative bacilli.
- the pharmaceutical composition of the present invention may be used in the treatment of skin infections as described herein below.
- Skin infection is most commonly caused by an infection with primarily Staphylococcus aureus, and sometimes by Streptococcus pyogenes.
- S. aureus are frequently found as part of the normal skin flora and can cause a range of illnesses from minor skin infections to life-threatening diseases.
- Methicillin-resistant S. aureus (MRSA) have become resistant to most antibiotics and are consequently very difficult to treat.
- the pharmaceutical composition of the present invention may be used in the treatment of urinary tract infection as described herein below.
- Urinary tract infection is a bacterial infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a simple cystitis (a bladder infection) and when it affects the upper urinary tract it is known as pyelonephritis (a kidney infection). Both types of urinary tract infection are most commonly caused by Escherichia coli, however other bacteria, viruses or fungi may rarely be the cause.
- the pharmaceutical composition of the present invention may be used in the treatment of upper respiratory tract infections as described herein below.
- Upper respiratory tract infections are the illnesses caused by an acute infection which involves the upper respiratory tract: nose, sinuses, pharynx or larynx. This commonly includes: tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold. Up to 15% of acute pharyngitis cases may be caused by bacteria, most commonly Streptococcus pyogenes ("Strep Throat”) and Haemophilus influenza.
- the pharmaceutical composition of the invention is administered in a pharmaceutical formulation according to the invention as described herein in the section "Pharmaceutical compositions - formulations".
- Very preferred formulations for administration to patients suffering from pneumonia or upper respiratory tract infections may be selected from the group consisting of the administration forms for pulmonary and/or bronchial administration described herein above in the section "Pharmaceutical composition - formulations”.
- pneumonia and upper respiratory tract infections may be treated by oral or parenteral administration of the pharmaceutical composition of the invention.
- Very preferred formulations for administration to patients suffering from skin infections may be selected from the group consisting of the administration forms for topical administration described herein above in the section "Pharmaceutical composition - formulations".
- skin infections may be treated by oral or parenteral administration of the pharmaceutical composition of the invention.
- Very preferred formulations for administration to patients suffering from urinary tract infections may be selected from the group consisting of the administration forms for oral and/or parenteral administration described herein above in the section
- Very preferred formulations for administration to patients suffering from peptic ulcers may be selected from the group consisting of the administration forms for oral administration described herein above in the section "Pharmaceutical composition - formulations".
- peptic ulcer may be treated by parenteral administration of the pharmaceutical composition of the invention.
- Very preferred formulations for administration to patients suffering from bacterial infection of the oral cavity may be selected from the group consisting of the
- bacterial infections of the oral cavity may be treated by parenteral administration of the pharmaceutical composition of the invention.
- the dosage requirements will vary with the particular drug composition employed, the route of administration and the particular subject being treated. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained using conventional course of treatment determination tests.
- the daily oral dosage regimen will generally be from about 0.01 to about 80 mg/kg of total body weight.
- the daily parenteral dosage regimen will generally be from about 0.001 to about 80 mg/kg of total body weight.
- the daily topical dosage regimen will generally be from about 0.1 mg to about 150 mg, administered one to four, preferably two or three times daily.
- the daily inhalation dosage regimen will generally be from about 0.01 mg/kg to about 1 mg/kg of total body weight.
- the daily oral dosage regime will preferably be from about 1 to about 40 mg/kg of total body weight. In another embodiment the daily oral dosage regime will preferably be from about 3 to about 30 mg/kg of total body weight.
- the dose administered should be an "effective amount” or an amount necessary to achieve an “effective level” in the individual patient.
- the actual dose and schedule can vary, depending on inter-individual differences in pharmacokinetics, drug distribution, and metabolism.
- the "effective level” can be defined, for example, as the blood or tissue level desired in the patient that corresponds to a concentration of one or more compounds according to the invention.
- the subject to be treated according to the present invention is in one embodiment a mammal, such as a human, a dog, a cat, a horse and a cow. In a preferred
- the subject to be treated is a human.
- the subject to be treated according to the present invention is to be treated until the bacterial infection is significantly reduced or disappeared. If the bacterial infection reoccurs the treatment using the pharmaceutical composition according to the present invention may start again by a new period of administration of the pharmaceutical composition. Examples
- Example 1 Inhibition of bacterial growth
- a zone inhibition test was performed in order to evaluate the anti-microbial properties of the pharmaceutical composition of the invention.
- the test was performed according to the generally accepted guidelines in the field (e.g. Brock and Madigan: Biology of Microorganisms, 5 th ed. Englewood Cliffs, New Jersey: Prentice-Hall, 1988; World organization for Animal Health (OIE) (2012) Guideline 2.1 ; Laboratory Methodologies for bacterial Antimicribial Susceptability testing; Ph. Eur. 7 th ed. 2.7.2. Microbiological Assay of Antibiotics).
- the tablet is grinded aseptically and diluted in order to resemble the action taking place when a tablet is dissolved in the stomach of an individual being treated.
- step 9 for each dilution.
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Abstract
The present invention relates to pharmaceutical compositions comprising at least one strontium salt and the uses thereof in the treatment of clinical conditions, wherein bacterial infection is a primary factor of the pathogenesis. It is a further object of the present invention to provide uses of a pharmaceutical composition comprising at least one strontium salt in the manufacture of a medicament for the treatment of bacterial infection.
Description
Str&ntium as anti microbial compound Field of invention
The present invention relates to pharmaceutical compositions comprising at least one strontium salt and the uses thereof in the treatment of clinical conditions, wherein bacterial infection is a primary factor of the pathogenesis. Background of invention
Bacterial infections are an increasing problem in the health care system. Several bacterial species have developed resistance towards traditional antibiotics and patients worldwide are now dying of infections that previously could have been cured by traditional antibiotics like penicillin.
