MXPA00011649A - Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract - Google Patents
Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tractInfo
- Publication number
- MXPA00011649A MXPA00011649A MXPA/A/2000/011649A MXPA00011649A MXPA00011649A MX PA00011649 A MXPA00011649 A MX PA00011649A MX PA00011649 A MXPA00011649 A MX PA00011649A MX PA00011649 A MXPA00011649 A MX PA00011649A
- Authority
- MX
- Mexico
- Prior art keywords
- preparation
- agent
- liposomes
- carrier
- process according
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 97
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 82
- 210000002345 respiratory system Anatomy 0.000 title claims abstract description 24
- 239000004599 antimicrobial Substances 0.000 title claims description 26
- 230000001737 promoting Effects 0.000 title claims description 5
- 200000000019 wound Diseases 0.000 title claims description 4
- 230000035876 healing Effects 0.000 title claims description 3
- 230000003110 anti-inflammatory Effects 0.000 title description 5
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229920000153 Povidone-iodine Polymers 0.000 claims abstract description 15
- 229960001621 povidone-iodine Drugs 0.000 claims abstract description 15
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 229940121363 anti-inflammatory agents Drugs 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- 239000002502 liposome Substances 0.000 claims description 77
- 239000000969 carrier Substances 0.000 claims description 46
- NFQHZOZOFGDSIN-UHFFFAOYSA-N 2,4-dinitro-N-(propylideneamino)aniline Chemical compound CCC=NNC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O NFQHZOZOFGDSIN-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 239000002245 particle Substances 0.000 claims description 19
- 239000000443 aerosol Substances 0.000 claims description 17
- 229940079593 drugs Drugs 0.000 claims description 17
- 239000000843 powder Substances 0.000 claims description 17
- 230000003115 biocidal Effects 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- 210000001519 tissues Anatomy 0.000 claims description 15
- 230000002421 anti-septic Effects 0.000 claims description 14
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 12
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 12
- 239000011630 iodine Substances 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 239000003242 anti bacterial agent Substances 0.000 claims description 11
- 239000003357 wound healing promoting agent Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 230000029663 wound healing Effects 0.000 claims description 10
- 229940064005 Antibiotic throat preparations Drugs 0.000 claims description 9
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 claims description 9
- 229940042052 Antibiotics for systemic use Drugs 0.000 claims description 9
- 229940042786 Antitubercular Antibiotics Drugs 0.000 claims description 9
- 229940093922 Gynecological Antibiotics Drugs 0.000 claims description 9
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 claims description 9
- 239000000654 additive Substances 0.000 claims description 9
- 229940079866 intestinal antibiotics Drugs 0.000 claims description 9
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 claims description 9
- 230000002035 prolonged Effects 0.000 claims description 9
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 claims description 8
- 210000000621 Bronchi Anatomy 0.000 claims description 8
- 210000003437 Trachea Anatomy 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 8
- 239000004005 microsphere Substances 0.000 claims description 8
- -1 for example Chemical class 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 150000002989 phenols Chemical class 0.000 claims description 7
- 239000002537 cosmetic Substances 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- 150000002736 metal compounds Chemical class 0.000 claims description 6
- 239000002105 nanoparticle Substances 0.000 claims description 6
- 239000007921 spray Substances 0.000 claims description 6
- 206010006451 Bronchitis Diseases 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 230000000240 adjuvant Effects 0.000 claims description 5
- 239000000645 desinfectant Substances 0.000 claims description 5
- 230000000249 desinfective Effects 0.000 claims description 5
- 150000002731 mercury compounds Chemical class 0.000 claims description 5
- 229940100892 mercury compounds Drugs 0.000 claims description 5
- 238000007634 remodeling Methods 0.000 claims description 5
- 201000003883 cystic fibrosis Diseases 0.000 claims description 4
- 239000007903 gelatin capsule Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 230000001629 suppression Effects 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 235000019156 vitamin B Nutrition 0.000 claims description 4
- 239000011720 vitamin B Substances 0.000 claims description 4
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical class C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 claims description 3
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 claims description 3
- 229960001334 Corticosteroids Drugs 0.000 claims description 3
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims description 3
- 235000004866 D-panthenol Nutrition 0.000 claims description 3
- 239000011703 D-panthenol Substances 0.000 claims description 3
- 229960003949 Dexpanthenol Drugs 0.000 claims description 3
- 206010013023 Diphtheria Diseases 0.000 claims description 3
- 208000005721 HIV Infections Diseases 0.000 claims description 3
- 210000000987 Immune System Anatomy 0.000 claims description 3
- 208000001388 Opportunistic Infections Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 229930003270 Vitamin B Natural products 0.000 claims description 3
- 150000001251 acridines Chemical class 0.000 claims description 3
- 230000001154 acute Effects 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 230000003444 anaesthetic Effects 0.000 claims description 3
- 230000000111 anti-oxidant Effects 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 229940111121 antirheumatic drugs Quinolines Drugs 0.000 claims description 3
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 claims description 3
- 229940027985 antiseptics and disinfectants Silver compounds Drugs 0.000 claims description 3
- 150000001545 azulenes Chemical class 0.000 claims description 3
- 201000009267 bronchiectasis Diseases 0.000 claims description 3
- 239000003246 corticosteroid Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 238000005469 granulation Methods 0.000 claims description 3
- 230000003179 granulation Effects 0.000 claims description 3
- 150000002357 guanidines Chemical class 0.000 claims description 3
- 150000007975 iminium salts Chemical class 0.000 claims description 3
- 150000002496 iodine Chemical class 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 claims description 3
- 230000002335 preservative Effects 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 3
- 150000003248 quinolines Chemical class 0.000 claims description 3
- 150000003379 silver compounds Chemical class 0.000 claims description 3
- 229940100890 silver compounds Drugs 0.000 claims description 3
- 239000001648 tannin Substances 0.000 claims description 3
- 235000018553 tannin Nutrition 0.000 claims description 3
- 229920001864 tannin Polymers 0.000 claims description 3
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 claims description 3
- 201000008827 tuberculosis Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000000241 respiratory Effects 0.000 claims description 2
- RRAFCDWBNXTKKO-UHFFFAOYSA-N Eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 claims 4