With advances in medicinal chemistry, most of today's antibacterials are semisynthetic modifications of various natural compounds. These include, for example, the beta- lactam antibacterials, which include the penicillins (produced by fungi in the genus Penicillium), the cephalosporins, and the carbapenems. Compounds that are still isolated from living organisms are the aminoglycosides, whereas other antibacterials— for example, the sulfonamides, the quinolones, and the oxazolidinones— are produced solely by chemical synthesis
Antibacterial antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most target bacterial functions or growth processes. Those that target the bacterial cell wall (penicillins and cephalosporins) or the cell membrane (polymixins), or interfere with essential bacterial enzymes
(quinolones and sulfonamides) have bactericidal activities. Those that target protein synthesis (aminoglycosides, macrolides, and tetracyclines) are usually bacteriostatic.
Further categorization is based on their target specificity. "Narrow-spectrum" antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria.
Strontium is an alkaline earth metal and as other alkaline earth elements strontium has an oxidation number of +2 making it very reactive. Strontium is present in a small amount in normal diet and in most products comprising calcium due to the similarities of the two elements.
Dabsie et al. (2009) have tested the effect of strontium chloride on the growth of Streptococcus mutans. No growth inhibition is observed after exposure to four different concentrations of strontium chloride. There is a great need for new improved antimicrobial compounds and for treatments of clinical conditions, wherein bacterial infection is a primary factor of the pathogenesis. Also there is a need for local treatments, which do not involve systemic administration of antibacterial compounds, in conditions were the antibacterial infection is limited to e.g. the skin.
The present invention surprisingly demonstrates that strontium salts function as antibacterial compounds against both gram-positive and gram-negative bacteria.
Summary of invention
Provided is a pharmaceutical composition comprising at least one strontium salt for use in treatment of a bacterial infection, wherein the pharmaceutical composition is for systemic administration and wherein the pharmaceutical composition is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
Also provided is a method of treatment and/or prevention of a bacterial infection comprising administration to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising at least one strontium salt and is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
In one embodiment the present invention also relates to the treatment of clinical conditions, wherein bacterial infection is the primary factor of pathogenesis.
It is a further object of the present invention to provide uses of a pharmaceutical composition comprising at least one strontium salt in the manufacture of a medicament for the treatment of bacterial infection.
Additional preferred embodiments of the above mentioned objects of the invention will be further described in detail herein below.
Figures
Figure 1 : Helicobacter pylori zone inhibition test performed as described in example 1. A) internal no. 15770,03, B) internal no. 15770,03, C) internal no. 15770,04, D) internal no. 15770,04, E) internal no. 16441 ,01 , F) internal no. 16441 ,02, G) internal no.
16441 ,03. The result is also summarized in table 1 of Example 1. Figure 2: Streptococcus pneumonia zone inhibition test performed as described in example 1 . A) internal no. 15770,03, B) internal no. 15770,03, C) internal no. 15770,04, D) internal no. 15770,04, E) internal no. 16441 ,01 , F) internal no. 16441 ,02, G) internal no. 16441 ,03. The result is also summarized in table 2 of Example 1 . Figure 3: Staphylococcus aureus zone inhibition test performed as described in example 1 . A) internal no. 15770,03, B) internal no. 15770,03, C) internal no. 15770,04, D) internal no. 15770,04, E) internal no. 16441 ,01 , F) internal no. 16441 ,02, G) internal no. 16441 ,03. The result is also summarized in table 3 of Example 1 .
Detailed description of the invention
Definitions
Treatment: The terms "treatment" and "treating" as used herein refer to the
management and care of a patient for the purpose of combating a condition, disease or disorder. The patient to be treated is preferably a mammal, in particular a human being. The patients to be treated according to the present invention can be of various ages.
Pathogenesis: The term "pathogenesis of a disease" as used herein refer to the mechanism that causes the disease. The term can also describe the origin and development of the disease, and whether it is acute, chronic, or recurrent. Most
diseases are caused by multiple factors, however one factor will be the primary factor of pathogenesis. In one embodiment of the present invention the pharmaceutical composition of the invention is for use in treatment of clinical conditions wherein bacterial infection is the primary factor of pathogenesis.
The present invention relates to a pharmaceutical composition comprising at least one strontium salt for use in treatment of a bacterial infection, wherein the pharmaceutical composition is for systemic administration and wherein the pharmaceutical composition is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
Also disclosed is a method of treatment and/or prevention of a bacterial infection comprising administration to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising at least one strontium salt and is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
Further details relating to the invention is described herein below.
Strontium
Strontium is an alkaline earth metal and as other alkaline earth elements strontium has an oxidation number of +2 making it very reactive. Four stable isotopes of strontium exists, 84, 86, 87 and 88, the latter being the most prevalent. The radioactive isotopes 89 and 90 are less preferable to use with the present invention due to their toxicity. Thus, in one embodiment of the present invention at least one strontium salt is selected from the group of: strontium ascorbate, strontium aspartate in either L- and/or D-form, strontium benzenesulfonate, strontium camphorate, strontium carbonate, strontium chloride, strontium citrate, strontium ethanesulfonate, strontium fumarate, strontium gluconate, strontium glutamate in either L- and/or D-form, strontium glutarate, strontium lactate, strontium malate, strontium maleate, strontium malonate, strontium
methanesulfonate, strontium nitrate, strontium oxalate, strontium phosphate, strontium pyruvate, strontium ranelate, strontium silicate, strontium succinate, strontium sulphate and strontium tartrate. In another embodiment at least one strontium salt is selected from the group consisting of: strontium chlorides, strontium carbonate and strontium silicates.
In another embodiment a strontium silicates according to this invention may be SrSi02 and SrSi04.
In another embodiment a strontium chloride according to this invention may be selected from the group consisting of SrCI2, SrCl2-2-H20, SrCl2-6-H20 differing in the extent of hydration. In a preferred embodiment the strontium chloride is Strontium chloride anhydrous.
Strontium is present in a small amount in normal diet and in most products comprising calcium due to the similarities of the two elements.
The naturally occurring salts of strontium, such as the carbonate and sulphate salts, have very low water solubility. In contrast, other strontium salts, such as strontium chloride, strontium hydroxide, strontium nitrate, strontium oxide and strontium acetate have very high solubilities in the range from 225-800 g/l in water.
In one embodiment of the present invention the pharmaceutical composition comprises at least one water-insoluble strontium salt.