- 239000005770 Eugenol Substances 0.000 claims 2
- 229960002217 Eugenol Drugs 0.000 claims 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N Thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 claims 2
- 239000005844 Thymol Substances 0.000 claims 2
- 230000001684 chronic Effects 0.000 claims 2
- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 claims 2
- 229960004068 hexachlorophene Drugs 0.000 claims 2
- 229930007823 thymol Natural products 0.000 claims 2
- 229960000790 thymol Drugs 0.000 claims 2
- 230000002757 inflammatory Effects 0.000 claims 1
- 229960002358 iodine Drugs 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000005755 formation reaction Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 7
- 210000004379 Membranes Anatomy 0.000 description 7
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 210000003491 Skin Anatomy 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000002685 pulmonary Effects 0.000 description 6
- 239000008347 soybean phospholipid Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000012475 sodium chloride buffer Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 4
- 229940064004 Antiseptic throat preparations Drugs 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229940067606 Lecithin Drugs 0.000 description 4
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 4
- 230000000844 anti-bacterial Effects 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 230000017423 tissue regeneration Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 210000004072 Lung Anatomy 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020648 Hyperkeratosis Diseases 0.000 description 2
- 206010020649 Hyperkeratosis Diseases 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241000048284 Potato virus P Species 0.000 description 2
- 229940069328 Povidone Drugs 0.000 description 2
- 229960000707 Tobramycin Drugs 0.000 description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-N Tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000000845 anti-microbial Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000004027 cells Anatomy 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L disodium butanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000008151 electrolyte solution Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 230000001976 improved Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000000977 initiatory Effects 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 238000011085 pressure filtration Methods 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- WLNARFZDISHUGS-MIXBDBMTSA-N 4-[[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-4-oxobutanoic acid Chemical compound C1C=C2C[C@@H](OC(=O)CCC(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 WLNARFZDISHUGS-MIXBDBMTSA-N 0.000 description 1
- 206010069351 Acute lung injury Diseases 0.000 description 1
- 229960000458 Allantoin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N Amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 208000006673 Asthma Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 241000498849 Chlamydiales Species 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 208000007451 Chronic Bronchitis Diseases 0.000 description 1
- DHSUYTOATWAVLW-WFVMDLQDSA-N Cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 1
- 229960004912 Cilastatin Drugs 0.000 description 1
- 206010013453 Disseminated tuberculosis Diseases 0.000 description 1
- 229940112141 Dry Powder Inhaler Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 241001428586 Human adenovirus D8 Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229960002182 IMIPENEM Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N IMIPENEM Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010024971 Lower respiratory tract infection Diseases 0.000 description 1
- 210000003205 Muscles Anatomy 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229940076185 Staphylococcus aureus Drugs 0.000 description 1
- 108060008443 TPPP Proteins 0.000 description 1
- 229940029983 VITAMINS Drugs 0.000 description 1
- 229940021016 Vitamin IV solution additives Drugs 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002009 allergen Effects 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000002924 anti-infective Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 229960000626 benzylpenicillin Drugs 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 201000008325 diseases of cellular proliferation Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic Effects 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002458 infectious Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000002855 microbicide agent Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000001235 sensitizing Effects 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000021092 sugar substitutes Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000003253 viricidal Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
Abstract
Use of an anti-inflammatory agent such as povidone iodine for the preparation of a pharmaceutical composition for the treatment of diseases of the lower respiratory tract which are susceptible to the administration of such agents.
Description
PREPARATIONS FOR THE APPLICATION OF ANTI-INFLAMMATORY AGENTS, ESPECIALLY ANTISEPTIC AND / OR PROMOTING AGENTS OF WOUND HEALING, IN THE LOWER RESPIRATORY ROUTES
FIELD OF THE INVENTION The invention relates to preparations for the application of agents with anti-inflammatory properties, especially antiseptic and / or that promote wound healing, in the lower respiratory tract. The preparations are specifically applied to the trachea, bronchi and alveoli in the lower respiratory tracts of humans and animals. In addition, the invention relates to a method for preventing or treating infections by appending a pharmaceutical preparation.
BACKGROUND OF THE INVENTION A plurality of different antibiotic and antiseptic agents are known for the topical treatment of infectious diseases. A decisive disadvantage of the antibiotic agent is that the infectious bacterium has primary resistances and it is possible that it acquires secondary resistances against these agents. In addition, antibiotics quite often can lead to patient sensitization. The use, for example, of antiseptics that release halogen, such as povidone iodine, also known as iodine polyvidone or iodine-PVP, ie the complex iodine-poly (l-vinyl-2-pyrrolidin-2-one), can prevent the resistances. Also, compared to antibiotics, antiseptic agents are very rarely allergenic. Currently, infectious diseases of the respiratory tract are treated with antibiotics. The application of antibiotic agents through the respiratory tract has been subject to several reviews and articles with emphasis on the lower respiratory tract. Ramsey et al., For example, describes the intermittent administration of inhaled tobramycin in patients with cystic fibrosis, in "The New England Journal of Medicine", Volume 340, Number 1, 1999, p. 23-30. The aerosolization of imipenem / cilastatin to prevent acute lung injury induced by pseudomonas has been investigated by Wiener-Kronish in "Journal of Antimicrobial Chemotherapy" (1996) 38, p. 809-818). The pulmonary applications of different antibiotic agents, such as benzyl penicillin, tobramycin or amikacin, for the treatment of infectious diseases, are described by Schreier in several recent reviews, for example, in "Medical applications oí: liposomes", Papahadjopoulos and Lasic (eds. ), Elsevier 1998. However, treatment with antibiotics induces the complications known to experts. For example, patients suffering from acute or chronic bronchitis are often treated with antibiotics to relieve symptoms. Many times, this only induces resistance of the bacteria responsible for the symptoms. Many diseases of the respiratory tract are caused by viruses. Antibiotics are ineffective in these cases and patients are not cured of infections. The use of antiseptics and / or wound healing promoting agents, for external application to humans and animals, is disclosed in our first patent EP 0 639 373. Specifically, it is shown therein that the liposomal preparations of iodine-PVP are applicable topically to the external part of the eye. These preparations, in general, are presented in the form of cream, ointment, lotion, gel or a formulation of drops. Liposomes are well-known carriers for drugs and therefore the application of drugs in liposomal form has often been investigated. An overview related to pulmonary delivery of drugs encapsulated in liposomes, in asthma therapy, is presented in the review "Pulmonary delivery of liposomes" (H. Schreier, in "Journal