The water soluble strontium salt according to the invention has a solubility in the range from 1 g/100 ml water to 250 g/100 ml water, such as from 5 g/100 ml water to 250 g/100 ml water, for example from 10 g/100 ml water to 250 g/100 ml water, such as from 20 g/100 ml water to 250 g/100 ml water, such as from 40 g/100 ml water to 225 g/100 ml water, for example from 50 g/100 ml water to 200 g/100 ml water.
The water insoluble strontium salt according to the invention has a solubility in the range from 0.0001 g/100 ml water to 0.900 g/100 ml water, such as from 0.0001 g/100 ml water to 0.500 g/100 ml water, for example from 0.0001 g/100 ml water to 0.100
g/100 ml water, such as from 0.001 g/100 ml water to 0.05 g/100 ml water, for example from 0.001 g/100 ml water to 0.06 g/100 ml water.
Thus, in one embodiment of the present invention the pharmaceutical composition comprises at least one water soluble strontium salt with a solubility above 20 g/100 ml water combined with at least one water insoluble strontium salt with a solubility below 0.0001 g/100 ml water.
In another embodiment of the present invention the pharmaceutical composition comprises at least on strontium salt with a solubility above 20g/100 ml water.
In another embodiment of the present invention the pharmaceutical composition comprises at least one strontium salt with a solubility below 0.0001 g/100 ml water. Suitable strontium salts for use according to the invention may be prepared from an organic or inorganic acid.
The inorganic acid for preparing strontium salts may be selected from the group consisting of boric acid, bromous acid, chloric acid, diphosphoric acid, disulfuric acid, dithionic acid, dithionous acid, fulminic acid, hydrazoic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, hydrogen sulphide, hypophosphoric acid, hypophosphorous acid, iodic acid, iodous acid, metaboric acid, metaphosphoric acid, metaphosphorous acid, metasilicic acid, nitrous acid, orthophosphoric acid, orthophosphorous acid, orthosilicic acid, phosphoric acid, phosphinic acid, phosphonic acid, pyrophosphorous acid, selenic acid, sulfonic acid, thiocyanic acid and thiosulfuric acid.
The organic acid for making strontium salts may be selected from the group consisting of C2H5COOH, C3H7COOH, C4H9COOH, (COOH)2, CH2(COOH)2, C2H4(COOH)2, C3H6(COOH)2, C4H8(COOH)2, C5H10(COOH)2, fumaric acid, maleic acid, malonic acid, lactic acid, citric acid, tartaric acid, oxalic acid, ascorbic acid, benzoic acid, salicylic acid, pyruvic acid, L- and D-aspartic acid, phthalic acid, carbonic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, camphoric acid, gluconic acid, L- and D- glutamic acid, trifluoroacetic acid, ranelic acid, 2,3,5,6-tetrabromobenzoic acid, 2,3,5,6- tetrachlorobenzoic acid, 2,3,6-tribromobenzoic acid, 2,3,6-trichlorobenzoic acid, 2,4-
dichlorobenzoic acid, 2,4-dihydroxybenzoic acid, 2,6-dinitrobenzoic acid, 3,4- dimethoxybenzoic, abietic acid, acetoacetic acid, acetonedicarboxylic acid, aconitic acid, acrylic acid, adipic acid, alpha-ketoglutaric acid, anthranilic acid, benzilic acid, arachidic acid, azelic acid, behenic acid, benzenesulfonic acid, beta-hydroxybutyric acid, brassidic acid, capric acid, chloroacrylic acid, cinnamic acid, citraconic acid, crotonic acid, cyclopentane-1 ,2-dicarboxylic acid, cyclopentanecarboxylic acid, cystathionine, decanoic acid, erucic acid, ethylenediaminetetraacetic acid, fulvic acid, fumaric acid, gallic acid, glutaconic acid, glutaric acid, gulonic acid, heptanoic acid, hexanoic acid, humic acid, hydroxystearic acid, isophthalic acid, itaconic acid, lanthionine, lauric acid (dodecanoic acid), levulinic acid, linoleic acid (cis,cis-9,12- octadecadienoic acid), malic acid, m-chlorobenzoic acid, melissic acid, mesaconic acid, methacrylic acid, monochloroacetic acid, myristic acid (tetradecanoic acid), nonanoic acid, norvaline, octanoic acid, oleic acid (cis-9-octadecenoic acid), ornithine, oxaloacetic acid, palmitic acid (hexadecanoic acid), p-aminobenzoic acid, p- chlorobenzoic acid, petroselic acid, phenylacetic acid, p-hydroxybenzoic acid, pimelic acid, propiolic acid, propionic acid, p-tert-butylbenzoic acid, p-toluenesulfonic acid, pyruvic acid, sarcosine, sebacic acid, serine, sorbic acid, stearic acid (octadecanoic acid), suberic acid, succinic acid, terephthalic acid, tetrolic acid, threonine, thyronine, tricarballylic acid, trichloroacetic acid, trimellitic acid, trimesic acid, tyrosine, ulmic acid and cyclohexanecarboxylic acid.
All acids, which FDA has regarded as safe for use in pharmaceutical compositions may be used in the present invention. In one embodiment the at least one water insoluble strontium salt is combined with at least one water soluble strontium salt.
In one embodiment the water soluble strontium salt may be selected from the group consisting of: strontium chloride, strontium bromide, strontium nitrate, strontium hydroxide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium pyruvate, strontium alpha-ketoglutarate, strontium maleate, strontium succinate, strontium fumarate, strontium ascorbate, strontium tartate, strontium glutarate, strontium methanesulfonate, strontium benzenesulfonate and strontium sulphide.
In one embodiment the water insoluble strontium salt may be selected from the group consisting of: strontium carbonate and strontium sulphate.
In one embodiment of the present invention the pharmaceutical composition comprise 55-99.95 % of strontium in the form of a water soluble strontium salt and 0.05 to 45 % strontium in the form of a water insoluble strontium salt, or such as 60-95 % strontium in the form of a water soluble strontium salt and 5-40 % strontium in the form of a water insoluble strontium salt, or such as 70-90 % strontium in the form of a water soluble strontium salt and 10-30 % strontium in the form of a water insoluble strontium salt, or such as 75 % strontium in the form of a water soluble strontium salt and 25 % strontium in the form of a water insoluble strontium salt.