P1166
mt - ^. i, rf rf > m. 4. . , -, > ', -, _ "> .J .. ^,. .. " , f, .. '. "j, Ai..Í. Z of Controlled Reeléase ", 24, 1993, pp. 209-223) The physicochemical characterization of liposomal aerosols and also their therapeutic applications to the respiratory tract, they are shown in it. Drugs that have been investigated for pulmonary delivery through liposomes include, for example, anti-cancer agents, peptides, enzymes, anti-asthmatic and anti-allergenic compounds and as mentioned above, also antibiotics. The formulation of liposomal aerosols or aerosols of liposome powders, which utilize for example a dry powder inhaler have also been described by H. Schreier in "Formulation and in vitro perfomance of liposome powder aerosols" (STP Pharma Sciences 4, 1994, p. 38-44). Although much attention has been paid to liposomes as carriers of drugs, as can be seen from the documents cited, it seems that there is no previous technique related to liposomes and other particulates as carriers of anti-inflammatory agents, especially antiseptics and / or wound healing promoting agents, parcí applications in the body, especially in the lower respiratory tract, including the trachea, bronchi and alveoli. Some of the prior art mentioned above, is related to preparations
P1166
? l: t - < rt t.? liposomal It should be understood that there are alternative drug carriers, of a similarly particulate type. These drug carriers can often be used and also in the context of this invention, instead of liposomes and include microspheres (usually comprising lipophilic polymers), nanoparticles, "Large Porous Particles" and molecules of drug substances coated in a manner individual, for example, made using pulse laser deposition techniques (PLD). These PLD methods can be used to apply coatings to powdered drugs and to modify the surface properties and release rate in a variety of drug systems. Hereinafter, when reference is made to liposome or particulate carriers, it will be understood that this is to incorporate said alternative carriers, as well. It is known in the art that the administration of Li particles susceptible to inhalation through the respiratory tract can be carried out by nebulization or aerosolization of preparations of liposomes, microspheres, Large Porous Particles, PLD or nanoparticles or by inhalation of the dry powder of the respective preparation.
Apparently there is a notable lack of interest in the technique, to apply disinfectants to the inner parts of the body, N except perhaps in extreme cases of septic complications that endanger life. In general, it seems that antibiotic preparations are preferred, even considering their disadvantages discussed above. An object of the present invention is to provide an anti-inflammatory, especially antiseptic or wound healing promoter preparation, that is well tolerated, easily applicable, that provides prolonged release and a prolonged topical effect of the active agent in the lower respiratory tract. According to the invention, this object is achieved since the preparation comprises at least one anti-inflammatory agent, especially antiseptic and / or wound healing promoting agent, in the form of a particulate carrier preparation, as defined in the independent claim 1. The invention further comprises a method of treating the lower respiratory tract, in humans and animals, as defined in the independent claims 21 and 22. The dependent claims further define ventilated embodiments of the invention.
P1166
^^^ * ^^ 4 ^^^^^ In the context of this invention, it is understood that anti-inflammatory agents include antiseptic agents, antibiotic agents, corticosteroids and wound healing agents, as defined below. In the context of this invention, it is understood that the antiseptic agents include those disinfectants which are pharmaceutically acceptable and suitable for the treatment of the lower respiratory tract, to the extent that they can be formulated according to the invention. More specifically, antiseptic agents include, among others, compounds that release oxygen and halogens; metal compounds, for example, silver and mercury compounds; organic disinfectants including formaldehyde releasing compounds, alcohols, phenols including alkyl- and airylphenols, as well as halogenated phenols, quinolines and acridines, hexahydropyrimidines, quaternary ammonium compounds and iminium salts and guanidines. Wound healing agents comprise agents that promote granulation and epithelization, for example, dexpanthenol, allantoins, azulenes, tannins and vitamin B type compounds. The invention has as a precedent the fact
P1166
^^^^ ¡^^^^ i surprising that particulate carriers, especially liposomes, but also microspheres, nanoparticles and coated drug substance molecules, are quite suitable as carriers for antiseptic agents, especially for povidone iodine and agents that promote wound healing, for application in the lower respiratory tract. The preparations according to this invention allow the prolonged release of the agent or agents and provide a prolonged and topical activity at the desired site of action, by interaction with cell surfaces. In another aspect, the invention is based on a surprising and unexpected additional fact. It is well known in the art that the formation of new body tissue can cause problems. Thus, it is known that the repair of the body tissue can be accompanied by the formation of scar tissue, which can be detrimental from a functional and / or cosmetic point of view or at least undesirable. Hyperkeratosis and the uncontrolled proliferation of tissue can cause serious damage that leads to dysfunctions and, of course, can also be cosmetically undesirable. After infections and inflammations, the recovery or scarring of tissue can cause neoplasms and intergrowth. It is well known
P1166 in the technique that in the cure of diseases, the appropriate remodeling of tissue is not only desirable, but in fact necessary. Now, it has been found with surprise that the use of anti-inflammatory agents, alone or in combination with other agents of this type, leads to a markedly less formation of undesirable body tissue in the course of tissue repair and other growth processes. tissue In this way, the formation of scar tissue is reduced, in the skin and also in the mucosa and in other tissues, such as muscle tissue or that of internal organs. Hyperkeratosis can be completely suppressed and the intergrowth or formation of neoplasm in the cure of non-infectious diseases is also greatly reduced. An object that is achieved by the invention is therefore related to an improved tissue repair in the body. This is achieved by the invention through the application of anti-inflammatory agents, in the form of a particulate carrier preparation as defined in the independent claims. The anti-inflammatory, antiseptic and / or wound healing promoter preparation can be administered to the respiratory tract by means of a nebulizing agent loaded in the carrier preparation