In another embodiment of the present invention the pharmaceutical composition comprise 55-99.95 % of strontium in the form of a water insoluble strontium salt and 0.05 to 45 % strontium in the form of a water soluble strontium salt, or such as 60-95 % strontium in the form of a water insoluble strontium salt and 5-40 % strontium in the form of a water soluble strontium salt, or such as 70-90 % strontium in the form of a water insoluble strontium salt and 10-30 % strontium in the form of a water soluble strontium salt, or such as 75 % strontium in the form of a water insoluble strontium salt and 25 % strontium in the form of a water soluble strontium salt.
Specific examples of strontium salts for use according to the present invention may be found herein below in the section "Pharmaceutical composition - strontium". Pharmaceutical composition
The present invention relates to a pharmaceutical composition comprising at least one strontium salt for use in treatment of a bacterial infection, wherein the pharmaceutical composition is for systemic administration. The pharmaceutical composition of the present invention may preferably be in the form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
In one embodiment of the present invention the pharmaceutical composition is in the form selected from the group consisting of: cream, ointment, gel, lotion, foam and emulsified gel. In another embodiment of the present invention the pharmaceutical composition is in the form selected from the group consisting of: stick, patch, membrane, tampon, suppositories, sponges and strip.
In another embodiment of the present invention the pharmaceutical composition is in the form selected from the group consisting of: capsule, tablet, powder, pill, cachet, dispersible granule and lozenge.
In another embodiment of the present invention the pharmaceutical composition is in the form of eye drops.
In another embodiment of the present invention the pharmaceutical composition is in the form of an inhalator.
Pharmaceutical composition - strontium
The amount of strontium obtained in 1 gram of strontium salt depends on the molecular weight of the compound, relative to the number of strontium molecules therein, thus a salt with low molecular weight per strontium molecule maybe preferred.
This may be expressed as the effective ratio of the salt. The effective ratio (Re) may be defined as, Re = (strontium (mg))/(strontium salt (mg))
The higher effective ratio the smaller amount of the salt is required. As a relatively large amount of the active ingredient is required a strontium salt with a high effective ratio is preferred.
It is preferred that the Re of the strontium salt comprised by the strontium comprising pharmaceutical composition is more than 0.20, or more than 0.25 or 0.30, such as more than 0.31 such as more than 0.32, such as more than 0.33, such as more than 0.34, such as more than 0.36, such as more than 0.38 more preferably more than 0.40, or such as more than 0.42, such as more than 0.44 such as more than 0.46, such as
more than 0.50, such as more than 0.52, such as more than 0.54, such as more than 0.56, such as more than 0.58 or such as more than 0.60.
In an embodiment the Re of the strontium salt comprised by the strontium comprising pharmaceutical composition is more than 0.35 preferably more than 0.40 and most preferably at least 0.45 or 0.5.
The high Re of strontium carbonate makes it a preferred salt as low amounts of the salt provide high amounts of the active ingredient. Thus, in one embodiment the at least one strontium salt is strontium carbonate.
The solubility or availability of strontium in the stomach may be improved by combining two or more strontium salts. Thus in an embodiment the pharmaceutical composition comprises at least two strontium salts or such three strontium salts, or more than three strontium salts. In one embodiment the pharmaceutical composition comprises two strontium salts.
In one embodiment of the present invention the pharmaceutical composition comprises at least two strontium salts. The strontium salts for use in said pharmaceutical composition may be any strontium salt which may be prepared from an organic or inorganic acid. Examples of organic and inorganic acids from which strontium salts may be prepared can be found herein above in the section "Strontium".
The effective ratio (Re) described above may also be considered in relation to compositions comprising at least two strontium salts. Then the ratio is calculated as the total weight of strontium divided by the total weight of the at least two strontium salts (' and ").
Re=Strontium(mg)/(Stontiumsalt '(mg) + Stontiumsalt" (mg))
It is preferred that the Re of the at least two strontium salts is more than 0.30, such as more than 0.31 such as more than 0.32, such as more than 0.33, such as more than 0.34, such as more than 0.36, such as more than 0.38, such as more than 0.40, or such as more than 0.42, such as more than 0.44 such as more than 0.46, such as more than 0.50, such as more than 0.52, such as more than 0.54, such as more than 0.56, such as more than 0.58.
In an embodiment the Re of the at least two strontium salts is 0.30-1 .00, such as 0.35- 0.80, such as 0.40-0.59, preferably 0.46-0.58 or more preferably 0.50-0.57.
In another embodiment the Re of the strontium salt comprised by the strontium composition is more than 0.35 preferably more than 0.40 and most preferably at least 0.45 or 0.5.
In one embodiment the pharmaceutical composition comprises at least two strontium salts. Such a combination may further serve to optimize the effect of the composition and/or minimize undesirable effect of the compounds used. For example high intake of certain compounds, such as carbonates, may alter the pH in the stomach and intestine and thereby affect the uptake and secretion of other compounds in an unfavorable way. In alternative embodiments this may be an advantage as carbonate may neutralize the gastric juice, this may be particular favorable in situation of acidity of the stomach or acid indigestion.
By the combination of two or more strontium salts the desired effect may be obtained. In one embodiment of the present invention the pharmaceutical composition comprises strontium carbonate and at least one other strontium salt as described herein above in the section "Strontium".
In another embodiment of the present invention the pharmaceutical composition comprises strontium chloride and at least one other strontium salt as described herein above in the section "Strontium".
In one embodiment where two or more strontium salts are combined it is preferred that the first strontium salt is strontium carbonate and the second strontium salt is selected from the group consisting of: strontium chloride and strontium silicate.
In another embodiment were the pharmaceutical composition comprises two strontium salts it is preferred that the first strontium salt is strontium carbonate and the second strontium salt is strontium chloride.
The strontium comprising pharmaceutical composition according to the invention may comprise the two strontium salts in different percentage. Thus, strontium chloride may
contribute with 1 -99.95 % of the total amount of strontium comprised by the
composition.