P1166 particulate or by inhalation of dry powder of the respective preparation. For example, a liposome preparation can be made by loading liposomes with PVP iodine by a conventional procedure. It is also possible to compress the charged liposomes, optionally together with auxiliary materials, such as low molecular weight sugars, preferably lactose, into a strongly compressed solid drug reservoir. This stock of medicament can then be rubbed or micronized or otherwise treated to give the powder in the form of a particle. The resulting liposome preparation can be administered by inhalation of the preparation in the form of an aerosol powder, for example as described in "Acute Effects of Liposome Aerosol Inhalation on Pulmonary Function in Helathy Human Volunteers" (Thomas et al., Preliminary report , Vo 99, 1991, p.1268-1270). The pressures for preparing the stock of strongly compressed solid medicament are preferably in the range between 50 and 500 MPa. Said drug pool is described in WO 94/14490 and a device for administration is disclosed in WO 93/24165. In general, the nature or constitution of liposomes is not critical. The liposomal preparation, for example as described in EP 0 639 373, can
P1166
^? Yes ^. x i l administered by inhalation as an aerosol. The disclosure of EP 0 639 373 is considered part of the present, for reference. The preparations according to this invention apparently do not contain only the active agent, such as povidone iodine, encapsulated in the particulate carrier, especially in liposomes. It seems that there is also some amount of agent that is not contained within the carrier. The preparations according to the invention often show a marked initial effect which is observed in addition to the slower prolonged release of the active agent from the carrier. This effect is observed especially when the carrier contains liposomes. Without wishing to be limited to a theoretical explanation, it is now assumed that in addition to the active agent encapsulated within the liposomes, some active agent is present outside the liposomes and probably in a dispersed form adhered to the outer surfaces of the liposomes. This may be due to the association of the active agent molecules with the liposome membrane or the active agent molecules that form a layer on the liposome surface, this layer partially or even completely coating the liposome externally. The type and quantity of this initial effect of the agent may be influenced, for example, by the choice of concentration parameters.
P1166 Amphiphilic substances known generally in the prior art to form liposome membranes, with the proviso that they are pharmaceutically acceptable for the intended application, can be used in the context of the invention. At present, liposome-forming systems comprising lecithin are preferred. Such systems may comprise hydrogenated soy lecithin in addition to disodium cholesterol succinate hexahydrate; specifically it is preferred to use hydrogenated soy lecithin as the sole membran forming agent. The methods known in the prior art for forming liposomal structures are described in the documents cited above and can generally be used in the context of the invention. In general terms, these methods comprise mechanical agitation of a suitable mixture containing the membrane-forming substance and water or an aqueous solution. Filtration through suitable membranes is preferred to form a practically uniform liposome size. The average size of the liposomes according to this invention can vary over a wide range, generally of about 1 to 50 μm, preferably in the range of 1 to 30 μm in diameter. For solutions, the smallest average diameters, for example, diameters of approximately 10 nm, may be more suitable. The liposomes according to this invention have a practically uniform size in the range of between about 20 and 30 μm in diameter for application to the trachea, in the range of between about 10 and 20 μm in diameter for application to the bronchi and between about 1 and 6 μm, especially between 2 and 5 μm in diameter for application to the alveoli. When alternative particulate carriers are used, they are usually prepared as is known in the art. In this way, microspheres that are used to deliver a very wide range of therapeutic or cosmetic agents are made in the manner described, for example, in WO 95/15118. In some cases nanoparticles may be used, with the proviso that they can be loaded with a sufficient amount of active agent and can be administered to the lower respiratory tract, according to this invention. They can be prepared according to methods known in the art, such as those described by Heyder (GSF München) in "Drugs delivered to the lung, Abstracts IV, Hilton Head Island Conference, May 1998. Methods using a deposition apparatus
P1166
you * t to . ^^^^^^? ^^^^ jgg by pulse laser (PLD) and a polymeric target to apply coatings to powdered drugs in a non-aqueous short process, are also suitable for the formation of particulate preparations according to this invention. These have been described, for example, by Taiton et al., "Novel Coating Method for Improved Dry Delivery," Univ. Of Florida UF 1887 (1998). Another suitable supply system employs Large Porous Particles such as those exhibited by David A.
Edwards et al. in "Large Porous Particles for Pulmonary Drug Delivery" (Science, 20, June 1997, Vol. 276, pp. 1868-1871). The average size of the large porous particles according to this invention can be, for example, in the range of about 5 to 20 μm in diameter for
application to the alveoli. Preferred anti-inflammatory agents comprise antiseptic agents, antibiotics, corticosteroids and wound healing promoters, as substances alone or in combination with each other. Preferred antiseptic agents comprise the well-known pharmaceutical substances that provide fast effect, a wide range of activity, low systemic toxicity and good tissue compatibility. They can be selected, for example, from the group
comprises metal compounds, phenolic compounds,
P1166
iMMilMaMtifciWhiiitMeA ^. ^ ... * *. *, m. . ..., ... ", ^" ._ ... to*-.. . ._u, ...,., < jsAi, detergents, iodine and iodine complexes. A preferred antiseptic agent is povidone iodine. Preferred wound healing promoting agents comprise substances which for said application are described in the literature. These preferred agents include substances that are known to promote epithelization. These include vitamins, specifically B vitamins, allantoin, some sugars, etc. Some presently preferred embodiments of the invention comprise anti-inflammatory agents or combinations thereof that show positive effects in tissue repair, especially with respect to the remodeling of functional and cosmetic tissue. In these modalities, the active agent is often an antiseptic, such as iodine-PVP or an antibiotic. In preferred embodiments, the preparations of the invention containing anti-inflammatories, especially antiseptics and / or wound healing promoting agents may further comprise agents of the anesthetic type. The preparations of the invention may also contain other commonly used agents, including adjuvants and additives, antioxidants, preservatives or consistency-forming agents such as additives to adjust viscosity, emulsifiers, etc.