In an embodiment the pharmaceutical composition comprises at least 50 % strontium chloride. The pharmaceutical composition may preferably comprise more strontium in the form of strontium chloride than in the form of strontium carbonate, with respect to molar percentages. In preferred embodiments the compositions comprise such as 55- 99.95 % of strontium in the form of strontium chloride and 0.05 to 45 % strontium in the form of strontium carbonate, or such as 60-95 % strontium in the form of strontium chloride and 5-40 % strontium in the form of strontium carbonate, or such as 70-90 % strontium in the form of strontium chloride and 10-30 % strontium in the form of strontium carbonate, or such as 75 % strontium in the form of strontium chloride and 25 % strontium in the form of strontium carbonate.
In one embodiment the pharmaceutical composition comprises 100% strontium chloride.
In an embodiment the pharmaceutical composition comprises strontium carbonate, wherein the amount of strontium carbonate contribute with such as at least 0.05 % of the strontium of the composition in other embodiments strontium carbonate contribute with at least 0.1 %, such as 1 %, such as at least 5 or 10 %, even such as at least 15 or 20 % of strontium is contributed by strontium carbonate. In specific embodiments strontium carbonate contribute with at least 25 %, such as 30 % or alternatively such as 40 or 50 % of the strontium of the composition. In other embodiments strontium carbonate contribute with at least 60%, such as 70% or alternatively such as 75-95% of the strontium of the composition.
Pharmaceutical composition - Secondary active ingredients
The pharmaceutical composition of the present invention may be combined with a secondary active ingredient. The secondary active ingredient may be administered separately, sequentially and/or simultaneously with the pharmaceutical composition of the invention. Thus, the secondary active ingredient may be administered as a separate medicament or together with the strontium comprising pharmaceutical composition in a combined medicament.
Pharmaceutical composition - formulations
Pharmaceutical compositions containing a strontium salt according to the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa, unless otherwise described herein.
The pharmaceutical compositions may be formulated in a number of different ways depending on the condition to be treated, the individual to be treated and the location of disease. Accordingly, the pharmaceutical composition is preferably formulated according to the need of the specific embodiment of the present invention.
For example the pharmaceutical composition may be in a form selected from the group consisting of cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
The pharmaceutical composition according to the present invention may in one embodiment be formulated in a wide variety of formulations for local administration, such as a gel, an emulsified gel, an ointment, a cream, a foam, a solution or a lotion. In another embodiment the pharmaceutical composition of the present invention is formulated in a wide variety of formulations for oral administration, such as in the form of a powder, tablet, pill, capsule, cachet, dispersible granule or lozenge. Other forms suitable for oral administration may include liquid form preparations including emulsions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
In one embodiment the pharmaceutical composition of the present invention is in the form of a tablet or capsule. This is particularly useful when the bacterial infection to be treated is present in or associated with the gastrointestinal tract. Tablets or capsules may also be used when general systemic administration is needed. Tablets are solid pharmaceutical dosage forms containing the strontium salt with or without suitable diluents and may be prepared by different methods known to the person skilled in the art. Tablets may vary in shape and may accordingly be discoid, round, oval, oblong, cylindrical or triangular. They may vary in size and weight depending on the amount of strontium salt present and the intended method of administration.
Capsules are solid pharmaceutical dosage forms in which the strontium salt is enclosed in either a hard or soft, soluble container or shell of a suitable material, e.g. gelatine. Capsules are usually oblong in shape and can vary in size depending on the amount of strontium salt present and the intended method of administration.
Tablets and capsules may contain pharmaceutically acceptable carriers together with the strontium salt. The pharmaceutically acceptable carriers can be either solid or liquid. A solid carrier can be one or more excipients which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
These preparations may also contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
In one embodiment the pharmaceutical composition of the present invention is in the form of a capsule.
In one embodiment of the present invention the pharmaceutical composition is in the form of a powder. In powders, the carrier is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
In one embodiment of the present invention the pharmaceutical composition is in the form of an emulsion. Emulsions may be prepared in solutions in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
In another embodiment the pharmaceutical composition of the present invention may in one embodiment be formulated in a wide variety of formulations for parenteral administration, such as in the form suitable for injection, infusion, topical delivery, nasal delivery, pulmonary delivery, bronchial delivery or transdermal delivery.
For injections and infusions the formulations may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules, vials, pre-filled syringes, infusion bags, or can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters, and may contain formulatory agents such as preserving, wetting, emulsifying or
suspending, stabilizing and/or dispersing agents.
The formulations for injection will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution.
In one embodiment of the present invention the compounds may also be administered topically. Regions for topical administration include the skin surface and also mucous membrane tissues of the vagina, rectum, nose, mouth, and throat. The topical composition will typically include a pharmaceutically acceptable carrier adapted for topical administration. Thus, the composition may take the form of a ointment, lotion, sexual lubricant, cream, foam, aerosol, suppository, implant, inhalant, tablet, capsule, dry powder, balm or lozenge, for example. Methods for preparing such compositions are well known in the pharmaceutical industry.
The compounds of the present invention may be formulated for topical administration to the epidermis in situations where the bacterial infection is present as a skin infection. Topical administration forms may be in the form of an ointment, cream or lotion, or as a transdermal patch. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin or a fatty acid. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
Patches may take many different forms. Typically a patch comprises a polymer and an adhesive. The strontium salt may be deposited on the patch in the form of a solution, gel, cream and/or ointment. The patch may be an occlusive patch. The patch may be in the form of a thin membrane. This may in particular be the case for administration of strontium salt to a mucosal membrane, for example for nasal administration, for administration to the mouth or for buccal administration, or for administration to the genital region.
Lotions according to the present invention also include those suitable for application to the eye in situations where the bacterial infection is present in the eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide.
In one embodiment of the present invention the pharmaceutical composition is intended for nasal, pulmonary and/or bronchial administration. This is particularly useful when the bacterial infection to be treated is a bacterial infection of the upper or lower pulmonary tract. Formulations for use in nasal, pulmonary and/or bronchial
administration are normally administered as aerosols in order to ensure that the aerosolized dose actually reaches the mucous membranes of the nasal passages, bronchial tract or the lung. The term "aerosol particle" is used herein to describe the liquid or solid particle suitable for nasal, bronchial or pulmonary administration, i.e., that will reach the mucous membranes.
Typically aerosols are administered by use of a mechanical devices designed for pulmonary and/or bronchial delivery, including but not limited to nebulizers, metered dose inhalers, and powder inhalers. With regard to construction of the delivery device, any form of aerosolization known in the art, including but not limited to spray bottles, nebulization, atomization or pump aerosolization of a liquid formulation, and aerosolization of a dry powder formulation, can be used.
Liquid Aerosol Formulations in general contain a compound of the present invention in a pharmaceutically acceptable diluent. Pharmaceutically acceptable diluents include but are not limited to sterile water, saline, buffered saline, dextrose solution, and the like.
Formulations for dispensing from a powder inhaler device will normally comprise a finely divided dry powder containing pharmaceutical composition of the present invention and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device. Dry powder formulations for inhalation may also be formulated using powder-filled capsules, in particularly capsules the material of which is selected from among the synthetic plastics.
The formulation is formulated to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy and known to the person skilled in the art. The propellant may be any propellant generally used in the art. Specific non-limiting examples of such useful propellants are a chlorofluorocarbon, a hydrofluorocarbon, a
hydrochlorofluorocarbon, or a hydrocarbon.
The formulations for nasal administration may in one embodiment involve solutions or suspensions which are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray this may be achieved for example by means of a metering atomizing spray pump.
The formulations of the present embodiment may also include other agents useful for pH maintenance, solution stabilization, or for the regulation of osmotic pressure.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
Pharmaceutical composition - time of exposure
The pharmaceutical composition of the present invention may be administered in many different formulation forms as outlined herein above. Common for all the administration forms of the present invention it is preferred that the subject to which the
pharmaceutical composition is administered is exposed to the pharmaceutical composition for a prolonged period of time.
Systemic administration in general (e.g. oral and parenteral administration) will exposure the subject to which the pharmaceutical composition is administered for a prolonged period of time.
In one embodiment of the present invention the pharmaceutical composition may be in the form intended for local administration, e.g. a patch or membrane containing the pharmaceutical composition. A local administration within the scope of the present invention is intended to be left at the site of treatment for more than 5 minutes of time, such as for more than 10 minutes, for example for more than 15 minutes, such as for more than 20 minutes, for example for more than 25 minutes, such as for more than 30 minutes, for example for more than 45 minutes such as for more than 1 hour. Bacteria
In one embodiment the pharmaceutical composition comprising at least strontium salt as described herein above in the section "Pharmaceutical composition" is for treatment and/or prevention of a Gram-positive bacterial infection.
Gram-positive bacteria are bacteria that are stained dark blue or violet by Gram staining. Most pathogens in humans are Gram-positive organisms. Gram-positive bacteria of medical interest are among others: Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium and Listeria.
Preferably the pharmaceutical composition of the invention is used in treatment and/or prevention of a bacterial infection by a bacterium selected from the group consisting of Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes.
In one embodiment the pharmaceutical composition comprising at least strontium salt as described herein above in the section "Pharmaceutical composition" is for treatment and/or prevention of a Gram-positive bacterial infection.
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. Gram-negative bacteria of medical interest include a multitude of species. Some of them primarily causes respiratory problems (Hemophilus influenza, Klebsiella pneumonia, Legionella pneumophila, Pseudomonas aeruginosa), some cause primarily urinary problems (Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens), some causing sexsually transmitted diseases
(Niesseria gonorrhoeae) and some primarily cause gastrointestinal problems
(Helicobacter pylori, Salmonella entertidis, Salmonella typhi). Preferably the pharmaceutical composition of the invention is for treatment and/or prevention of a bacterial infection caused by a bacterium selected from the group consisting of Helicobacter pylori, Eschericha coli, Enterotoxigenic Eschericha coli (ETEC), Pseudomonas aeruginosa, Klebsiella pneumonia, Campylobacter jejuni, Legionella pneumophila and Niesseria gonorrhoeae.
In an even more preferred embodiment the pharmaceutical composition of the invention is used in treatment and/or prevention of a bacterial infection caused by a bacterium selected from the group consisting of Helicobacter pylori, Eschericha coli, Enterotoxigenic Eschericha coli (ETEC), Pseudomonas aeruginosa, Klebsiella pneumonia, and Niesseria gonorrhoeae.
Clinical condition
In one embodiment the present invention relates to a pharmaceutical composition for use in the treatment of clinical conditions, wherein bacterial infection is a primary factor of the pathogenesis
The clinical condition to be treated according to the present invention is any clinical condition associated with bacterial infection. Clinical conditions wherein bacterial infections are a primary factor of pathogenesis may according to the invention in one embodiment be any of the clinical conditions selected from the group consisting of: botulism, pseudomembranous colitis, tetanus, listoriosis, skin infection, acute infective endocarditis, septicemia, middle ear infection, necrotizing pneumonia, toxic shock syndrome, pneumonia, meningitis, acute enteritis, scarlet fever, urinary tract infections, peptic ulcer, upper respiratory tract infections, bronchitis, Legionnaire's disease, gonorrhea, septic arthritis and rheumatic fever.
In one embodiment of the present invention the pharmaceutical composition of the present invention may be used in the treatment of peptic ulcers as described herein below.
A peptic ulcer, also known as PUD or peptic ulcer disease is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm. As many as 70-90% of such ulcers are associated with Helicobacter pylori. A major causative factor (60% of gastric and up to 90% of duodenal ulcers) is chronic inflammation due to Helicobacter pylori that colonizes the antral mucosa.
In one embodiment of the present invention the pharmaceutical composition of the present invention may be used in the treatment of bacterial infections in the oral cavity as described herein below.
Bacterial infections in the oral cavity may be the caused by oral bacteria which includes streptococci, lactobacilli, staphylococci, and corynebacteria. A major oral bacteria is Streptococcus mutans, which may be the cause of caries.