In general, the concentrations in the preparation, particle sizes, active agent loads, etc., in the case of alternative carriers, will be selected so that they basically correspond to the parameters that are analyzed in the present with respect to the liposomal preparations. Selecting and providing said parameters, among others, based on a simple experimentation, is within the reach of a person with ordinary experience in this technique. At present, a rather preferred use of the liposomal preparations of the invention is the treatment of lower respiratory tract infections, including trachea, bronchi and alveoli, especially when the liposomal preparations contain povidone iodine. Also in this indication, the antiseptic preparations of the invention, especially those containing iodine PVP, have the great advantage of not causing resistances and of inducing much less allergic reactions, while permitting a very cost-effective therapy with an effect of spread spectrum. A povidone iodine liposomal preparation according to this invention is effective, for example, against viruses. In addition a liposomal preparation of a microbicidal agent such as povidone iodine, provides prolonged release of the agent from the liposomes to deliver the agent to the regions
P1166 lung, for example to the alveolar region of the lung. This leads to a prolonged effect of the antimicrobial substance and thus to a less frequent application, in comparison with the preparations of antiseptic solution in common use. The present invention is also useful in the treatment of infectious diseases or for the relief of diseases such as HIV infections that are accompanied by opportunistic infections. Also patients who have suppressed the immune system, for example, after organ transplantation, can be treated according to the invention. In particular, bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria, chronic and acute tuberculosis can be treated with the povidone iodine preparation according to the invention. Another rather preferred use is in tissue repair, especially in the remodeling of functional and cosmetic tissue. The preparations according to this invention may have a variety of forms, which are suitable for administration through the lower respiratory tract, including pharmaceutically acceptable solid or liquid forms which are suitable for the generation of inhalable particles. The preparations according to this invention may therefore be in the form of an aerosol (powder) or in the form of a compressed solid drug reservoir, preferably a circular tablet, more preferably a gelatin capsule, a powder, a spray, an emulsion , a dispersion, a suspension or even a solution containing the carrier and the agent or agents. In general, the amount of active agents in a preparation of the invention will be determined on the one hand by the desired effect and on the other by the transport capacity of the carrier preparation for the agent. For preparations of the invention having large amounts of active agents or high doses of active agent, solid, liquid or gel preparations are often preferred for nebulized preparations or aerosols or for powdered powders or aerosols. In general terms, the amount of active agent in a carrier preparation of the invention can vary in concentrations between the lower limit of effectiveness of the agent and the maximum load of the agent in the respective carrier preparation. More specifically, for an antiseptic agent, such as povidone iodine, a solution or dispersion in a carrier preparation of the invention, especially when the carrier is a liposomal preparation, may contain between 0.1 and 10 g of agent in 100 g of preparation. Such
P1166
The preparation will normally have a content between 1 and 5 g of liposomal membrane-forming substance, especially lecithin, per 100 g of preparation. An aerosol or spray preparation of the invention will often comprise up to 50 mg, although it could comprise up to 100 mg and more of liposomal active agent formulation and can be administered, for example, by 5 spray doses, each containing 20 mg of the formulation of liposomal active agent. The preparation will generally comprise at least 10% by weight of active agent such as Iodine-PVP, in the charged liposomes (or alternative carrier particles), but can comprise up to 50% by weight or even more of active agent. When the active agent is iodine-PVP, the amount of available iodine will generally be approximately 10% by weight (based on the Iodine-PVP). From the examples of modalities, more specific formulations will be evident. The features and advantages of this invention will be seen in greater detail from the subsequent description of the preferred embodiments. In these embodiments that include the best form, povidone iodine is exemplified as an antiseptic agent and the liposomes are selected as carrier. However, this should not be considered as a restriction of this invention to
P1166 antiseptic agents or among antiseptic agents, to the povidone iodine and / or to the liposomes as the carrier, although said preparations are specifically preferred. A preferred method for producing the liposomes of the invention, can generally be described as follows: The lipid membrane-forming components, for example, lecithin, are dissolved in a suitable solvent, for example, chloroform or a 2: 1 mixture. of methanol and chloroform and filtered under sterile conditions. Then, a lipid film is produced on a sterile substrate of high surface area, for example glass beads, by controlled evaporation of the solvent. In some cases, it may be sufficient to form the film on the inner surface of the container used to evaporate the solvent, without having to use a specific substrate to increase the surface. An aqueous system is prepared from electrolyte components and the active agent (one or more) to be incorporated into the liposome preparation. An aqueous system of this type can comprise, for example, 10 mmol / l of hydrogenated sodium phosphate and 0.9% of sodium chloride at pH 7.4.; the aqueous system will also comprise, at least the desired amount of the active agent, which in the exemplary embodiments is iodine
P1166
...; ..,. ajii t i povidona. Many times, the aqueous system will comprise an excess amount of the agent or agents. In general, liposomes are formed by agitating the aqueous system in the presence of the film formed by the lipid components. In this step, other additives can be added to improve the formation of the liposome; for example, sodium cholate can be added. The formation of liposomes can also be influenced by mechanical action, such as pressure filtration, for example, through polycarbonate membranes or centrifugation. In general, the base liposomal dispersion will be subjected to washing, for example, with electrolyte solution as used to prepare the active agent solution described above. When the liposomes with the required size distribution have been obtained, they can be redispersed in an electrolyte solution such as the one already described, which often comprises sugars, such as sucrose or a suitable sugar substitute. The dispersion can be dried by freezing and lyophilized. Before use, it can be reconstituted by the addition of water and suitable mechanical stirring at the transition temperature of the lipid component, which for hydrogenated soy lecithin is, for example, 55 ° C. In the following Examples, the
P1166 hydrogenated soy lecithin (EPIKUR0NMR) 200 SH available from Lukas Meyer, Germany or PH0SP0LIP0NMR 90 H available from Nattermann Phospholipid GmbH, Germany). However, instead of lecithin, other pharmaceutically acceptable liposome membrane forming substances can be used and it will be easy for the person skilled in the art to select alternative liposome forming systems, from what is described in the prior art.