In one embodiment of the present invention the pharmaceutical composition of the present invention may be used in the treatment of pneumonia as described herein below.
Pneumonia is most commonly caused by an infection with primarily Streptococcus pneumoniae, and sometimes by Haemophilus influenzae, Chlamydophila pneumoniae, Mycoplasma pneumoniae and less often by Staphylococcus aureus, Moraxella catarrhalis, Legionella pneumophila and gram-negative bacilli.
In one embodiment of the present invention the pharmaceutical composition of the present invention may be used in the treatment of skin infections as described herein below. Skin infection is most commonly caused by an infection with primarily Staphylococcus aureus, and sometimes by Streptococcus pyogenes. S. aureus are frequently found as part of the normal skin flora and can cause a range of illnesses from minor skin infections to life-threatening diseases. Methicillin-resistant S. aureus (MRSA) have become resistant to most antibiotics and are consequently very difficult to treat.
In one embodiment of the present invention the pharmaceutical composition of the present invention may be used in the treatment of urinary tract infection as described herein below. Urinary tract infection is a bacterial infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a simple cystitis (a bladder infection) and when it affects the upper urinary tract it is known as pyelonephritis (a kidney infection). Both types of urinary tract infection are most commonly caused by Escherichia coli, however other bacteria, viruses or fungi may rarely be the cause.
In one embodiment of the present invention the pharmaceutical composition of the present invention may be used in the treatment of upper respiratory tract infections as described herein below.
Upper respiratory tract infections are the illnesses caused by an acute infection which involves the upper respiratory tract: nose, sinuses, pharynx or larynx. This commonly includes: tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold. Up to 15% of acute pharyngitis cases may be caused by bacteria, most commonly Streptococcus pyogenes ("Strep Throat") and Haemophilus influenza.
Preferably, for treatment of a clinical condition wherein bacterial infections are a primary factor of pathogenesis the pharmaceutical composition of the invention is administered in a pharmaceutical formulation according to the invention as described herein in the section "Pharmaceutical compositions - formulations". Very preferred formulations for administration to patients suffering from pneumonia or upper respiratory tract infections may be selected from the group consisting of the administration forms for pulmonary and/or bronchial administration described herein above in the section "Pharmaceutical composition - formulations". In one embodiment pneumonia and upper respiratory tract infections may be treated by oral or parenteral administration of the pharmaceutical composition of the invention.
Very preferred formulations for administration to patients suffering from skin infections may be selected from the group consisting of the administration forms for topical administration described herein above in the section "Pharmaceutical composition - formulations". In one embodiment skin infections may be treated by oral or parenteral administration of the pharmaceutical composition of the invention.
Very preferred formulations for administration to patients suffering from urinary tract infections may be selected from the group consisting of the administration forms for oral and/or parenteral administration described herein above in the section
"Pharmaceutical composition - formulations".
Very preferred formulations for administration to patients suffering from peptic ulcers may be selected from the group consisting of the administration forms for oral administration described herein above in the section "Pharmaceutical composition - formulations". In one embodiment peptic ulcer may be treated by parenteral administration of the pharmaceutical composition of the invention.
Very preferred formulations for administration to patients suffering from bacterial infection of the oral cavity may be selected from the group consisting of the
administration forms for topical and/ or oral administration described herein above in the section "Pharmaceutical composition - formulations". In one embodiment bacterial infections of the oral cavity may be treated by parenteral administration of the pharmaceutical composition of the invention.
Dosages and dosing regimes
The dosage requirements will vary with the particular drug composition employed, the route of administration and the particular subject being treated. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained using conventional course of treatment determination tests.
The daily oral dosage regimen will generally be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen will generally be from about 0.001 to about 80 mg/kg of total body weight. The daily topical dosage regimen will generally be from about 0.1 mg to about 150 mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen will generally be from about 0.01 mg/kg to about 1 mg/kg of total body weight.
In one embodiment the daily oral dosage regime will preferably be from about 1 to about 40 mg/kg of total body weight. In another embodiment the daily oral dosage regime will preferably be from about 3 to about 30 mg/kg of total body weight.
The dose administered should be an "effective amount" or an amount necessary to achieve an "effective level" in the individual patient.
When the "effective level" is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharmacokinetics,
drug distribution, and metabolism. The "effective level" can be defined, for example, as the blood or tissue level desired in the patient that corresponds to a concentration of one or more compounds according to the invention. The subject to be treated according to the present invention is in one embodiment a mammal, such as a human, a dog, a cat, a horse and a cow. In a preferred
embodiment the subject to be treated is a human.
The subject to be treated according to the present invention is to be treated until the bacterial infection is significantly reduced or disappeared. If the bacterial infection reoccurs the treatment using the pharmaceutical composition according to the present invention may start again by a new period of administration of the pharmaceutical composition. Examples
Example 1 : Inhibition of bacterial growth
A zone inhibition test was performed in order to evaluate the anti-microbial properties of the pharmaceutical composition of the invention. The test was performed according to the generally accepted guidelines in the field (e.g. Brock and Madigan: Biology of Microorganisms, 5th ed. Englewood Cliffs, New Jersey: Prentice-Hall, 1988; World organization for Animal Health (OIE) (2012) Guideline 2.1 ; Laboratory Methodologies for bacterial Antimicribial Susceptability testing; Ph. Eur. 7th ed. 2.7.2. Microbiological Assay of Antibiotics).
The tablet is grinded aseptically and diluted in order to resemble the action taking place when a tablet is dissolved in the stomach of an individual being treated.
Zone of Inhibition Test
1 ) Prepare a suspension of the test bacteria in 0.9% NaCI. The concentration of cells at OD550 -0.2 is about 1 x 108 CFU/ml.
2) Dilute the suspension (to dilution 10"8) and pour 1 mL into the appropriate
medium (from dilution 10"4-10"8).
3) The plates are incubated at appropriate temperature and oxygen conditions for about 24 hour.
4) Count the colonies and calculate the CFU/mL.
) The correct medium is inoculated with the test bacteria from the appropriate dilution to obtain a concentration of approximately 104 CFU/ml.
) Solidify approximately 25 ml of the inoculated medium in Petri dishes of 9cm in diameter.