Modality The impli cative I In a 1000 ml glass flask, equipped with glass beads to increase the surface, 51.9 m of cholesterol and 213 mg of hydrogenated soy lecithin were dissolved in a sufficient quantity of a mixture of methanol and chloroform in proportion of 2: 1. Then, the solvent was evaporated in vacuo, until a film formed on the inner surface of the flask and on the glass beads. o 2.4 g of PVP iodine were separately dissolved
(containing about 10% available iodine) in 12 ml of water. Again in a separate vessel, 8.77 g of sodium chloride and 1.78 g of Na2HP04.2H20 were dissolved in 400 ml of water. More water was added until
P11S6
lij.
have a total volume of 980 ml and then approximately 12 ml of IN hydrochloric acid were added to adjust the pH to 7.4. Water was added to this solution until it had exactly 1000 ml. In a fourth vessel, 900 mg of sucrose and 57 mg of disodium succinate were dissolved in 12 ml of water. The PVP iodine solution was then added to the lipid film in the flask and the mixture was stirred until the film dissolved. This produced 1.a. formation of liposomes from the hydrated lipids in the flask. The product was centrifuged and the supernatant liquid discarded. The 12 ml of the sucrose solution was added and the product was centrifuged again. Then, the supernatant liquid was discarded again. In this step, an additional washing step can be performed, using the sucrose solution or the sodium chloride buffer solution. After the last centrifugation step and the supernatant was discarded, 12 ml of sodium chloride buffer was added and the liposomes were homogeneously distributed therein. The product was divided into vials, each containing 2 ml of liposome dispersion, and subjected to a freeze drying step. After freeze drying, each vial
P1166
^ mmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmm; . J. | 1 j. iA ^^ ,.
comprised approximately 40 mg of solids. The method of the Exemplary Modality I has a minor disadvantage, since the PVP iodine solution used, due to the high percentage of solids, is more viscous and thus more difficult to handle.
Modality Ei emplificativa II In a 2000 ml flask fitted with glass beads to increase the surface, 173 mg were dissolved
of hydrogenated soy lecithin and 90 mg of disodium succinate, in approximately 60 ml of a methanol / chloroform mixture in the ratio of 2: 1. The solvent was removed in vacuo until a film formed. 4 g of PVP iodine were dissolved (10% iodine
available) in 40 ml of the sodium chloride buffer solution described in Exemplary Modality I and added to the lipid film in the flask. Then the flask was shaken until the film dissolved and the liposomes formed. The product was centrifuged and the supernatant liquid discarded. To the liposomal pellet produced in this way, sodium chloride buffer solution was added to make up 40 ml and the step of
centrifugation. Again the supernatant was discarded. In
P1166
^^^^^^^^ aMjfc ^ this stage, the washing step could be repeated, if necessary. After the final centrifugation and decantation steps, 140 mL of sodium chloride buffer solution was again added to the precipitated liposomes. The homogeneous dispersion was then distributed in vials, each vial with a content of approximately 2 ml of liposome dispersion and they were subjected to a freeze drying step.
This produced approximately 200 mg of frozen dried solids, per vial. As in the Exemplary Modality I, the aforementioned method uses a hydration step after film formation in
presence of organic solvents and reaches inclusion rates of 5 to 15%. These methods usually produce larger and often multilamellar liposomes. The above mentioned methods can
modified by a high pressure filtration step through a suitable membrane, for example, a polycarbonate membrane after the crude liposomes have been formed ° or after some of the subsequent washing steps or directly using homogenization to
high pressure. This produces much smaller liposomes
P116S fc «^ ft» fa < unilamellar with respect to increased amounts of encapsulated agent. In place of high pressure homogenization, other methods of the prior art which are known to provide uniformly small size liposomes can be employed.
Eiemplificative Modality III A gelatin capsule, which is suitable for the generation of inhalable particles, was prepared from 10 20 g of povidone iodide liposomes containing lyophilized material (?????) according to the general preparation before mentioned and 20 mg of lactose applying pressures up to 500 MPa. From the hard clause obtained, an aerosol powder or powder was generated by 15 abrasion methods using a powder inhaler (Orbital-Inhaler from Brin Tech International Ltd). It is also possible to prepare modalities similar to those described above, which comprise an agent capable of promoting the healing of the wounds and which is used instead of the antiseptic agent, but not together with it, such as for example povidone iodide which is exposed to the examples of the previous modality. At present, however, the use of agents that promote wound healing is preferred, in express cases, in addition to the antiseptic agent. or 25 For the application of the preparations of the
P1166
^^ g ^ »^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ »^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ well-known processes such as inhalers, powder inhalers, two-chamber gas pressure gaskets, aerosol spray dispensers, nebulizers, compressors, etc.
Modality EI emplificativa IV The liposomal preparations were prepared by means of an air operated nebulizer. The exit and aerosol characteristics of liposomes with the nebulizer have been previously described. The resulting droplets had an average mass aerodynamic diameter of approximately 2.4 μm and were therefore suitable for deposition in the alveolar region. With the preparations of the invention, the following efficacy tests were carried out:
Test I This was an ip-vitro test of the bactericidal effect provided by a liposomal povidone iodine preparation of the invention. The test was based on the quantitative suspension test as described in "Richtlinien der Deutschen Gesellschaft für Hygiene und Mikrobiologie", 1989. In this test, the bactericidal agent is used to kill the Staphylococcus aureus (ATCC 29213), a major problem in the hygiene of
P1166
t i l a, i ^ faith ¿< fcj a rr. ^. Hospitals. The liposomal preparation used was that of the Exemplary Modality I. At different contact times between 1 and 120 minutes, the minimum concentration of the preparation in water that had the ability to kill staphylococci was determined. These results are shown in Table 1.
TABLE 1 Contact Time (Minutes) Bactericidal Concentration 1, 2, 3, 4 > 0.060% 5, 30, 60 > 0.015% 120 > 0.007%
The results show that at short contact times (between 1 and 4 minutes) the bactericidal concentration is as low as 0.06% and that at long contact times
(120 minutes) the bactericidal concentration can be as low as 0.007%.
Test II The virucidal and chlamydial activity of liposomal iodine-PVP has been studied in cell cultures by Wutzler et al., 9th European Congress of Clinical Microbiology and Infectious Diseases, Berlin, March 1999.
P1166
- rf .í -m 4? In cell cultures, liposomal iodine-PVP is quite effective against herpes simplex virus type I and adenovirus type 8, while long-term cytotoxicity experiments indicated that the liposomal form is more tolerated than aqueous iodine-PVP by the most of the cell lines that were tested. Iodine-PVP in liposomal form is not genotoxic.
Test III A liposomal hydrogel preparation of 3% iodine PVP was compared with a 3% PVP iodine ointment in which the active agent was not in liposomal form. The agent was applied to standardized in vitro cultures of rat skin and peritoneal explants, such as screening for tissue compatibility of the skin and anti-infective for wounds. The growth rate of the cultured explants was studied after 30 minutes of exposure and incubation with a test substance. Again, the considerably good tolerance of the liposome preparation was clearly demonstrated with the results, in terms of peritoneal growth rate and skin growth rate. With the ointment, the peritoneal growth rate reached 85% and the growth rate of
P1166
** * -A.4 ^ ~ £ * -t ^^^^^^^ j ^ ^^^^ skin reached 90%; with the liposomal hydrogel formulation, the peritoneal growth rate was 96% and the skin growth rate was 108%; these values were compared with 100% values in a control test using Ringer's solution as the agent.
P1166
Claims (43)
- CLAIMS; A process for manufacturing a pharmaceutical preparation for the application of antiseptic agents and / or agents that promote the healing of wounds to the lower respiratory tract, characterized in that the preparation contains at least one of the agents combined with a particulate carrier.
- 2. The process according to claim 1, characterized in that the particulate carrier comprises at least one of the following: a liposome preparation, a preparation of microspheres, a preparation of nanoparticles, a preparation of Large Porous Particles, a preparation of coated molecule with laser pulse polymer.
- 3. The process according to claim 1 or 2, characterized in that at least the major part of the agent is encapsulated inside the carrier, especially a liposome or microsphere carrier.
- The process according to any of claims 1 to 3, characterized in that the antiseptic agent is selected from compounds that release oxygen and halogen; metal compounds, for example, silver and mercury compounds; organic disinfectants including compounds that release formaldehyde, alcohols, phenols that include alkyl- and P116S arylphenols as well as halogenated phenols, quinolines and acridines, hexahydropyrimidines, quaternary ammonium compounds and iminium salts and guanidines.
- The process according to claim 4, characterized in that the antiseptic agent is selected from the group comprising metal compounds, for example, mercury compounds, phenolic derivatives such as thymol, eugenol and hexachlorophene, iodine and iodine complexes.
- 6. The process according to claim 5, characterized in that the antiseptic agent is povidone iodine.
- The process according to any of claims 1 to 6, characterized in that the wound healing promoting agent is selected from agents that promote granulation and epithelization such as dexpanthenol, allantoins, azulenes, tannins, compounds of the vitamin B series. or agents of similar action.
- The process according to any of the preceding claims, characterized in that the preparation contains at least one antiseptic and at least one wound healing promoting agent.
- The process according to any of the preceding claims, characterized in that the carrier particles, especially the liposomes, have an essentially uniform size in the range of between P116S A3fe. "* * Í about 1 and about 50 μm, preferably between the range of about 1 and 30 μm.
- The process according to claim 9, characterized in that the carrier particles, especially the liposomes, have an essentially uniform size in the range of between about 20 and 30 μm in diameter for application to the trachea, in the range of about 10. and 20 μm in diameter for application to the bronchi and between approximately 1 to 6 μm, especially between 2 and 5 μm in diameter for application to the alveoli.
- The process according to any of the preceding claims, characterized in that the carrier preparation, in particular of liposomes, releases the agent for a prolonged period of time, preferably a period of time extending to several hours in duration.
- The process according to claim 11, characterized in that the carrier preparation, in particular liposomes, releases the agent at approximately the same rate of release in the period of time of release.
- The process according to any of the preceding claims, characterized in that the preparation further comprises at least one active agent P1166 anesthetic.
- The process according to any of the preceding claims, characterized in that the preparation contains additives and adjuvants as preservatives, antioxidants and consistency modifying additives.
- 15. The process according to any of claims 1 to 14, wherein the preparation is in a form suitable for administering the lower respiratory tract and comprises the carrier loaded with the active agent, especially in the form of liposomes, preferably in the form of an aerosol, especially in powder form in eierosol.
- 16. The process according to any of claims 31 to 14, wherein the preparation is in the form of a compact solid drug reservoir, preferably a ring tablet, more preferably a gelatin capsule, a powder, a spray, an emulsion , a dispersion, a suspension or a solution containing the carrier and the agent or agents in a liquid or solid pharmaceutically acceptable formulation, which is suitable for the generation of inhalable particles.
- 17. The process according to any of the preceding claims, the preparation is in a suitable form or to be administered by the routes Lower respiratory P1166, comprising: a) liposomes comprising a pharmaceutically acceptable liposomal membrane-forming substance; and 5 b) a PVP iodine solution of 0.1 to 2% (with approximately 10% of iodine available in the PVP iodine complex) and that at least most of it is encapsulated by the liposome membranes, where the liposomes they are in size Practically uniform between about 1 and 50 μm, and where appropriate, the formulation further comprises additives, adjuvants and auxiliary substances commonly used in pharmaceutical formulations.
- 18. The process according to claim 17, characterized in that the liposomes are of an essentially uniform size in the range of between about 20 and 30 μm in diameter for application to the trachea, in the range of between about 10 and 20 μm. diameter for application to the bronchi and 20 between approximately 1 and 6 μm in diameter, preferably between approximately 2 and 5 μm in diameter for application to the alveoli.
- 19. The process according to any of claims 1 to 18, wherein the preparation is 25 suitable for the treatment of infectious diseases or P1166 - ~ -ii > ^?,? ii 'etor, t.,?, l' l 'V, p the alleviation of diseases such as HIV infections that are accompanied by opportunistic infections or a suppressed immune system.
- 20. The process according to any of claims 1 to 18, wherein the preparation is suitable for the treatment of bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria and / or tuberculosis, acute or chronic.
- 21. The process according to any of claims 1 to 20, wherein the preparation is suitable for treatments of remodeling and repair of functional and cosmetic tissue.