) Prepare 4 wells per dish.
) Grind tablet aseptically and dilute 1 :1 , 1 :5 and 1 :10 using Maximum Recovery Diluent pH 7.
) Transfer 200 μΙ_ or 0.2 g of one of the concentrations in triplets and a blind control of Maximum Recovery Diluent to a dish.
0) Repeat step 9 for each dilution.
1 ) Let the liquids allow diffusing into the agar at room temperature for 1 h before incubation at appropriate temperature and oxygen conditions for about 18h.2) Measure inhibition zones with a precision of 0.1 mm using a Kaefler zone measuring instrument.
Results
Table 1
As demonstrated above, a comparable inhibition zone of more than 14 mm is observed with three of the test tablets. No inhibition zone is observed in the control well. These results here are derived from the data provided in figure 1.
Table 2
As demonstrated above, a comparable inhibition zone of more than 22 mm is observed with three of the test tablets. No inhibition zone is observed in the control well. These results here are derived from the data provided in figure 2.
Table 3
As demonstrated above and in figure 3, a comparable inhibition zone of more than 26 mm is observed with all of the test tablets in the 2x dilution series. No inhibition zone is observed in the control well. These results here are derived from the data provided in figure 3.
Claims
A pharmaceutical composition comprising at least one strontium salt for use in treatment of a bacterial infection, wherein the pharmaceutical composition is for systemic administration and wherein the pharmaceutical composition is in a formulation selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
The pharmaceutical composition comprising at least one water-insoluble strontium salt.
The pharmaceutical composition according to claim 2, wherein the water- insoluble strontium salt is selected from the group consisting of: strontium carbonate and strontium sulphate.
The pharmaceutical composition of claims 2-3, wherein the water-insoluble strontium salt is strontium carbonate.
The pharmaceutical composition according to claim 1 , wherein the strontium salt(s) are selected from the group consisting of: strontium camphorate, strontium chloride, strontium citrate, strontium ethanesulfonate, strontium gluconate, strontium lactate, strontium malate, strontium nitrate, strontium oxalate, strontium phosphate, strontium ranelate and strontium silicate.
The pharmaceutical composition according to claim 1 -5, wherein the strontium salt(s) are selected form the group consisting of: strontium carbonate, strontium silicates and strontium chloride.
The pharmaceutical composition according to any of the claims 1 and 5-6, wherein the composition comprises a strontium chloride selected from the group consisting of: SrCI2, SrCI2-2-H20, SrCI2-6-H20.
8. The pharmaceutical composition according to claim 7, wherein the strontium chloride is Strontium chloride anhydrous.
9. The pharmaceutical composition according to claims 1 -8, wherein the bacterial infection is caused by gram-positive bacteria.
10. The pharmaceutical composition according to claim 9, wherein the gram- positive bacteria is selected from the group consisting of: Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium and Listeria.
1 1 . The pharmaceutical composition according to claim 10, wherein the gram- positive bacteria is selected from the group consisting of: Clostridium botulinum,
Clostridium difficile, Clostridium perfringens, Clostridium tetani, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes
12. The pharmaceutical composition according to claims 1 -8, wherein the bacterial infection is caused by gram-negative bacteria.
13. The pharmaceutical composition according to claim 12, wherein the gram- negative bacteria is selected from the group consisting of: Hemophilus,
Klebsiella, Escherichia, Salmonella, Proteus, Enterobacter, Serratia, Shigella, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio, and Legionella.
14. The pharmaceutical composition according to claim 13, wherein the gram- negative bacteria is selected from the group consisting of: Helicobacter pylori, Eschericha coli, Enterotoxigenic Eschericha coli (ETEC), Pseudomonas aeruginosa, Klebsiella pneumonia, and Niesseria gonorrhoeae.
15. The pharmaceutical composition according to any of the preceding claims, wherein said composition is not dissolved in the oral cavity and accordingly strontium is not released in the oral cavity.
16. The pharmaceutical composition according to any of the preceding claims, wherein said composition is in the form of a tablet, pill or capsule.
17. The pharmaceutical composition according to claim 16, wherein said composition is in the form of a capsule.
18. The pharmaceutical composition according to claims 1 -15, wherein said
composition is in the form of a cream, gel, or ointment.
19. The pharmaceutical composition according to claims 1 -15, wherein said
composition is in the form of an emulsion.
20. The pharmaceutical composition according to any of the preceding claims, wherein said composition is for use in treatment of pneumonia primarily caused by bacterial infection.
21 . The pharmaceutical composition according to any of the claims 1 -19, wherein said composition is for use in treatment of peptic ulcers primarily caused by bacterial infection.
22. The pharmaceutical composition according to any of the claims 1 -19, wherein said composition is for use in treatment of bacterial infection of the oral cavity.
23. The pharmaceutical composition according to any of the claims 1 -19, wherein said composition is for use in treatment of skin infection primarily caused by bacterial infection.
24. The pharmaceutical composition according to any of the claims 1 -19, wherein said composition is for use in treatment of urinary tract infection primarily caused by bacterial infection.
25. A method of treatment and/or prevention of a bacterial infection comprising administration to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising at least one strontium salt, wherein said pharmaceutical composition is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
26. The method of claim 25, wherein the pharmaceutical composition is as defined in any of the claims 1 -19.
27. The method of claims 25-26, wherein the subject in need is a mammal.
28. Use of a pharmaceutical composition comprising at least one strontium salt in the manufacture of a medicament for the treatment of microbial infection, wherein said medicament is in a form selected from the group consisting of: cream, ointment, gel, lotion, foam, stick, patch, membrane, tampon, strip, capsule, tablet, suppositories, sponges, eye drops, inhalator, emulsified gel, powder, pill, cachet, dispersible granule, lozenge, and emulsions.
29. The use of claim 28, wherein the pharmaceutical composition is as defined in any of the claims 1 -19.
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DKPA201270580 | 2012-09-20 | ||
DKPA201270580 | 2012-09-20 | ||
US201261712609P | 2012-10-11 | 2012-10-11 | |
US61/712,609 | 2012-10-11 |
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