- 22. A method for preventing or treating infections in the lower respiratory tract of humans or animals, by applying to those routes, a pharmaceutical preparation comprising at least one antiseptic agent and / or an agent that promotes wound healing, the agent is combined with a particulate carrier in the preparation.
- 23. A method for the repair and remodeling of aids, in functional or cosmetic form, in lower respiratory tracts of humans or animals, by applying to said routes a pharmaceutical preparation comprising at least one agent promoting wound healing. and / or an antiseptic, especially anti-? P1166 ^^^^^ 4 ^^ fc »^ ™ inflammatory, with a particular carrier.
- The method according to claim 22 or 23, wherein the carrier comprises at least one liposomic preparation, a microsphere preparation, a nanoparticle preparation, a Large Porous Particle preparation or a preparation of polymer coated molecules by laser pulses.
- 25. The method according to claim 22 or 23, wherein at least the major part of the agent is encapsulated within the carrier, especially a liposome or microsphere carrier.
- 26. The method according to claim 23, wherein the anti-inflammatory agent is selected from antiseptic agents, antibiotics, corticosteroids and wound healing promoters.
- The method according to claim 22 or 23, wherein the antiseptic agent is selected from compounds that release oxygen and halogen; metal compounds, for example, silver and mercury compounds; organic disinfectants including formaldehyde releasing compounds, alcohols, phenols including alkyl- and arylphenols, as well as halogenated phenols, quinolines and acridines, hexahydropyrimidines, quaternary ammonium compounds and iminium salts and guanidines.
- P1166 The method according to claim 22 or 23, wherein the antiseptic agent is selected from the group comprising metal compounds, for example, mercury compounds, phenolic derivatives such as thymol, eugenol and hexachlorophene., iodine and iodine complexes.
- 29. The method according to claim 22 or 23, wherein the antiseptic agent is povidone iodine.
- The method according to claim 22 or 23, wherein the wound healing promoting agent is selected from granulation and epithelization promoting agents such as dexpanthenol, allantoins, azulenes, tannins, compounds of the vitamin B series or agents of similar action.
- 31. The method according to claim 22 or 23, wherein the preparation contains at least one antiseptic and at least one wound healing promoting agent.
- 32. The method according to claim 22 or 23, wherein the carrier particles, especially the liposomes, have an essentially uniform size in the range of between about 1 and 50 μm, preferably between about 1 and 30 μm.
- The method according to claim 32, wherein the carrier particles, especially the liposomes, have an essentially uniform size in the range of P1166 Í.? i?.?,? riApr..A.3m ¿¿l? r ?. i between about 20 and 30 μm in diameter for application to the trachea, in the range of between about 10 and 20 μm in diameter for application to the bronchi and in the range of between about 1 and 6 μm in diameter, especially between 2 and 5 μm, for application in the alveoli.
- 34. The method according to claim 22 or 23, wherein the carrier preparation, in particular of liposomes, releases the agent for a prolonged period of time, preferably a period of time extending to several hours in duration.
- 35. The method according to claim 22 or 23, wherein the carrier preparation, especially liposomes, releases the agent at approximately the same rate of release in the time period of release.
- 36. The method according to claim 22 or 23, wherein the preparation further comprises at least one anesthetic active agent.
- 37. The method according to claim 22 or 23, wherein the preparation contains additives and adjuvants as preservatives, antioxidants and consistency modifying additives.
- 38. The method according to claim 22 or 23, wherein the preparation is in a suitable form P1166 t - ?. s * •, i. * ... fc »« ^. > . . . .- .".... , " ." 1 . . ..- -afea h * k.t, kA JKaBatet &? for administration by the lower respiratory tract, and comprises the carrier loaded with the active agent, especially in the form of liposomes, preferably in the form of an aerosol, especially in the form of an aerosol powder.
- 39. The method according to claim 22 or 23, wherein the preparation is in the form of a compact solid drug reservoir, preferably a ring tablet, more preferably a gelatin capsule, a powder, a spray, an emulsion, a dispersion, a suspension or a solution containing the carrier and the agent or agents, in a liquid or solid pharmaceutically acceptable formulation, which is suitable for the generation of the inhalable particles.
- 40. The method according to claim 22 or 23, the preparation is in a form suitable for administration to the lower respiratory tract, comprising: a) liposomes comprising a pharmaceutically acceptable liposomal membrane substance or former; and b) a PVP iodine solution of 0.1 to 2% (with approximately 10% of available iodine in the PVP iodine complex) and that at least most of it is encapsulated by the liposome membranes, P1166 wherein the liposomes are practically uniform in size between about 1 and 50 μm, and where appropriate, the formulation also comprises additives, adjuvants and auxiliary substances commonly used in a pharmaceutical formulation.
- 41. The method according to claim 22 or 23, wherein the liposomes are of essentially uniform size, between about 20 and 30 μm in diameter for application to the trachea, between about 10 and 20 μm in diameter for application to the bronchi and between about 1 and 6 μm, preferably between about 2 and 5 μm in diameter for application to the alveoli.
- 42. The method according to claim 22 or 23, wherein the preparation is suitable for the treatment of infectious diseases or the relief of diseases such as HIV infections that are accompanied by opportunistic infections or a suppressed immune system.
- 43. The method according to claim 22 or 23, where the preparation is suitable for the treatment of bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria and / or tuberculosis, acute and chronic. P1166 ^ m L-í -
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/086,895 | 1998-05-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00011649A true MXPA00011649A (en) | 2002-07-25 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU752018C (en) | Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract | |
US7297344B1 (en) | Preparations for the promotion of wound healing in the upper respiratory tract and/or ear | |
EP1180018B1 (en) | Use of antiseptics in the manufacture of a pharmaceutical preparation for the prevention and treatment of infections and/ or functional tissue remodelling in the interior of the human body | |
US7364749B1 (en) | Preparations for the application of anti-infective and/or anti-inflammatory agents | |
US7300667B1 (en) | Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract | |
MXPA00011649A (en) | Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract | |
MXPA00011651A (en) | Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the upper respiratory tract and/or the ear |